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1
Cottarelli, A. "FIBROBLAST GROWTH FACTOR BINDING PROTEIN 1 (FGFBP1) CONTRIBUTES IN THE ESTABLISHMENT AND MAINTENANCE OF THE BLOOD BRAIN BARRIER." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/262620.
Full textAbstract:
The Blood Brain Barrier (BBB) is a highly specialized vascular structure whose aim is to tightly regulate the permeability between the blood flow and the Central Nervous System (CNS). To this purpose, the ECs in the brain need to present some peculiar features: the presence of high-resistance tight junctions (TJs) to block paracellular permeability, the lack of fenestrations, and the expression of some specific transmembrane transporters to selectively allow the entrance of nutrients and the exit of toxic metabolites. The high level of specialization of the brain microvasculature is obtained as a result of the interaction of the endothelial compartment with the other components of the so-called NeuroVascular Unit (NVU), such as the Basement Membrane (BM), pericytes and astrocyte end-feet.
The canonical Wnt/β-catenin pathway, that is specifically activated in CNS vessels during development, regulates BBB initiation and maintenance. Moreover, inactivation of this pathway in vivo leads to angiogenic defects in the CNS and not in other vascular regions.
Affymetrix analysis previously performed in our group provided a list of genes whose transcription is selectively regulated upon Wnt3a stimulation in murine primary ECs isolated from brain (bMEC). One of the most upregulated transcripts is that of Fibroblast Growth Factor Binding Protein 1 (FGFBP1) gene.
FGFBP1 is a cargo protein that, after being secreted in the extracellular matrix (ECM), is able to non-covalently bind the FGF immobilized in the ECM and to mobilize it, protecting it from degradation and presenting it to FGF tyrosine-kinase receptor on the cell membrane.
Given the capability of Wnt3a stimulation to selectively induce FGFBP1 expression in brain ECs, we hypothesized that this protein could be involved in the process of initiation and/or maturation of the BBB.
In this work, we demonstrate in vivo in the zebrafish model that FGFBP1 knock down by morpholino presents vascular abnormalities in the brain and in the trunk, together with cerebral hemorrhages and impaired permeability. Taking advantage of the endothelial-specific FGFBP1 knock out murine model, we further demonstrate that inhibition of endothelial FGFBP1 expression affects brain vascular development, causing vascular defects and increased BBB permeability and also influencing the number of pericytes and the composition of the BM. Finally, we show in vitro that FGFBP1 absence promotes a “tip-like” phenotype and an increase in the expression of Plvap in bMECs.
In conclusion, our work proposes a novel role for FGFBP1 in the maintenance of the properties of the BBB and in the regulation of the complex interactions of the endothelial compartment with the other components of the NVU.
2
BonDurant, Lucas Donald. "Regulation of glucose homeostasis by FGF21." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6060.
Full textAbstract:
Fibroblast Growth Factor 21 (FGF21) is an endocrine hormone derived from the liver that exerts pleiotropic effects on the body to maintain overall metabolic homeostasis. During the past decade, there has been an enormous effort to understand the physiological roles of FGF21 in regulating metabolism and to identify the mechanism for its potent pharmacological effects to reverse diabetes and obesity. Through both human and rodent studies, it is now evident that FGF21 is dynamically regulated by nutrient sensing and consequently functions as a critical regulator of nutrient homeostasis. In addition, recent studies with new genetic and molecular tools have provided critical insight into the actions of this exciting endocrine factor. Dissection of these FGF21-regulated pathways has tremendous potential for new targeted therapies to treat metabolic disease. The goals of this thesis are 1) to identify FGF21’s physiological role as a carbohydrate-regulated signal of macronutrient-specific satiety and 2) to determine the mechanism and tissues responsible for mediating the pharmacological effects of FGF21.
To address the first goal, we used different FGF21 genetic knockout mouse models to determine if loss of FGF21 would affect macronutrient preference. We found that loss of FGF21 led to an increase in simple sugar intake whereas this had no effect on other macronutrients such as lipid or protein. To further characterize the relationship between carbohydrates and FGF21, in vitro and in vivo techniques revealed that FGF21 transcription in the liver increased in response to carbohydrate intake and this was dependent on the presence of a transcription factor activated by carbohydrates, ChREBP. We next addressed whether or not increased FGF21 levels would affect preference for simple sugars. We found that in response to increased circulating levels of FGF21, either through genetic overexpression or pharmacological administration, FGF21 would lead to a significant decrease in caloric and non-caloric sweeteners. Finally, we were able to determine that FGF21 was signaling to the hypothalamus to mediate this suppression of simple sugar intake through region specific knockout of the co-receptor beta-klotho.
To address the pharmacological actions of FGF21, we generated an adipose-specific KLB KO mouse using mice that express Cre-recombinase under the adiponectin promoter. These mice lack the co-receptor for FGF21 in adipose tissue and are a more reliable adipose knockout model than previous studies that have used aP2-Cre mice. We were able to determine that the acute glucose lowering effects of FGF21 are mediated through direct signaling to adipose tissue and that FGF21 enhances insulin sensitivity by increasing glucose uptake in brown adipose tissue. However, FGF21 mediates its chronic effects, including lowering body weight and triglycerides, by signaling to some other non-adipose tissue. Overall our work has shown that FGF21 can significantly regulate glucose metabolism through multiple mechanisms.
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Ribas, Aulinas Francesc. "Regulació de FGF21 en la cèl·lula muscular." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/284546.
Full textAbstract:
Tot i que el fetge és considerat com el principal lloc de producció del FGF21 sistèmic, sobretot en condicions de dejuni i sota control de PPARα, darrerament s’han acumulat diverses evidències que indiquen que FGF21 també pot actuar com a mioquina, un factor hormonal que pot ser produït i alliberat a la circulació pel múscul esquelètic. Concretament, s’ha observat que pacients que pateixen malalties neuromusculars causades per alteracions en la funció mitocondrial, com ara mutacions i deplecions al DNA mitocondrial, presenten valors d’expressió d’FGF21 incrementats, així com també els de la seva secreció a la circulació. Per tant, alguns indicis mostren que el múscul pot ser un lloc de producció i secreció d’FGF21 associat a l’estrès mitocondrial muscular. Durant la realització d’aquesta tesi, hem trobat que l’expressió i la secreció d’FGF21 en un context de cèl•lula muscular estan íntimament associades amb la diferenciació miogènica tant en rosegadors com en models humans. Per contra, els nivells dels seus receptors es mantenen bastant estables, mentre que pel que fa al cofactor β-Klotho, necessari pel seu procés de senyalització, no es detecta expressió del transcrit. Aquest fet suggereix, que la cèl•lula muscular podria ser una font d’expressió i secreció d’FGF21, però no un teixit diana d’aquesta.
A part, s’ha identificat el factor miogènic MyoD com a un regulador molt potent de la transcripció del gen FGF21, així com també se n’ha mapat la regió del promotor responsable de vehicular aquest efecte. D’altra banda, s’han intentat descriure altres factors de transcripció i coreguladors que poden actuar com a activadors o inhibidors, els quals poden estar involucrats en el control de la transcripció gènica d’FGF21, com ara els PPARs, PGC-1α o Sirt1, així com també esbrinar els efectes de diversos activadors naturals i sintètics. En aquest sentit, val la pena destacar que dins d’un context en presència del factor miogènic MyoD s’ha identificat a PPARα, juntament amb el seu activador, com a un clar activador de l’activitat transcripcional d’aquest promotor. PGC-1α, sembla actuar de la mateixa manera, potenciant-ne l’efecte en presència de MyoD. Per contra, Sirt1 s’ha revelat com a un inactivador de l’activitat transcripcional del gen FGF21 en presència del factor MyoD. Altres experiments indiquen que el tractament amb diferents àcids grassos no sorgeixen cap efecte sobre l’expressió ni la secreció del gen en el context muscular, sinó més aviat el contrari, malgrat que la cèl•lula muscular es mostrava sensible a l’acció dels àcids grassos sobre altres gens.
De la mateixa manera que ja indicaven determinats indicis bibliogràfics, vam poder comprovar que pacients de patologia MNGIE (miopatia associada a alteracions del DNA mitocondrial), mostraven la presència d’alts nivells d’FGF21 circulants. Així doncs, intentant mimetitzar una disfunció mitocondrial experimentalment, utilitzant inhibidors de la cadena respiratòria/fosforilació oxidativa, es van poder confirmar aquests increments d’expressió i secreció d’FGF21 per part de les cèl•lules musculars. Investigant una mica més a fons la mecanística de tot el procés, es va veure que l’increment de la producció d’espècies reactives d’oxigen derivades d’aquesta disfunció, provocava una inducció de la p38-MAP cinasa i conseqüentment l’activació ATF2, el qual és capaç d’interaccionar amb el seu lloc d’unió en la regió proximal del promotor del gen FGF21, provocant així aquest efecte sobre el gen FGF21 a les cèl•lules miogèniques. Alhora, s’ha descrit que la presència de MyoD és imprescindible per tal que es doni la resposta de la transcripció del gen FGF21 a la disfunció mitocondrial induïda experimentalment, justificant la resposta d’increment de la secreció d’FGF21 per part de les cèl•lules musculars en resposta a aquesta disfunció. Aquests canvis en la secreció d’FGF21 per part de les cèl•lules miogèniques en resposta a les afectacions a nivell mitocondrial, també poden ser un reflex del mecanisme fisiològic pel qual es detecten canvis a nivell d’estatus energètic a nivell muscular. D’aquesta manera, un increment de l’alliberació d’FGF21 podria desencadenar diferents respostes metabòliques adaptatives a nivell sistèmic. Aquest procés posa de manifest la gran capacitat que té la funció mitocondrial, per tal d’influenciar en el metabolisme sistèmic a través de la senyalització mitocondrial retrògrada. Així doncs, aquest mecanisme de senyalització permet l’expressió i alliberació de molècules d’acció endocrina com ara FGF21 i reforça la idea de considerar el múscul esquelètic com a una important font d’FGF21, la qual podem considerar com a una mioquina.Although the liver is generally considered the main production site for fibroblast growth factor-21 (FGF21), high FGF21 levels have been found to be associated with neuromuscular mitochondrial genetic diseases, and there are indications that shows muscle as a source of FGF21 production under conditions of muscular mitochondrial stress. In this thesis we describe that FGF21 expression and release is associated with myogenic differentiation in different muscular cell lines. However, FGFRs transcription levels don’t change across differentiation and β-Klotho is undetectable, suggesting that muscle cells as a source but not as a target of FGF21. Furthermore we have identified MyoD as a major controller of FGF21 gene transcription, as well as we have mapped the most important region in the promoter responsible for MyoD-dependent regulation. Moreover, we determined the role of some transcription factors and co-regulators potentially involved in the control of FGF21 gene transcription, such as PPARs, PGC-1α or Sirt1, as well as several natural and synthetic agents (e.g. fatty acids) On the other hand, mimicking mitochondrial dysfunction by the use of respiratory chain/oxidative phosphorylation inhibitors resulted in enhanced expression and release of FGF21 by muscle cells. Increased production of reactive oxygen species, subsequent induction of p38-MAP kinase and activation of an ATF2-binding site at the proximal promoter region of the FGF21 gene were found to comprise the major mechanism connecting mitochondrial dysfunction and enhanced FGF21 gene transcription in myogenic cells. Furthermore, we show that MyoD is required for the responsiveness of FGF21 gene transcription to experimentally induced mitochondrial dysfunction, which explains the preferential response of muscle cells to enhanced FGF21 secretion in response to mitochondrial alterations. FGF21 release by muscle cells in response to mitochondrial alterations may reflect a physiological mechanism by which the sensing of internal energetic status by muscle tissue results in the release of FGF21 to favor systemic metabolic adaptations. This process highlights the capacity of mitochondrial function to influence systemic metabolism by retrograde signaling, which leads to the expression and release of molecules with endocrine action, such as FGF2,1 and reinforces the concept of considering the skeletal muscle as an important source of the FGF21, as well as to consider FGF21 as a myokine.
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Ribas, Aulinas Francesc. "Regulació de FGF21 en la cèl.lula muscular." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/284546.
Full textAbstract:
Tot i que el fetge és considerat com el principal lloc de producció del FGF21 sistèmic, sobretot en condicions de dejuni i sota control de PPARα, darrerament s’han acumulat diverses evidències que indiquen que FGF21 també pot actuar com a mioquina, un factor hormonal que pot ser produït i alliberat a la circulació pel múscul esquelètic. Concretament, s’ha observat que pacients que pateixen malalties neuromusculars causades per alteracions en la funció mitocondrial, com ara mutacions i deplecions al DNA mitocondrial, presenten valors d’expressió d’FGF21 incrementats, així com també els de la seva secreció a la circulació. Per tant, alguns indicis mostren que el múscul pot ser un lloc de producció i secreció d’FGF21 associat a l’estrès mitocondrial muscular. Durant la realització d’aquesta tesi, hem trobat que l’expressió i la secreció d’FGF21 en un context de cèl•lula muscular estan íntimament associades amb la diferenciació miogènica tant en rosegadors com en models humans. Per contra, els nivells dels seus receptors es mantenen bastant estables, mentre que pel que fa al cofactor β-Klotho, necessari pel seu procés de senyalització, no es detecta expressió del transcrit. Aquest fet suggereix, que la cèl•lula muscular podria ser una font d’expressió i secreció d’FGF21, però no un teixit diana d’aquesta.
A part, s’ha identificat el factor miogènic MyoD com a un regulador molt potent de la transcripció del gen FGF21, així com també se n’ha mapat la regió del promotor responsable de vehicular aquest efecte. D’altra banda, s’han intentat descriure altres factors de transcripció i coreguladors que poden actuar com a activadors o inhibidors, els quals poden estar involucrats en el control de la transcripció gènica d’FGF21, com ara els PPARs, PGC-1α o Sirt1, així com també esbrinar els efectes de diversos activadors naturals i sintètics. En aquest sentit, val la pena destacar que dins d’un context en presència del factor miogènic MyoD s’ha identificat a PPARα, juntament amb el seu activador, com a un clar activador de l’activitat transcripcional d’aquest promotor. PGC-1α, sembla actuar de la mateixa manera, potenciant-ne l’efecte en presència de MyoD. Per contra, Sirt1 s’ha revelat com a un inactivador de l’activitat transcripcional del gen FGF21 en presència del factor MyoD. Altres experiments indiquen que el tractament amb diferents àcids grassos no sorgeixen cap efecte sobre l’expressió ni la secreció del gen en el context muscular, sinó més aviat el contrari, malgrat que la cèl•lula muscular es mostrava sensible a l’acció dels àcids grassos sobre altres gens.
De la mateixa manera que ja indicaven determinats indicis bibliogràfics, vam poder comprovar que pacients de patologia MNGIE (miopatia associada a alteracions del DNA mitocondrial), mostraven la presència d’alts nivells d’FGF21 circulants. Així doncs, intentant mimetitzar una disfunció mitocondrial experimentalment, utilitzant inhibidors de la cadena respiratòria/fosforilació oxidativa, es van poder confirmar aquests increments d’expressió i secreció d’FGF21 per part de les cèl•lules musculars. Investigant una mica més a fons la mecanística de tot el procés, es va veure que l’increment de la producció d’espècies reactives d’oxigen derivades d’aquesta disfunció, provocava una inducció de la p38-MAP cinasa i conseqüentment l’activació ATF2, el qual és capaç d’interaccionar amb el seu lloc d’unió en la regió proximal del promotor del gen FGF21, provocant així aquest efecte sobre el gen FGF21 a les cèl•lules miogèniques. Alhora, s’ha descrit que la presència de MyoD és imprescindible per tal que es doni la resposta de la transcripció del gen FGF21 a la disfunció mitocondrial induïda experimentalment, justificant la resposta d’increment de la secreció d’FGF21 per part de les cèl•lules musculars en resposta a aquesta disfunció. Aquests canvis en la secreció d’FGF21 per part de les cèl•lules miogèniques en resposta a les afectacions a nivell mitocondrial, també poden ser un reflex del mecanisme fisiològic pel qual es detecten canvis a nivell d’estatus energètic a nivell muscular. D’aquesta manera, un increment de l’alliberació d’FGF21 podria desencadenar diferents respostes metabòliques adaptatives a nivell sistèmic. Aquest procés posa de manifest la gran capacitat que té la funció mitocondrial, per tal d’influenciar en el metabolisme sistèmic a través de la senyalització mitocondrial retrògrada. Així doncs, aquest mecanisme de senyalització permet l’expressió i alliberació de molècules d’acció endocrina com ara FGF21 i reforça la idea de considerar el múscul esquelètic com a una important font d’FGF21, la qual podem considerar com a una mioquina.Although the liver is generally considered the main production site for fibroblast growth factor-21 (FGF21), high FGF21 levels have been found to be associated with neuromuscular mitochondrial genetic diseases, and there are indications that shows muscle as a source of FGF21 production under conditions of muscular mitochondrial stress. In this thesis we describe that FGF21 expression and release is associated with myogenic differentiation in different muscular cell lines. However, FGFRs transcription levels don’t change across differentiation and β-Klotho is undetectable, suggesting that muscle cells as a source but not as a target of FGF21. Furthermore we have identified MyoD as a major controller of FGF21 gene transcription, as well as we have mapped the most important region in the promoter responsible for MyoD-dependent regulation. Moreover, we determined the role of some transcription factors and co-regulators potentially involved in the control of FGF21 gene transcription, such as PPARs, PGC-1α or Sirt1, as well as several natural and synthetic agents (e.g. fatty acids) On the other hand, mimicking mitochondrial dysfunction by the use of respiratory chain/oxidative phosphorylation inhibitors resulted in enhanced expression and release of FGF21 by muscle cells. Increased production of reactive oxygen species, subsequent induction of p38-MAP kinase and activation of an ATF2-binding site at the proximal promoter region of the FGF21 gene were found to comprise the major mechanism connecting mitochondrial dysfunction and enhanced FGF21 gene transcription in myogenic cells. Furthermore, we show that MyoD is required for the responsiveness of FGF21 gene transcription to experimentally induced mitochondrial dysfunction, which explains the preferential response of muscle cells to enhanced FGF21 secretion in response to mitochondrial alterations. FGF21 release by muscle cells in response to mitochondrial alterations may reflect a physiological mechanism by which the sensing of internal energetic status by muscle tissue results in the release of FGF21 to favor systemic metabolic adaptations. This process highlights the capacity of mitochondrial function to influence systemic metabolism by retrograde signaling, which leads to the expression and release of molecules with endocrine action, such as FGF2,1 and reinforces the concept of considering the skeletal muscle as an important source of the FGF21, as well as to consider FGF21 as a myokine.
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Brooks, Nicole E. "Fibroblast Growth Factor 21 Expression in Mice with Altered Growth Hormone Action: Links to Obesity, Type 2 Diabetes Mellitus, and Increased Longevity." Ohio University Honors Tutorial College / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ouhonors1461161246.
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Ameka, Magdalene Khang'ai. "The role of FGF21 in regulating energy homeostasis." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5908.
Full textAbstract:
Fibroblast Growth Factor 21 (FGF21) is a hormone that is produced from the liver which has pleiotropic effects. Physiologically, FGF21 increases energy expenditure, increases glucose uptake, enhances glucose tolerance, and increases peripheral insulin sensitivity. Pharmacologically, FGF21 reverses obesity and diabetes in animal models and significantly improves metabolic profiles in humans through unknown mechanisms. We hypothesized that the physiological actions of FGF21 may provide insights to explain FGF21’s beneficial pharmacological effects. The overall theme of this work was to identify the elusive mechanism by which FGF21 regulates energy homeostasis. In chapter 1, I review some adipokines and hepatokines that regulate energy homeostasis. In chapter 2, I provide background on fibroblast growth factors (FGFs), metabolic FGFs, and the tissue-specific effects of FGF21. In chapter 3, I will review the role of growth factors in thermoregulation. In chapter 4, we use tissue-specific loss of function models to investigate the trajectory of FGF21’s thermogenic effects during prolonged cold. In chapter 5, we specifically address the necessity and sufficiency of FGF21 signaling directly to adipose tissue, and the contribution of the adipokine adiponectin in mediating FGF21’s metabolic effects. In chapter 6, I summarize our results, reflect upon the ramifications of these results, and briefly address potential future experiments given our results on the physiological and pharmacological actions of FGF21 in adipose tissues.
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Coleman, Stacey J. "The role of nuclear FGFR1 and FGF2 in pancreatic cancer." Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8403.
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Patients who are diagnosed with pancreatic ductal adenocarcinoma (PDAC) face a dismal prognosis. One reason for this is the dense stroma that is a characteristic of PDAC, which may preclude drugs from accessing the tumour cells. Pancreatic stellate cells (PSCs) are the key cell responsible for desmoplasia in PDAC and it is becoming clear that they are a promising target for therapy. Over-expression of FGFs and their receptors is a feature of PDAC and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. The aim of my research was 1) to understand the role and function of nuclear FGFR1 and FGF using 2D based assays; 2) to use a physiologically relevant 3D organotypic model to study the effects of blocking nuclear FGFR1 and FGF2 in PSCs; 3) to assess whether this target could provide a novel therapeutic strategy in PDAC. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localised to the nucleus in activated PSCs but not cancer cells. Inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition in vitro, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. Cancer cells co-cultured on top of collagen/Matrigel gels together with PSCs showed marked invasion of both cancer cells and PSCs. However, FGFR inhibition blocked invasion of both PSCs and cancer cells. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle-treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra-cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion. Thus, for 6 patients with PDAC which is resistant to conventional chemotherapy, targeting the stroma by blocking nuclear FGFR1 and FGF2 in PSCs identifies a novel therapeutic approach.
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Kristofersdottir, Isidora Anna. "Effect of FGF21 on short-term white adipocyte adiponectin secretion." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-18682.
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Reduced levels of white adipocyte hormone adiponectin have been observed in obese individuals with type 2 diabetes (T2D). Higher adiponectin levels are monotonically associated with a lower risk of T2D and hence increasing circulating adiponectin levels is of great interest in diabetic research. A novel compound, called fibroblast growth factor 21 (FGF21), is showing great potential in treatment of obesity and T2D. In animal models with obesity and T2D FGF21 increases glucose uptake, improves lipid homeostasis, decreases fat mass and increases circulating adiponectin levels. In this study, theaim is to explore the acute effect of FGF21 on white adipocyte adiponectin secretion. Adiponectinsecretion experiments were performed on primary murine adipocytes incubated with FGF21 for 30minutes and adiponectin levels were measured with ELISA and normalised to total protein content.To study the signalling pathway of FGF21, a separate batch of murine adipocytes were pretreated with an Epac and PI3K inhibitor prior to addition of FGF21. Results from this thesis show that FGF21potently stimulates short-term adiponectin release via PI3K-dependent pathways with no effect on adiponectin synthesis.
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Guash, Géraldine. "Caractérisation moléculaire du symdrome myéloprolifératif 8p12 impliquant le gène FGFR1." Aix-Marseille 2, 2001. http://www.theses.fr/2002AIX22013.
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Elsayed, Asmaa. "A Polymorphism in the FGF21 Gene is a Novel Risk Variant for Metabolic-Associated Steatohepatitis." Thesis, The University of Sydney, 2020. https://hdl.handle.net/2123/22453.
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Background: Metabolic associated fatty liver disease (MAFLD) afflicts about a quarter of the global population. A proportion of these patients develop chronic inflammation which can progress to cirrhosis and cancer. Sugar consumption is a major risk factor of MAFLD progression and a human FGF21 variant (rs838133) was recently found to be a risk variant for increased sugar consumption. Whether this variant is a novel risk factor for MAFLD is unknown. Methods: We studied the association of FGF21 rs838133 with liver disease severity and the metabolic profile of patients with MAFLD. Functional investigations were undertaken using allele-specific expression of FGF21 in liver, by measurement of serum FGF21 by ELIZA, bioinformatics analysis and by complementary mouse studies. Results: FGF21 rs838133 was associated with an increased risk of metabolic associated steatohepatitis (MASH), but not simple steatosis. The variant did not affect hepatic FGF21 expression or splicing, but likely affects FGF21 mRNA structure. Compared to healthy controls, patients with MAFLD have higher serum FGF21 levels (p < 0.05). This difference was more profound in patients with MASH (162 ± 47.26, p < 0.01) compared to those with simple steatosis (155.2 ± 51.98, p < 0.01). Similarly, FGF21 levels increased with progression of the NAS score and with fibrosis (p <0.05, for both). Consistently, there was a positive correlation between FGF21 levels and blood glucose, HOMA-IR, AST, GGT, triglycerides, total bile acids and primary bile acids (p < 0.05, for all). In mouse models of liver injury, Fgf21 expression was increased by a high sucrose diet, and in two liver injury models, namely bile duct ligation (p < 0.05, for both) and a methionine and choline deficient diet (p < 0.0001). There was no correlation between serum levels of FGF21 and other FGF family proteins (FGF19, FGF23). Conclusion: FGF21 rs838133 is a novel risk variant for MASH, likely via a change in mRNA folding and subsequently, stability. FGF21 serum levels are likely increased in MASH due to hepatic resistance and correlates with markers of glycaemic profile and bile acids in these patients. Different members of the FGF family of proteins are likely regulated by different mechanisms.
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Bayoumi, Ali. "Mistranslation drives alterations in protein levels and the effects of a synonymous variant at the FGF21 locus." Thesis, The University of Sydney, 2020. https://hdl.handle.net/2123/24549.
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Background: Fibroblast growth factor 21 (FGF21) is a liver-derived hormone with pleiotropic beneficial effects on metabolism. Paradoxically, FGF21 levels are elevated in metabolic diseases. Interventions that restore metabolic homeostasis reduce FGF21. Whether abnormalities in FGF21 secretion or resistance in peripheral tissues is the initiating factor in altering FGF21 levels and function in humans is unknown.
Methods: I have studied the role of the rs838133 polymorphism in regulating FGF21 protein expression in-vivo and in-vitro. Then, I explored the mechanisms by which this single nucleotide polymorphism (SNP) modulates FGF21 production. I utilized RiboLace methodology to examine FGF21 production associated with the ribosomal translationally active fraction. Next I developed an in-vitro genetic model to help resolve the paradox of FGF21 expression in metabolic disorders. Furthermore, I studied the association between rs838133 and the expression of FGF21 receptors and activity. Finally, I related my findings back to tissue and explored the functional impact of rs838133 on hepatic inflammation.
Results: I have shown that the minor (A) allele of the rs838133 polymorphism is associated with higher levels of circulating and hepatic FGF21 and it is not associated with the expression of fibroblast growth factor receptor 1 (FGFR1), Klotho-β (KLB) nor fibroblast activation protein (FAP) and hence and does not alter FGF21 signalling or activity. Then I identified an unanticipated mechanism for the FGF21 levels variation which is a genotype dependant alteration in the translational rate of FGF21. This alteration is most probably the primary event which results in FGF21 levels disturbance. Furthermore, I have demonstrated that codon bias and secondary mRNA structure are pivotal elements of the effect of rs838133 on the FGF21 translation rate. Additionally, I have proposed that ribosomal protein lateral stalk subunit P0 (RPLP0) could be the link between metabolic stress and FGF21 overexpression in metabolic disorders. Finally, I have related my results back to tissue and identified that under metabolic stress, the rs838133 has a deferential inflammatory response in-vivo and in-vitro.
Conclusion: My results highlight a dominant role for translation of the FGF21 protein to explain variations in blood levels that is at least partially inherited. These results provide a framework for translational reprogramming of FGF21 to treat metabolic diseases.
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Rupérez, Gonzalo Celia. "Papel de las cardiocinas FGF21 y Metrnl en la hipertrofia cardíaca." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/674020.
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El objetivo principal de esta tesis fue el estudio de la función de dos nuevas cardiocinas, FGF21 y Metrnl, durante el desarrollo de la patología cardíaca. Se dividió en los siguientes apartados:
PARTE 1:
Caracterización del papel de la proteína FGF21 en corazón en un contexto de obesidad, utilizando como modelo ratones deficientes en esta proteína sometidos a una dieta rica en grasas.
Estudio de los mecanismos mediante los cuales FGF21 lleva a cabo su función cardioprotectora en estas condiciones.
PARTE 2:
Caracterización de la proteína Metrnl como nueva cardiocina y potencial biomarcador de patología cardíaca.
Estudio de las funciones de esta proteína en corazón en un contexto de hipertrofia cardíaca, utilizando como modelo ratones deficientes en Metrnl y la recuperación de la expresión cardíaca de Metrnl mediante vectores adeno-asociados y estudios in vitro utilizando el modelo de cardiomiocitos neonatales en cultivo.Cardiokines are proteins produced and secreted by the heart, that have an important role in the correct maintenance of its function. In the present work, a new role for FGF21 (Fibroblast Growth Factor 21) has been described. Also, we prove that Metrnl (Meteorin-like) is a novel cardiokine with relevant cardioprotective functions. Our group first reported that FGF21 is responsible for cardioprotective mechanisms against hypertrophy development and oxidative stress. FGF21 is a secretable protein with a well-known role in glucose homeostasis regulation, ketogenesis and thermogenic activation, though the potential FGF21 protection against obesity effects in the heart remained unknown to the date. Therefore, in the present work we first describe how FGF21 deficiency causes excessive myocardial accumulation of lipidic vessels, leading to hypertrophy and cardiac dysfunction. FGF21 protective actions against lipotoxicity are mediated by autophagy (and lipophagy) increased activity, due directly to FGF21 signaling pathway activation. Metrnl is a protein secreted by the adipose tissue and the skeletal muscle, that increases energy expenditure and decreases inflammation. Although Metrnl is highly expressed in the cardiac muscle, as far as we know there are no reports regarding its cardiac function. Here we first characterized Metrnl as a new cardiokine, produced and secreted mostly by cardiomyocytes. Metrnl expression is increased in response to a wide range of cardiac stress conditions, and it has autocrine effects in the cardiomyocytes as well, where Metrnl increases PGC1α expression, a transcriptional co-activator with extensively reported anti-hypertrophic properties. Metrnl absence induces cardiac alterations, that include an anomalous hypertrophy pattern where the interventricular septum thickness is increased, more fibrosis and changes in the activation profile of cardiac immune cells. Metrnl expression recovery is enough to correct those alterations and to protect against cardiac hypertrophy. Finally, Metrnl potential as a cardiac pathology biomarker has been evaluated within a large cohort of patients with heart failure. We concluded that Metrnl is a strong prognostic biomarker of survival in these patients. As a summary, the present work contributes to a better understanding of the roles of the cardiokines FGF21 and Metrnl, and its relevance for the maintenance of the cardiac function.
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Pérez, Martí Albert. "The role of FGF21 in the metabolic response to amino acid restriction." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/401895.
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Obesity and associated metabolic diseases have reached epidemic proportions, affecting not only high-income countries but also low- and middle-income ones. In this context, the search for therapeutic approaches to treat obesity is becoming a priority worldwide.
In this regard, the metabolic hormone fibroblast growth factor 21 (FGF21) has been identified as a potential candidate for the treatment of obesity and metabolic syndrome. Previous work by our group described that FGF21 is highly induced in liver in response to leucine deprivation and that the transcription factor ATF4 mediates this induction. The present work is the follow-up of this initial observation.
To delve deeper into the molecular mechanisms that regulate FGF21 expression during leucine deprivation, we focused on the transcriptional repressor Rev-erbα, which functions both as a core repressive component of the cell autonomous clock and as a regulator of metabolic genes.
Our results reveal a consistent negative correlation between Fgf21 and the Pgc-1α/heme/Rev-erbα axis across various nutritional states and that a decrease in Rev-erbα activity enhances the ATF4-mediated upregulation of the human FGF21 promoter. Consequently, we propose a model whereby the induction of Fgf21 upon leucine deprivation is the consequence of the sum of two factors: binding of the activator ATF4 to the promoter and the absence of the repressor Rev-erbα.
Given the coincidence between the effects of leucine deprivation and those observed during FGF21 treatment, we analysed the role of FGF21 during leucine deprivation. In the current study, we demonstrate that weight loss, downregulation of key lipogenic genes in liver and WAT, and BAT activation in response to leucine deprivation are partly FGF21-dependent.
Given the unfeasibility to translate single amino acid deprivation to humans, we focussed on low-protein diets (LPDs) as a more realistic approach.
The LPD increased circulating FGF21 levels with an associated upregulated expression in liver. Analysis of serum human samples from the PREDIMED study extended the correlation between LPD and FGF21 to humans. The ATF4-mediated upregulation of Fgf21 in liver was partially responsible for the weight loss observed in mice fed a LPD, since the liver specific Fgf21 knockout mice (LFgf21KO) mice were partially protected from this loss.
Focusing on the effects of FGF21 on scWAT and given the capacity of FGF21 to produce the browning of white fat depots, we examined the activation of the thermogenic programme in this tissue. Accordingly, scWAT browning caused by the LPD did not occur in mice lacking hepatic Fgf21. As UCP1 activity is related to EE, the blunted induction of Ucp1 in the LPD-fed LFgf21KO mice, may contribute to the reduction in weight loss observed in this mouse model under these circumstances.
The administration of the b-blocker propranolol to protein-restricted mice allowed us to distinguish between the roles of FGF21 and noradrenaline. While Ucp1 expression was upregulated independently of adrenergic signalling, Dio2 and Pparγ expression was blunted by propranolol treatment. These results point to the induction of Ucp1 as a direct effect of liver-delivered FGF21 on scWAT and discard a CNS-mediated effect.
In addition, the LPD improved glucose tolerance, and this improvement was not observed in LFgf21KO mice, indicating a role of FGF21 in glucose metabolism during protein restriction.
Our findings show that the effects of a LPD depend, at least in part, on the circulating levels of FGF21 and consequently on the liver production of this growth factor. Given the parallelism between the results of our study in humans and those in mice, we postulate that modulation of dietary protein content can bring about changes in the circulating levels of FGF21 in mice and humans.L’obesitat i les malalties metabòliques que en deriven són un problema de salut mundial. En aquest context, la recerca d’estratègies terapèutiques pel tractament de l’obesitat ha esdevingut una prioritat. En aquest sentit, el factor metabòlic fibroblast growth factor 21 (FGF21), ha estat identificat com a un prometedor candidat pel tractament de l’obesitat i la síndrome metabòlica. El nostre laboratori va descriure que en resposta a la privació de leucina els nivells de FGF21 augmenten dràsticament i que el factor de transcripció activating transcription factor (ATF4) n’és el responsable. Els resultats d’aquesta tesi són la continuació i desenvolupament d’aquesta observació inicial. Aprofundint en els mecanismes de regulació que controlen l’expressió de FGF21 en resposta a la privació de leucina, els nostres resultats indiquen que el repressor transcripcional Rev-erbα participa significativament en aquesta regulació i que la disminució dels nivells de Rev-erbα correlacionen amb una activació del promotor de FGF21. A més a més, en aquest estudi demostrem que la pèrdua de pes, la disminució de l’expressió de gens lipogènics en fetge i teixit adipós blanc, així com l’activació del teixit adipós marró en resposta a la privació de leucina són, al menys parcialment, dependents de FGF21. Finalment, amb la finalitat de fer els nostres resultats traslladables a humans, demostrem que una dieta amb baix contingut proteic augmenta les nivells circulants de FGF21 en ratolins i humans, i que això succeeix a través de l’increment d’ATF4. L’increment dels nivells de FGF21 degut a la restricció proteica provoquen l’increment de l’expressió dels gens termogènics en el teixit adipós blanc subcutani, la pèrdua de pes i la millora la tolerància a la glucosa. El conjunt d’aquest resultats destaquen el paper clau del factor FGF21 com a mediador dels efectes metabòlics que es produeixen durant la restricció d’aminoàcids i suggereixen la disminució del contingut de proteïna de la dieta com a estratègia per incrementar-ne els nivells.
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Aldridge, Kishan Victoria. "Developmental genetic analysis of post-axial longitudinal limb reduction defect (PALLRD) in Miller syndrome and nonclassical Miller syndrome." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31520.
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This project aimed to provide a greater understanding of limb development through the characterisation of Mendelian disorders. The more specific aim was to identify the developmental basis of the Post Axial Longitudinal Limb Reduction Deformity (PALLRD) seen in the autosomal recessive Miller syndrome caused by mutations in Dihydroorotate Dehydrogenase (DHODH)[1]. In addition whole exome sequence analysis was used to identify further causative variants in a group of individuals with Non Classical Miller syndrome. These individuals were negative for mutations in DHODH although they had a clinically overlapping PALLRD. A single novel variant was discovered in Fibroblast Growth Factor Receptor 1 gene (FGF1) in one individual in this cohort. Due to the known vital role of FGF signaling in limb bud development the functional significance of this variant was investigated further[2]. In vitro data suggested that this variant has a dominant negative effect. Finally I compared the differential gene expression profile of embryonic mouse forelimb and hindlimb at a later stage of development. Digital Gene Expression Serial Analysis of Gene Expression (DGE-SAGE) produced gene-expression profiles of the forelimbs and hind limbs from 14.5 days post conception (d.p.c) murine embryos. This data included known differentially expressed genes as well as novel candidate genes that are putative regulators of limb growth. Whole mount In Situ Hybrisation (WISH) and Quantitative Real Time Polymerase Chain Reaction (qRTPCR) provided corroborating evidence for the differential expression of a subset of these genes between the forelimbs and hind limbs. This project suggests a role for DHODH in limb bud cell proliferation. It also demonstrates a novel potentially dominant negative mutation within FGFR1 in an individual with a limb deformity. Finally a subset of genes involved in regulating the differential growth between the forelimb and hindlimb were presented.
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Iroz, Alison. "Nutritional regulation of the hepatokine FGF21 in the liver : interdependence of the transcription factors ChREBP and PPARα." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC185/document.
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L’hépatokine FGF21 (Fibroblast Growth factor 21) joue un rôle primordial dans le contrôle de l’homéostasie énergétique. Des études chez l’Homme et l’animal mettent en évidence ses effets bénéfiques dans la lutte contre l’hyperglycémie, la dyslipidémie et l’obésité. Connue pour être induite en réponse au jeûne par le récepteur nucléaire PPARα (Proliferator Activated Receptor α), des études récentes suggèrent l’implication du facteur de transcription ChREBP (Carbohydrate Responsive Element Binding Protein) dans la réponse nutritionnelle de FGF21. Dans ce contexte, les objectifs de thèse ont été : 1) d’obtenir une meilleure compréhension de la régulation de FGF21 dans le foie par le jeûne et le glucose via les acteurs moléculaires ChREBP et PPARα ; 2) de déterminer la relevance physiologique de l’axe ChREBP-PPARα-FGF21 en réponse au glucose. Nos résultats mettent en évidence que l’expression hépatique de ChREBP est nécessaire à l’induction de FGF21 en réponse au glucose in vitro et in vivo. De manière inattendue, lorsque l’expression de PPARα est spécifiquement invalidée dans le foie, la réponse au glucose de FGF21 est diminuée de manière significative car ChREBP ne peut se lier à son élément de réponse de type ChoRE, présent sur le promoteur de fgf21. La réponse synergique de ChREBP et de PPARα sur FGF21 a été également mise en évidence dans des cultures primaires d’hépatocytes humains. Chez les souris invalidées pour PPARα dans le foie, l’absence de FGF21 circulant entraine une augmentation de la préférence au sucrose. Notre étude révèle l’existence d’un dialogue fonctionnel unique entre ChREBP et PPARα pour la régulation de FGF21 en réponse au glucoseThe hepatokine FGF21 (Fibroblast Growth factor 21) plays an important role in the control of energy homeostasis. Studies in humans and animals have established FGF21 as an important therapeutic target for its beneficial effects on hyperglycemia, dyslipidemia and obesity. Induced in response to fasting by the PPARα nuclear receptor (Proliferator Activated Receptor α), recent studies suggest the involvement of ChREBP (Carbohydrate Responsive Element Binding) in the nutritional response of FGF21. In this context, the thesis objectives were: 1) to obtain a better understanding of the regulation of FGF21 in the liver by fasting and glucose via the molecular actors ChREBP and PPARα; 2) to determine the physiological relevance of the ChREBP-PPARα-FGF21 axis in response to glucose. Our results demonstrate that hepatic expression of ChREBP is necessary for the induction of FGF21 in response to glucose in vitro and in vivo. Unexpectedly, when PPARα expression is specifically invalidated in the liver, the glucose response of FGF21 is significantly decreased as ChREBP cannot bind to its ChoRE response element present on the fgf21 promoter. The synergistic response of ChREBP and PPARα to FGF21 was also demonstrated in primary cultures of human hepatocytes. In mice deficient for PPARα in the liver, the absence of circulating FGF21 leads to an increase in their preference to sucrose. Our study reveals the existence of a unique functional dialogue between ChREBP and PPARα for the regulation of FGF21 in response to glucose
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Jambrina, Pallares Claudia. "Tratamiento de la diabetes y la obesidad mediante una terapia génica con FGF21." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/458031.
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La prevalencia de la diabetes tipo 2 (T2D) y la obesidad está incrementando a nivel mundial. Actualmente, las terapias disponibles no son apropiadas para todos los pacientes dada la heterogeneidad de la población obesa y con DT2 y por lo tanto, existe la necesidad de desarrollar nuevos tratamientos. El factor de crecimiento fibroblástico 21 (FGF21) es considerado como un prometedor agente terapéutico para la DT2 y la obesidad. No obstante, la proteína nativa FGF21 posee escasas propiedades farmacocinéticas, haciendo de la terapia génica una estrategia atractiva para obtener niveles circulantes de esta proteína elevados y contantes. En este trabajo, se han utilizado vectores virales adenoasociados (AAV) para modificar genéticamente el hígado y hacer que secrete FGF21. El tratamiento a ratones con obesidad inducida por una dieta alta en lípidos y ratones ob/ob causó una marcada reducción del peso corporal, de la hipertrofia y la inflamación del tejido adiposo, de la esteatosis, inflamación y fibrosis hepáticas y de la resistencia a la insulina durante más de un año. Este efecto terapéutico la obtuvo con ausencia de efectos adversos aunque el FGF21 sérico se mantuvo elevado durante todo el periodo. Por lo tanto, este estudio corroboró la seguridad del tratamiento y enfatizó el potencial de esta estrategia de terapia génica con FGF21 para tratar en un futuro la DT2 y la obesidad.The prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, and there is a need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, we used adeno-associated viral vectors (AAV) to genetically engineer the liver to secrete FGF21. Treatment of animals fed a high-fat diet for a long time or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis and insulin resistance for >1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Our study underscores the security of this treatment and the potential of FGF21 gene therapy to treat T2D and obesity.
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Chen, Pei-Yu. "Fibroblast Growth Factor Receptor-1 (FGFR1) in Vascular Smooth Muscle Cell Phenotypic Switch." Fogler Library, University of Maine, 2009. http://www.library.umaine.edu/theses/pdf/ChenPY2009.pdf.
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Correa, Fernanda de Azevedo. "Análise molecular dos genes NEUROD4, FGFR1 e PROKR2 em pacientes com hipopituitarismo congênito." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-11082015-145759/.
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INTRODUÇÃO: As Respostas Auditivas de Estado Estável permitem avaliação frequência específica em intensidades de até 120 dB NA e a detecção de audição residual em pacientes com perda auditiva severo-profunda. O objetivo deste estudo é comparar os limiares à RAEE e os resultados da avaliação comportamental em crianças com suspeita de surdez severo-profunda. MÉTODO: Estudo transversal para comparar respostas à RAEE e por audiometria com reforço visual (VRA) em 63 crianças candidatas ao implante coclear (126 orelhas) com idade entre 6 e 72 meses. Foram incluídas crianças com otomicroscopia normal, ausência de respostas ao PEATE clique a 90 dB NA e às emissões otoacústicas. Foram excluídas crianças com malformações de orelha interna, doenças do espectro da neuropatia auditiva, ou que não completaram a avaliação comportamental ou não atingiram ruído eletroencefalográfico < 30 nV durante a RAEE. Foram utilizados estímulos com tons contínuos sinusoidais (100% AM e 20% FM) nas frequências de 500, 1000, 2000 e 4000 Hz em intensidade máxima de 110 dB NA. Os limiares à VRA foram obtidos por tom warble nas frequências de 500, 1000, 2000 e 4000 Hz em cada orelha através de fones de inserção (ER-5A) ou tipo casco (TDH-39). A intensidade máxima de estimulação foi de 120 dB NA em cada frequência. RESULTADOS: Limiares comportamentais foram obtidos em 36,7% (185/504) de todas as frequências em todas as crianças, 9% em intensidade maior que 110 dB NA. Entre as 504 medidas da RAEE em 63 indivíduos, 53 limiares foram obtidos (10,5%). Ao todo, 89,5% das frequências testadas não apresentaram nenhuma resposta em 110 dB NA. A distribuição dos limiares à RAEE foi semelhante à da avaliação comportamental. A maioria das respostas foram em 500 Hz, diminuindo nas frequências agudas. A diferença média entre os limiares à VRA e à RAEE variou entre 0,09 e 8,94 dB. Foram realizadas 27 comparações entre RAEE e VRA: 12 em 500 Hz, 9 em 1000 Hz, 5 em 2000 Hz e 1 em 4000 Hz. Respostas ausentes foram observadas em ambos os testes em 38,1% em 0,5 KHz, 52,45% em 1 KHz, 74,6% em 2 KHz e 81,0% em 4 KHZ. A especificidade foi > 90% em 1, 2 e 4 KHz. Nas orelhas sem resposta comportamental em 120 dB NA, todos os limiares à RAEE estavam na faixa de perda profunda, 90% deles > 110 dB NA. CONCLUSÃO: A ausência de respostas nas altas intensidades na RAEE foi o principal achado (especificidade > 90%) o que prediz limiares comportamentais na faixa de surdez profundaIntroduction and Objective: ASSR allows frequency-specific evaluation in intensities up to 120 dB HL and detection of residual hearing in patients with severe-toprofound hearing loss. The aim of this study was to compare ASSR thresholds and behavioral test results in children with suspected severe-to-profound hearing loss. Methods: A cross sectional study was carried out to compare ASSR and Visual Reinforcement Audiometry (VRA) responses in 63 pediatric cochlear implant candidates (126 ears) aged between 6 to 72 months. We included children with normal otomicroscopy findings, absent responses to click-ABR at 90 dB HL and otoaccoustic emissions. We excluded children with inner ear malformations, auditory neuropathy spectrum disorder or who did not complete VRA or achieve EEG noise < 30 nV during the ASSR test. Air-conduction ASSR stimuli were continuous sinusoidal tones (100% AM and 20% FM) presented at 0.5, 1, 2 and 4 kHz starting at the maximum presentation level of 110 dB HL. VRA thresholds were acquired with warble tones presented at 0.5, 1, 2 and 4 KHz in each ear through ER-tone 5A or TDH-39 phones. Maximum presentation level was 120 dB HL for each frequency. Results: Behavioral thresholds were obtained in 36.7% (185/504) of all frequencies in all subjects, 9% were in intensities > 110 dB HL. Among 504 ASSR measurements from 63 subjects, 53 thresholds were obtained (10.5%). Overall 89.5% of the tested frequencies did not show any response at 110 dB HL. The distribution of ASSR responses was similar to the behavioral test results. Most responses were at 500 Hz, decreasing among the higher frequencies. Mean differences between behavioral and ASSR thresholds varied from 0.09 to 8.94 dB. Overall, 27 comparisons of behavioral and ASSR thresholds were obtained: 12 at 0.5 KHz, 9 at 1 KHz, 5 at 2 KHz and 1 at 4 KHz. Absent responses were observed in both tests in 38.1% at 0.5 KHz, 52.4% at 1 KHz, 74.6% at 2 KHz and 81.0% at 4 KHz. The specificity was > 90% at 1, 2 and 4 KHz. In ears with no behavioral response at 120 dB HL all ASSR thresholds were in the profound hearing loss range, 90% of them were equal or > than 110 dB HL. Conclusion: Among 63 pediatric CI candidates, absent responses to high-intensity ASSR was the major finding (specificity > 90%) predicting behavioral thresholds in the profound hearing loss range. These findings can be helpful to confirm the decision for cochlear implantation
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Ono, Kazuya. "FGFR1-Frs2/3 Signalling Maintains Sensory Progenitors during Inner Ear Hair Cell Formation." Kyoto University, 2014. http://hdl.handle.net/2433/188680.
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Kolanczyk, Maria Elzbieta. "Signaling mechanisms and developmental function of fibroblast growth factor receptors in zebrafish." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2009. http://nbn-resolving.de/urn:nbn:de:bsz:14-ds-1242722157657-12154.
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Fibroblast growth factor (Fgf) signaling plays multiple inductive roles during development of vertebrates (Itoh 2007). Some Fgfs, such as Fgf8, are locally secreted and signal over a long range to provide positional information in the target tissue (Scholpp and Brand 2004). Fgf ligands signal in a receptor-dependent manner via tyrosine kinase receptors, four of which have been so far identified. Fgf8 signaling was shown to depend both on receptor activation as well as endocytosis. The specificity of Fgf ligands and receptors as well as the function of receptors in the control of the Fgf signaling range have been, however, largely unclear. In this study, we show that the putative Fgf8 receptor Fgfr1 is duplicated in zebrafish and that it acts redundantly in the formation of the posterior mesoderm. Also, in overexpression studies we confirm the notion that receptor endocytosis influences Fgf8 signaling range. Through TILLING mutant recovery and morpholino knockdown studies we also show that Fgfr2 is required for growth and skeletal development in zebrafish, whereas Fgfr4 is required for pectoral fin specification and growth.
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Manousakidi, Sevasti. "Étude des activités du FGF1 dans les tumeurs ovariennes." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLV049.
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Le cancer ovarien comprend un groupe hétérogène de tumeurs pouvant affecter les cellules épithéliales, stromales ou germinales. Le traitement de ces tumeurs constitue un défi majeur car un taux important de patientes présentent une rechute suite à un traitement chimiothérapeutique. Il est donc important de comprendre les mécanismes de résistance à la chimiothérapie de ces tumeurs.Le facteur de croissance des fibroblastes 1 (FGF1) a été retrouvé surexprimé dans de nombreuses tumeurs dont les tumeurs ovariennes épithéliales de haut grade. Les études antérieures du laboratoire ont montré que le FGF1 exerce une activité anti-apoptotique via la modulation de la stabilité et des activités transcriptionnelles de p53. Le but de mon travail était donc de savoir si la surexpression du FGF1 était suffisante pour favoriser une résistance vis-à-vis de l’apoptose induite par des agents chimiothérapeutiques dans les tumeurs ovariennes et si le FGF1 pourrait réguler les activités de la protéine p53.À cet effet, nous avons utilisé trois lignées ovariennes ; la lignée de la granulosa ovarienne COV434, la lignée épithéliale A2780 et la lignée épithéliale résistante au cisplatine A2780cis qui surexprime le FGF1. L’invalidation du gène FGF1 par la technique CRISPR/Cas9 n’a pas permis de restaurer la sensibilité à la chimiothérapie dans les cellules A2780cis. D’autre part, nous avons montré que la surexpression du FGF1 confère une résistance à l’apoptose dans la lignée COV434, mais pas dans la lignée épithéliale A2780. Les mécanismes moléculaires de cette activité anti-apoptotique sont différents de ceux identifiés dans d’autres lignées. En effet, dans la lignée COV434 la surexpression du FGF1 a peu d’impact sur la stabilité de p53 et ne diminue pas son activité transcriptionnelle. De plus, nous montrons que la translocation mitochondriale de p53 joue un rôle important dans l’induction de l’apoptose par l’étoposide dans la lignée COV434. De plus, nous avons montré que, dans la lignée COV434, l’activité anti-apoptotique du FGF1 est exercée par une atténuation de la localisation mitochondriale de p53. Nos données préliminaires suggèrent la présence du FGF1 à la mitochondrie. En conclusion, l’ensemble de nos expériences permet de proposer un nouveau mode d’action pour le FGF1 qui n’a jamais été décrit auparavantOvarian cancer is an heterogenous group of tumors, able to affect epithelial, stromal or germ cells. The treatment of these tumors is a major challenge as a high rate of relapse is observed in ovarian cancer patients following chemotherapy.Fibrobast growth factor 1 (FGF1) is overexpressed in numerous tumors such as high grade ovarian epithelial tumors. Previous work realized in our laboratory showed that FGF1 has an anti-apoptotic activity which is mediated by the regulation of p53 stability and transcriptional activities. The aim of my work was to understand whether FGF1 overexpression is sufficient to induce resistance to chemotherapy-induced apoptosis in ovarian tumors and if FGF1 could modulate the activities of p53 protein.For this purpose, we used three ovarian cell lines; the COV434 ovarian granulosa cell line, the ovarian epithelial A2780 cell line and its counterpart A2780cis cell line which is resistant to ciplatin and overexpresses FGF1.FGF1 knock out experiments in A2780cis cell line, using the CRISPR/Cas9 system, did not show any restoration of the sensibility of these cells to cisplatin. Moreover, we showed that FGF1 overexpression in COV434 cell line renders these cells resistant to apoptosis while no effect was observed in A2780 cells. The molecular mechanisms underlying this anti-apoptotic activity differed from those identified in other cell lines previously. Indeed, in COV434 cell line, FGF1 overexpression has only a small impact on p53 stability and it does not reduce its transcriptional activity. Furthermore, we show here that p53 mitochondrial translocation plays an important role in the induction of apoptosis by etoposide in COV434 cells. Moreover, we provide evidence that FGF1 anti-apoptotic activity in COV434 cells relies upon the attenuation of p53 mitochondrial localization. Our preliminary results suggest that FGF1 could be found at the mitochondria. In conclusion, our findings let us propose a novel mode of action for FGF1 which has never been described previously
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Moure, Ortega Ricardo. "Alteraciones en la señalización de FGF21 asociadas a la terapia antirretroviral y a la adiposidad." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/456803.
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Tanto la infección por el virus VIH como el tratamiento antirretroviral se asocian con el desarrollo de alteraciones metabolicas relacionadas con la adiposidad, pudiendo íncluso desarrollar lipodistrofia.
Estudios previos han relacionado el desarrollo de estas complicaciones con fenómenos celulares de toxicidad mitocondrial, estrés de retículo, alteraciones en el proceso de adipogénesis, fibrosis y procesos de envejecimiento prematuro. Sin embargo, no se conoce en profundidad cómo afectan estos procesos a los depósitos adiposos. Es por esto que en el primer capítulo de esta tesis se ha realizado un estudio sobre la firma molecular de los lipomas que aparecen en pacientes de VIH. Así, se ha reportado que estas formaciones de tejido adiposo no presentan signos de inflamación, alteraciones en la adipogénesis ni de disfunción mitocondrial. Sin embargo, presentan un estado de alta proliferación y de envejecimiento prematuro y precoz. También se encontró que, dentro de los diferentes tipos de lipomas, los que aparecen en la zona dorsocervical (conocidos como "giba de búfalo") son los únicos que presentan patrones de expresión génica relacionados con la presencia de adipocitos marrones clásicos.
En el segundo capítulo se ha anaizado el efecto del nuevo fármaco antirretroviral elvitegravir sobre adipocitos humanos en cultivo. Este método ya se ha utilizado anteriormento con otros fármacos como una forma de alertar ante posibles efectos adversos que este nuevo fármaco pudiera producir sobre el tejido adiposo. Observamos que este fármaco no puede considerarse completamente "adipose friendly", ya que inhibe la adipogénesis y altera la expresión de adipoquinas y de citoquinas proinflamatorias.
Paradójicamente, a pesar de tener dificultades a la hora de almacenar grasa con normalidad en sus depósitos de tejido adiposo, estos pacientes desarrollan alteraciones metabólicas que normalmente aparecen en personas obesas, como resistencia a la insulina, diabetes tipo II o el desarrollo de enfermedades cardiovasculares. De la misma forma, estos pacientes tienen altos niveles circulantes de la hormona FGF21 y bajos niveles de su correceptor beta-klotho, el cual es necesario para que el organismo responda a los efectos antidiabéticos de esta hormona. Esta situación de aumento de FGF21 y bajada de beta-klotho recuerda al estado de resistencia a FGF21 que se observa en la obesidad y la diabetes tipo II. Por esto realizamos un estudio sistemático sobre el efecto que tienen los principales miembros de las diferentes familias de fármacos sobre células hepáticas, adiposas y musculares humanas. En algunos de los fármacos más utilizados, como el efavirenz, el elvitegravir y casi todos los inhibidores de la proteasa vírica, encontramos una alteración en el sistema FGF21/beta-klotho análoga a la que se observa en pacientes, caracterizada por la subida de FGF21 y la bajada de beta-klotho. Estas alteraciones parecen relacionarse con fenómenos de estrés de retículo y estrés oxidativo.
Aunque se conoce que beta-klotho es necesario para la correcta señalización de FGF21, no se conoce hasta qué punto la bajada en los niveles de beta-klotho puede afectar al correcto desarrollo de ciertas funciones en las que FGF21 está involucrada. Gracias a estudios con ratones y con cultivos primarios parcial o totalmente deficientes para el gen que codifica beta- klotho y para el de FGF21, determinamos como la caída en los niveles de este correceptor compromete la activación termogénica de los tejidos adiposos blanco y marrón. Esta disminución en la respuesta termogénica parece relacionarse con una implicación autocrina de FGF21 en la respuesta termogénica de los adipocitos.Both HIV infection and antiretroviral treatment are associated with the development of metabolic alterations related to adiposity, which may even include lipodystrophy development. Previous studies have related the development of these complications with mitochondrial toxicity, endoplasmic reticulum stress, and alterations in adipogenesis,. This thesis includes a study of the molecular signature of lipomas that appear in HIV patients. Thus, it has been observed that these adipose tissue formations do not show signs of inflammation, alterations in adipogenesis or mitochondrial dysfunction. Nevertheless, they present a highly proliferative state and signs of premature aging. It was also found that lipomas situated in the dorso-cervical area (known as "buffalo hump") are the only ones that present gene expression patterns related to the presence of classic brown adipocytes. Secondly, it has been analized the effect of the new antiretroviral drug elvitegravir on human adipocytes, reporting that this drug can’t be considered completely “adipose friendly”, since it inhibits adipogenesis and alters the expression and release of adipokines and proinflammatory cytokines. Paradoxically, lipodystrophic patients, develop metabolic abnormalities normally associated with obesity, such as insulin resistance, diabetes and hyperlipidemia. In the same way, these patients have high circulating levels of the hormone FGF21 and low levels of its co-receptor β-klotho, which is necessary for FGF21 signalling. This situation mimics the state of resistance to FGF21 observed in obesity and diabetes. Therefore, we performed a study on the effect of the main members of the different antiretroviral drug families on human liver, adipose and muscle cells. We found an alteration in the FGF21/β-klotho system similar to that seen in patients in some of the most commonly used drugs. Although β-klotho is known to be mandatoy for FGF21 signaling, it is not known to what extent the decline in β-klotho levels may affect certain functions in which FGF21 is involved. Using mouse models and primary cultures of adipocytes we determined how the drop in levels of this co-receptor compromises the thermogenic activation of white and brown adipose tissue. This decrease in thermogenic response seems to be related to an autocrine implication of FGF21 in the thermogenic response of adipocytes.
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Ciruna, Brian Garrett. "The role of FGFR1 signalling in the specification and morphogenesis of mesoderm during mouse gastrulation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ63717.pdf.
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Delmas, Elisabeth. "Régulation de l’apoptose dépendante de p53 par le FGF1 intracellulaire : caractérisation des mécanismes d’action." Thesis, Versailles-St Quentin en Yvelines, 2014. http://www.theses.fr/2014VERS0037/document.
Full textAbstract:
L’apoptose, ou mort cellulaire programmée, joue un rôle majeur au cours du développement embryonnaire et dans le maintien de l’homéostasie tissulaire chez l’adulte. La voie mitochondriale de l’apoptose est principalement activée par la protéine oncosuppressive p53. Le FGF1 est un facteur de croissance atypique, majoritairement intracellulaire et nucléaire qui induit la prolifération, la différenciation et la survie cellulaires. Dans les cellules PC12, le FGF1 présente des activités neurotrophique et anti-apoptotique vis-à-vis de l’apoptose dépendante de p53. De plus, il interagit avec la protéine p53. La localisation nucléaire du FGF1 semble nécessaire à ses activités intracellulaires ainsi qu’à son interaction avec p53.Au cours de ma thèse, j’ai étudié les activités neurotrophique et anti-apoptotique de différentes formes mutantes du FGF1. J’ai entrepris l’étude de l’activité intracellulaire de la forme FGF1K132E, forme mutante dont les activités extracellulaires sont inhibées. La mutation du résidu lysine 132 pourrait modifier la phosphorylation du résidu sérine 130 du FGF1, j’ai donc également étudié deux autres formes mutantes : le FGF1S130A, dont la phosphorylation est inhibée et le FGF1S130D dont la phosphorylation est mimée. Les résidus mutés (K132 et S130) sont situés dans le domaine C-terminal du FGF1.Cette étude nous a permis de montrer que la phosphorylation du FGF1 inhibe son activité anti-apoptotique mais ne modifie pas son activité neurotrophique, et que le domaine C-terminal du FGF1 est fortement impliqué dans la régulation de ses activités intracellulaires. Toutes ces formes mutantes sont capables d’être transloquées dans le noyau ce qui suggère que la localisation nucléaire du FGF1 soit nécessaire mais insuffisante pour ses activités intracellulaires. Par ailleurs, p53 peut interagir avec le FGF1WT et certaines formes mutantes, toutefois cette interaction n’est pas strictement corrélée à l’activité anti-apoptotique du FGF1, ce qui suggère l’existence d’autres régulations nucléaires qui restent à caractériser.Mes travaux ont permis pour la première fois de mettre en évidence le rôle de la phosphorylation du FGF1 et de son domaine C-terminal dans la régulation de ses activités intracellulaires. La poursuite de cette étude permettra de mieux caractériser le rôle nucléaire de ce facteur de croissance et de caractériser ses éventuelles interactions avec des protéines nucléaires comme p53Apoptosis, a form of programmed cell death, is required for embryonic development and tissue homeostasis. The mitochondrial pathway of apoptosis is mainly induced by p53, an oncosuppressor that acts as a transcription factor. FGF1 is one of the two prototypic members of the FGF family. Contrarily to most FGFs, FGF1 lacks a secretion peptide signal and acts mainly in an intracellular and nuclear manner. Intracellular FGF1 induces cell proliferation, differentiation and survival. In PC12 cells, FGF1 inhibits p53-induced apoptosis and interacts with p53. FGF1 nuclear localization seems to be required for its intracellular activities and its interaction with p53.To better characterize the FGF1 intracellular pathway, we studied neurotrophic and anti-apoptotic activities of several mutant forms of FGF1: the FGF1K132E that could affect FGF1 phosphorylation, and two phosphorylation-site mutant forms, i.e. the FGF1S130A (preventing phosphorylation) and the FGF1S130D (mimicking phosphorylation). All these mutations are localized in the C-terminal domain of FGF1. This study showed that phosphorylation inhibits FGF1 anti-apoptotic activity but not its neurotrophic activity in PC12 cells and that the FGF1 C-terminal domain is strongly involved in the regulation of its intracellular activities. Despite their different activities, all mutant forms are localized both in the cytosol and the nucleus. Therefore, nuclear localization is required but insufficient for FGF1 to display its intracellular activities.Besides, p53 can interact with wild-type and some of the mutant forms of FGF1. This interaction does not strictly correlate with FGF1 anti-apoptotic activity. Thus, the nuclear mechanisms regulating FGF1 intracellular activities remain to be characterized.Our study highlights for the first time the role of the phosphorylation and the C-terminal domain of FGF1 on the regulation of its intracellular activities. This work must continue on to further characterize FGF1 nuclear activities and its interactions with nuclear proteins such as p53
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Rajendran, Ranjithkumar [Verfasser]. "Evaluation of the fibroblast growth factor receptor 1 (FGFR1) in experimental autoimmune encephalomyelitis (EAE) / Ranjithkumar Rajendran." Gießen : Universitätsbibliothek, 2015. http://d-nb.info/1068922265/34.
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Elakad, Omar [Verfasser]. "Functional and diagnostic relevance of FGFR1-dependent signaling pathways in squamous cell lung cancer / Omar Elakad." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2020. http://d-nb.info/1218299207/34.
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Sacristán, Fraile Víctor. "Ingeniería genética del tejido adiposo o del músculo esquelético mediante vectores aav-fgf21 para el tratamiento de la diabetes y la obesidad." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/666658.
Full textAbstract:
La obesidad y la diabetis tipo 2 (DT2) se consideran las dos grandes epidemias del siglo XXI. A pesar del grave problema de salud, económico y social que representan, actualmente no existen terapias completamente efectivas. Asimismo, los tratamientos farmacológicos que se utilizan, frecuentemente presentan importantes efectos secundarios, por lo que es necesario encontrar nuevas aproximaciones terapéuticas para combatir estas epidemias.
Recientemente se ha descrito el factor de crecimiento fibroblástico (FGF21) como un prometedor agente terapéutico tanto para la obesidad como la DT2. FGF21 ejerce su función endocrina en múltiples tejidos diana, regulando la homeostasis energética. Multitud de aproximaciones terapéuticas se han centrado en el desarrollo de péptidos análogos o miméticos que mejoren sus propiedades farmacocinéticas. No obstante, la introducción de modificaciones en la molécula nativa no sólo puede inducir reacción inmunitaria, sino que tampoco evitan su administración periódica. La terapia génica presenta una gran ventaja respecto a estas estrategias terapéuticas, ya que permiten alcanzar niveles circulantes elevados y constantes de la proteína nativa mediante una única administración. Por ello, en esta tesis doctoral se utilizaron vectores virales adenoasociados (AAV) con la finalidad de transducir el músculo esquelético o el tejido adiposo, a fin de mediar elevados niveles circulantes de FGF21 para contrarrestar la obesidad y la DT2.
La administración local de vectores AAV de serotipo 9 codificantes para FGF21 (AAV9-FGF21) en el tejido adiposo epididimal incrementó los niveles circulantes de FGF21 y previno la obesidad y la resistencia a la insulina inducidas por una dieta alta en lípidos en ratones. Asimismo, la administración local de vectores AAV8-FGF21 en el tejido adiposo también fue capaz de revertir la obesidad y la resistencia a la insulina en ratones ob/ob. Los animales tratados con vectores AAV-FGF21 mostraron un incremento del gasto energético y una reducción del depósito de lípidos en el tejido adiposo y en el hígado, así como menor inflamación en los mismos.
La administración local de vectores AAV1-FGF21 en el músculo esquelético de ratones obesos y resistentes a la insulina medió resultados similares a los obtenidos mediante la administración de los vectores AAV8 y AAV9-FGF21 en el tejido adiposo. Además, la sobreexpresión de FGF21 en el músculo esquelético y, el consiguiente aumento de los niveles circulantes de FGF21, previnieron el desarrollo de hepatocarcinomas inducidos por el consumo crónico de una dieta alta en lípidos. Además, la administración de vectores AAV1-FGF21 en el músculo esquelético medó un envejecimiento más saludable de ratones controles, lo que se evidenció por el mantenimiento del peso corporal, una menor adiposidad y niveles de triglicéridos en hígado disminuidos así como una mejora de la resistencia a insulina mediada por la edad.
En conclusión, en esta tesis doctoral se ha demostrado que la ingeniería genética del tejido adiposo y del músculo esquelético mediante vectores AAV codificantes para FGF21 permitió prevenir y revertir la obesidad y la DT2 en modelos murinos obesos y de resistencia a la insulina. Además, el tratamiento con AAV-FGF21 en animales controles promovió que estos animales envejecieran de manera más saludable. Estos resultados proporcionan las bases para la traslación clínica de estas aproximaciones de terapia génica para el tratamiento de la DT2, la obesidad y sus comorbilidades asociadas en humanos en el futuro.Obesity and type 2 diabetes (T2D) are considered the epidemics of the 21st century. Despite the serious health, economic and social problems they represent, no completely effective therapies are available nowadays. Moreover, the current pharmacological treatments display important sides effects. Thus, there is a need to find new therapeutic approaches to combat these epidemics. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent against obesity and T2D. FGF21 exerts its endocrine function on multiple target tissues, regulating energy homeostasis. Many therapeutic approaches have focused on the development of analogue or mimetic peptides with improved pharmacokinetic properties. However, modifications of the native FGF21 can induce an immune reaction and do not avoid periodic administration. Gene therapy has a great advantage over these therapeutic strategies, since it allows reaching high and steady circulating levels of the native protein through a single administration. Therefore, this doctoral thesis used adeno-associated viral vectors (AAV) in order to transduce skeletal muscle or adipose tissue to mediate high circulating levels of FGF21 to counteract obesity and T2D. Local administration of AAV vectors of serotype 9 encoding FGF21 (AAV9-FGF21) in epididymal white adipose tissue increased circulating levels of FGF21 and prevented obesity and insulin resistance induced by a high fat diet (HFD) in mice. Likewise, local administration of AAV8-FGF21 vectors in adipose tissue was also able to reverse obesity and insulin resistance in ob/ob mice. Animals treated with AAV-FGF21 vectors showed increased in energy expenditure and reduction of lipid deposition in adipose tissue and in the liver, as well as lower inflammation in both tissues. Local administration of AAV1-FGF21 vectors in skeletal muscle of obese and insulin-resistant mice mediated similar results to those obtained by administration of AAV8 and AAV9-FGF21 vectors in adipose tissue. In addition, overexpression of FGF21 in skeletal muscle, and the subsequent increase in circulating levels of FGF21, prevented the development of hepatocarcinomas induced by the chronic intake of HFD. Furthermore, the administration of AAV1-FGF21 vectors in skeletal muscle expands healthspan in control mice, what was evidenced by the maintenance of body weight, lower adiposity and triglyceride levels in the liver as well as improved age-realated insulin resistance. In conclusion, the results of this doctoral thesis demonstrated that genetic engineering of adipose tissue and skeletal muscle using AAV vectors coding for FGF21 allowed to prevent and reverse obesity and T2D in murine models of obesity and insulin resistance. In addition, treatment with AAV-FGF21 in control animals improved healthspan. These results provide the basis for the clinical translation of these gene therapy approaches for the treatment of T2D, obesity and their associated comorbidities in humans in the future.
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Trisolini, Elena. "Targeted molecular characterization of adult midline and circumscribed gliomas for the identification of new potential targets for personalized therapy." Doctoral thesis, Università del Piemonte Orientale, 2020. http://hdl.handle.net/11579/114872.
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Diffuse midline gliomas (MLG) are primary brain tumours arising from thalamus, hypothalamus, brainstem, cerebellum or spinal cord, mainly occurring in children. In adults, less than 10% of diffuse gliomas arises in midline structures and recent works suggested that this subset of tumours
may present with phenotypic and molecular characteristics differing from both pediatric MLG and adult supratentorial gliomas.
Circumscribed gliomas (CG) are low-grade tumours but may progress to anaplasia. They have lower genetic complexity than diffuse gliomas and could be better candidate for targeted therapies, when complete surgical resection is not feasible.
Unravelling the genomic landscape of MLG and CG will better define the prognostic value of molecular biomarkers and identify new therapeutic strategies that could improve patient care. Adult patients with diagnosis of MLG and CG were retrospectively identified from «Maggiore della
Carità» Hospital and GH Pitié-Salpêtrière (Paris). Mutation analysis was performed by Sanger sequencing of the major hot-spots: IDH1, IDH2, H3F3A, HIST1H3B, FGFR1, TERT promoter. FISH analyses of NTRK1-2-3 rearrangements were performed by break-apart probes on tissue
microarray of MLG cases. We identified 116 (French) and 47 (Italian) patients. The two cohorts showed a lower percentage of
H3F3A mutations (20% vs 33%), the mutation was not associated to a worse prognosis. FGFR1 mutations were identified in 18% of cases and are restricted to MLG. NTRKs analysis in the Italian cohort showed NTRK1 translocations in 15% of cases.
We reported a high rate of FGFR1 mutations in optic nerve pilocytic astrocitomas and the presence of alternative BRAF activating mutations (Thr599_Val600insThr and Val600_Lys601>Glu). Our finding of frequent and potentially targetable FGFR1 and BRAF mutations and NTRK1
translocations have important therapeutical implications in the current context of clinical trials, and further reinforces the need for molecular analyses.
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Casteras, Sylvie. "Étude de la sensibilité à l’insuline du tissu adipeux en absence de production hépatique de glucose." Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10125.
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Le diabète de type 2, problème actuel de santé majeur, s'accompagne souvent du syndrome métabolique. Il est majoritairement admis que la production hépatique de glucose (PHG) excessive caractéristique de cette pathologie est due à une résistance à l'insuline. Nous avons testé si, à l'inverse, la suppression de la PHG induisait une amélioration de la sensibilité à l'insuline périphérique. La sensibilité à l'insuline de souris invalidées pour la Glucose-6-phosphatase (enzyme clé de la PHG) spécifiquement dans le foie (souris L-g6pc-/-) a été étudiée par des tests de tolérance au glucose et de sensibilité à l'insuline. L'effet stimulateur de l'insuline sur la voie PI3K/AKT a été analysé dans les tissus adipeux épididymaire (TAEpi) et sous cutané (TASC) des souris L-g6pc-/- et L-g6pc+/+. La morphologie du TASC et les principaux gènes du métabolisme adipocytaire ont également été étudiés. Les tests de tolérance au glucose et de sensibilité à l'insuline suggèrent une meilleure sensibilité à l'insuline des souris L-g6pc-/-. Ces souris présentent une meilleure activation de la voie PI3K/Akt en réponse à l'insuline par rapport aux sauvages, spécifiquement dans le TASC. Chez les souris L-g6pc-/-, l'absence de PHG induit une modification du métabolisme de ce tissu, avec une augmentation de l'expression des gènes du métabolisme oxydatif, et l'apparition d'adipocytes multiloculaires, exprimant des marqueurs de tissu adipeux brun, comme Ucp1 et Prdm16. L'apparition d'une population d'adipocytes bruns dans le TASC des souris L-g6pc-/- pourrait être due à FGF21. En effet, l'ARNm hépatique et la concentration plasmatique de FGF21 sont augmentés chez les souris L-g6pc-/-. Ce travail constitue la première démonstration qu'une absence de PHG induit une modification du tissu adipeux sous-cutané caractérisée par une différenciation en tissu adipeux brun, associée à une meilleure signalisation de l'insulineType 2 diabetes is a major health concern characterized by the association of metabolic syndrome with increased hepatic glucose production (HGP). Increased HGP is usually considered as a consequence of insulin resistance. We wondered whether, on the contrary, suppression of HGP could modulate peripheral insulin sensitivity. Mice deficient for liver G6pc, coding for the Glucose-6-phosphatase catalytic subunit, key enzyme of HGP (L-G6pc-/- mice), exhibited improved glucose tolerance and insulin sensitivity compared to wild type mice. Phosphoinositide 3-kinase/AKT pathway was greater induced by insulin in subcutaneous adipose tissue of L-G6pc-/- compared to wild type mice, whereas insulin similarly induced this pathway in epididymal adipose tissue of L-G6pc-/- and wild type mice. Analysis of adipose tissue metabolism revealed white to brown fat conversion specifically in subcutaneous adipose tissue of L-G6pc-/- mice. This change was characterized by the appearance of multilocular adipocytes expressing Ucp1 and Prdm16, correlated with increased expression of genes specific of oxidative pathway. L-G6pc-/- mice also displayed an increase levels in circulating FGF-21 that could be responsible for modifications of their subcutaneous adipose tissue. This data are the first demonstration that absence of HGP could modify peripheral insulin sensitivity and induce changes in adipose tissue metabolism
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Chalvon-Demersay, Tristan. "Rôle des acides aminés dans la limitation de l’adiposité sous régime hyperprotéique." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLA018/document.
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Plusieurs études ont montré que certaines kinases situées dans le foie, « mammalian target of rapamycin » (mTOR), « adenosine monophosphate-activated protein kinase » (AMPK) et « general control non-depressible kinase 2 » (GCN2) répondent à la disponibilité en acides aminés.L’objectif de nos études a été de préciser le rôle de deux de ces voies, l’AMPK et GCN2, dans les adaptations du métabolisme énergétique et de la synthèse protéique en réponse aux variations en protéines du régime. Pour cela, des souris de type sauvage et des souris KO n’exprimant plus la voie AMPK ou GCN2 dans le foie ont été nourries pendant trois semaines avec un régime faible, normal ou fort en protéines. Les analyses ont montré que les souris KO-AMPK foie spécifique et nourries sous régime normoprotéique adaptent leur métabolisme hépatique notamment en sécrétant le facteur fibroblastique FGF21 ce qui leur permet de compenser l’absence d’AMPK et de présenter des profils d’oxydation normaux.Au contraire, les souris KO-AMPK foie spécifique nourries avec des régimes faibles ou forts en protéines présentent des altérations des profils d’oxydation des lipides et des glucides liées à une absence de modification du métabolisme hépatique.La délétion de GCN2 dans le foie, quant à elle, n’a d’effet que sous régime faible en protéines : les souris KO-GCN2 foie spécifique présentent une plus faible oxydation lipidique et une plus forte oxydation glucidique que les souris sauvages en période postprandiale dû à l’absence d’induction de la sécrétion de FGF21.Concernant le métabolisme des protéines, les kinases GCN2 et AMPK ne semblent pas impliquées dans l’intensité du flux de synthèse protéique dans le foie et en périphérie dans le muscle en période postprandiale.En conclusion, ces travaux montrent que les délétions de l’AMPK et de GCN2 hépatiques affectent le métabolisme énergétique mais pas le métabolisme protéique et que les conséquences dépendent de la composition du régimeSeveral studies have reported that some kinases located in the liver respond to the availability of amino acids. These kinases are mammalian target of rapamycin '(mTOR), "adenosine monophosphate-activated protein kinase" (AMPK) and "general control non-depressible kinase 2" (GCN2).The aim of our study was to clarify the role of two of these signaling pathways, AMPK and GCN2 in the adaptations of energy and protein metabolism in response to the modulation of dietary protein content. Wild-type and liver AMPK-deficient or liver GCN2-deficient mice were fed either a low, a normal or high protein diet during three weeks. Analyzes showed that liver AMPK-deficient mice fed under a normo-protein diet exhibit an adapatation of liver metabolism and secret FGF21 which enables them to have normal postprandial oxidation profiles.In contrast, liver AMPK-deficient mice fed a low or a high protein diet exhibit an alteration in postprandial oxidation profiles. The deletion of GCN2 in the liver only has an effect under low protein diet as liver GCN2 deficient mice have a lower lipid oxidation and a higher carbohydrate oxidation linked to the absence of FGF21 secretion. Concerning protein metabolism, AMPK and GCN2 do not seem to be involved in protein synthesis rate in the posrprandial period in the liver and periphery in the postprandial muscle. In conclusion, these studies show that hepatic AMPK and GCN2 deletions affect energy metabolism, but not protein metabolism and that the consequences depend on diet composition
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Malchers, Florian [Verfasser], and Manolis [Akademischer Betreuer] Pasparakis. "FGFR1-Dependency Prediction by Genomic and Functional Analysis in Squamous Cell Lung Cancer / Florian Malchers. Gutachter: Manolis Pasparakis." Köln : Universitäts- und Stadtbibliothek Köln, 2014. http://d-nb.info/1061121267/34.
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Martínez, Garza Úrsula Montserrat. "The role of hepatic FGF21 (Fibroblast Growth Factor 21) in the maintenance of metabolic homeostasis during metabolic stress." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/671749.
Full textAbstract:
The excessive consumption of calorie-rich foods, together with a sedentary lifestyle, drive the actual global obesity pandemic. Obesity is the leading cause of several other metabolic disorders, such as diabetes, cardiovascular diseases, cancer, and non-alcoholic fatty liver disease (NAFLD).
Fibroblast growth factor 21 (FGF21) has been described as an anti-obesity and antidiabetic hormone because of its potent effects over glucose and lipid metabolism [1]. Also, recent publications suggest that FGF21 effects on the liver lead to a reduction in liver fat content and decrease fibrosis and inflammation [2,3]. For these reasons, FGF21 is considered as a candidate to treat obesity-related metabolic disorders.
Some of our previous results show that mice fed with a low protein diet (5% of protein intake) for seven days increased Fgf21 expression in the liver. Protein restriction mediated by hepatic FGF21 promoted weight loss and induced browning in subcutaneous white adipose tissue (scWAT) by an increase of uncoupling protein 1 (UCP1) expression [4].
The global aim of this project is to understand the role of hepatic FGF21 in the maintenance of metabolic homeostasis during high metabolic stress. This project's specific objectives are: 1) To study the effects of hepatic FGF21 on lipid homeostasis due to excessive acute fat storage caused by tunicamycin. 2) To analyze the effects of protein restriction on protecting against and counteracting the effects of a high lipid intake. 3) To understand the role of FGF21 in the metabolic response to fasting.
6 week-old male C57BL/6J mice were randomly divided into: 1.- a HFD group or a high-fat low- protein diet HFD-LP group for 10 weeks; 2.- 17h fasting or ad libitum feeding with chow diet; 3.- Injected with Tunicamycin, drug that induce ER stress and TG storage in the liver, or with a control. Body weight and food intake were recorded twice a week. All diets were formulated and produced by ResearchDiets and were designed to be isocaloric by equally varying protein and carbohydrate content while keeping fat constant. Glucose sensitivity was evaluated during the nutritional
intervention and the metabolic profile was analyzed after the sacrifice. Gene expression analysis of the main genes involved in lipid and glucose homeostasis were studied.
Protein restriction in obese mice counteract the effects of diet-induced obesity in part by the effects of hepatic FGF21. It prevents liver weight gain and reduces the expression of genes involved in fatty acid transport and lipid droplet formation in the liver. 17h fasting induces hepatic FGF21, and it contributes to energetic homeostasis maintenance during fasting by activating gluconeogenic genes expression. Hepatic FGF21 is a key factor involved in the metabolic homeostasis during metabolic stress.El consumo excesivo de alimentos ricos en calorías, junto con un estilo de vida sedentario, impulsa la actual pandemia mundial de obesidad. La obesidad es la causa principal de diversos trastornos metabólicos como la diabetes, enfermedades cardiovasculares, cáncer y el hígado graso no alcohólico (NAFLD). El factor de crecimiento de fibroblastos 21 (FGF21) se ha descrito como una hormona antiobesidad y antidiabética debido a sus potentes efectos sobre el metabolismo de la glucosa y los lípidos [1]. Además, publicaciones recientes sugieren que los efectos del FGF21 en el hígado conducen a una reducción del contenido de grasa hepática y disminuyen la fibrosis y la inflamación [2,3]. Por estas razones, FGF21 se considera un candidato para tratar los trastornos metabólicos relacionados con la obesidad. Algunos de nuestros resultados anteriores muestran que los ratones alimentados con una dieta baja en proteínas (5% de la ingesta de proteínas) durante siete días aumentaron la expresión de Fgf21 en el hígado. La restricción de proteínas mediada por el FGF21 hepático promovió la pérdida de peso y el pardeamiento inducido en el tejido adiposo blanco subcutáneo (scWAT) mediante un aumento de la expresión de la proteína desacoplante 1 (UCP1) [4]. El objetivo global de este proyecto es comprender el papel del FGF21 hepático en el mantenimiento de la homeostasis metabólica durante un estrés metabólico elevado. Los objetivos específicos de este proyecto son: 1) Estudiar los efectos del FGF21 hepático sobre la homeostasis lipídica debido al almacenamiento agudo excesivo de grasa provocado por la tunicamicina. 2) Analizar los efectos de la restricción proteica para proteger y contrarrestar los efectos de una ingesta elevada de lípidos. 3) Comprender el papel del FGF21 en la respuesta metabólica al ayuno. Se dividieron aleatoriamente ratones C57BL / 6J macho de 6 semanas de edad en: 1.- un grupo HFD o un grupo HFD-LP de dieta alta en grasas y baja en proteínas durante 10 semanas; 2.- 17h de ayuno o alimentación ad libitum con dieta control; 3.- Injección con Tunicamicina o control. La TM es un fármaco que induce estrés en el RE y almacenamiento de TG en el hígado. El peso corporal y la ingesta de alimentos se registraron dos veces por semana. Todas las dietas fueron formuladas y producidas por ResearchDiets y fueron diseñadas para ser isocalóricas por el contenido de proteínas y carbohidratos igualmente variable mientras se mantiene la grasa constante. Se evaluó la sensibilidad a la glucosa durante la intervención nutricional y se analizó el perfil metabólico después del sacrificio. Se realizó el análisis de la expresión génica de los principales genes implicados en la homeostasis de lípidos y glucosa. En conclusión, la restricción de proteínas en ratones obesos contrarresta los efectos de la obesidad inducida por la dieta en parte por los efectos del FGF21 hepático; previene el aumento de peso del hígado y reduce la expresión de genes implicados en el transporte de ácidos grasos y la formación de gotas de lípidos en el hígado. El ayuno de 17 h induce FGF21 hepático y éste contribuye al mantenimiento de la homeostasis energética durante el ayuno activando la expresión de genes gluconeogénicos. FGF21 hepático es un factor clave involucrado en la homeostasis metabólica durante el estrés metabólico. Bibliografía / Bibliography: 1. Sonoda, J.; Chen, M.Z.; Baruch, A. FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases. Horm. Mol. Biol. Clin. Investig. 2017, 30. 2. Maratos-Flier, E. Fatty liver and FGF21 physiology. Exp. Cell Res. 2017, 360, 2–5. 3. Kim, S.H.; Kim, K.H.; Kim, H.-K.; Kim, M.-J.; Back, S.H.; Konishi, M.; Itoh, N.; Lee, M.- S. Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress. Diabetologia 2015, 58, 809–818. 4. Pérez-Martí, A.; Garcia-Guasch, M.; Tresserra-Rimbau, A.; Carrilho-Do-Rosário, A.; Estruch, R.; Salas-Salvadó, J.; Martínez-González, M.Á.; Lamuela-Raventós, R.; Marrero, P.F.; Haro, D.; et al. A low-protein diet induces body weight loss and browning of subcutaneous white adipose tissue through enhanced expression of hepatic fibroblast growth factor 21 (FGF21). Mol. Nutr. Food Res. 2017, 61, 1–10.
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Delezoide, Anne-Lise. "Analyse pathogenique des malformations humaines dues aux mutations des genes fgfr1, 2 et 3 (doctorat : biologie du developpement)." Paris 5, 1998. http://www.theses.fr/1998PA05N142.
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Couderc, Bettina. "Etude des mecanismes d'action du fgfb (basic fibroblast growth factor) : potentialites oncogeniques." Paris 7, 1992. http://www.theses.fr/1992PA077307.
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L'ensemble des travaux est consacre a l'etude du mecanisme d'action et des potentialites oncogenique et antioncogenique du fibroblast growth factor basique (bfgf) sur des cellules endotheliales primaires (vasculaires bovines abae et fibroblastes de peau humains: fini) et sur des cellules transformees (neuroblastomes humains: k2 skn-be et cellules hela et cos 7). L'approche experimentale a constitue a utiliser des retrovirus vecteurs donnes de mo-mulv contenant l'information codant pour differentes formes de bfgf afin d'etablir differentes lignees cellulaires produisant ce facteur. Nous avons determine dans une 1ere partie que le gene codant pour le fgfb pouvait generer, par traduction alternative, deux formes d'un meme oncogene: une cytoplasmique qui transforme les cellules (fgfb de 18 kda) et une nucleaire qui immortalise les cellules (fgfb de 22,5 et 21 kda). La cooperation des 2 oncogenes donne un caractere tumorigene. La 2eme partie traite des interrelations entre le fgfb endogene et exogene et donc du role des recepteurs. La 3eme partie concerne l'effet de l'expression constitutive des differentes formes de fgfb sur des cellules transformees
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OLIVER-VALLETTE, LISA. "Les fgf1 et 2 : expression et roles possibles dans la dystrophie murine mdx." Paris 6, 1994. http://www.theses.fr/1994PA066748.
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La dystrophie murine, mdx apparait comme un excellent modele d'une part de la dystrophie humaine, dite de duchenne et d'autre part pour analyser les processus de degenerescence-regeneration musculaire. Nous avons concentre nos etudes sur l'expression et le role des fgfs dans cette dystrophie. Nous avons observe une nette augmentation du contenu en fgf1 dans tous les muscles et ce des la 3eme semaine. La localisation analysee par immunocytochimie du fgf1 montre que celui-ci est particulierement concentre dans les zones de necrose, la membrane basale mais egalement dans les noyaux centraux de fibres neoformees. Des cultures de cellules myoblastiques derivant des cellules satellites provenant de muscles normaux ou mdx ont ete realisees. Les fgf1 et 2 ont des effets proliferatifs differents sur ces deux types de cultures. Le role de l'uap (activateur du plasminogene de type urokinase) dans le processus de fusion a ete suggere par plusieurs travaux de la litterature. Nos resultats montrent que le taux basal de l'uap secrete par les cellules satellites mdx en culture est beaucoup plus eleve que celui observe dans le cas des cellules normales. Dans les deux types de cellules, les fgf1 et 2 augmentent fortement l'expression de l'uap. Les roles putatifs des fgfs aussi bien in vivo qu'in vitro sont discutes
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Quesada, López Tania Paloma. "The role of the G-protein coupled receptor 120 (GPR120) on the FGF21 system in white and brown adipose tissues." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/662931.
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Obesity prevalence has tripled in the last fifty years. For this reason, it is considered the pandemic of the century. It is characterized by the accumulation of metabolic abnormalities triggered by an increase in the size of fat depots in the body. Hence, new therapies to pursue an amelioration of metabolic abnormalities and adipose tissue dysfunction caused by this energy imbalance are being explored. The tissue responsible for the storage of fat is adipose tissue and it was considered just as an energy reservoir until recently. Currently, it is known to be actively involved in energy homeostasis at the same time that it fulfills endocrine functions. Adipose tissue is divided into two main types, white adipose tissue (WAT) and brown adipose tissue (BAT). While energy storage is the main role of WAT, BAT is able to dissipate energy in the form of heat leading to an increased energy expenditure. Surprisingly, it has been reported that WAT has the ability to recruit cells of the brown phenotype and thus increase its energy expenditure in a process denominated as browning. BAT activity and WAT browning are important components of energy expenditure and therefore potential therapeutic targets for the treatment of obesity and its comorbidities. In this work, we show that GPR120 activation, a membrane receptor for polyunsaturated fatty acids (PUFAs), promotes BAT thermogenic activity and WAT browning. The tissue that reported the highest levels of GPR120 expression is BAT, followed by colon and WAT different deposits. In addition, it was discovered that thermal stress (cold exposure) causes an induction in the expression of GPR120 in adipose depots. Likewise, the activation of GPR120 induces an increase in oxygen consumption. Conversely, mice deficient of GPR120 show decreased temperature and UCP1 expression in neonatal BAT and decreased browning after cold exposure in adult WAT. The administration of natural or synthetic agonists of GPR120, such as omega-3 PUFAs or GW9508, induced brown and beige adipocyte differentiation as well as their thermogenic activation and glucose oxidation. This activation by n-3 PUFAs was dependent of GPR120 expression. In addition to these findings, it was revealed that the activation of GPR120 induces the expression and release of fibroblast growth factor-21 (FGF21) by BAT and WAT at the same time that it increases plasma FGF21 levels. FGF21 is a hormonal factor able to induce thermogenic activation of BAT and browning of WAT, both associated with an improvement in metabolic conditions. In the absence of GPR120, the levels of FGF21 under cold stress conditions are decreased. Furthermore, n-3 PUFAs and synthetic agonists do not induce the expression and release of FGF21 in animals and cells deficient of GPR120. Regarding the effects on the activation of BAT, browning of WAT and the increase in glucose oxidation by the activation of GPR120, these are all compromised in mice or adipocytes lacking FGF21. Therefore, it is concluded that GPR120 activation induces BAT thermogenic activity and WAT browning through a mechanism that involves the induction of FGF21.La obesidad es pandemia del siglo XXI y se caracteriza por desencadenar anomalías metabólicas debido al exceso de grasa almacenada en el organismo. Ello urge la exploración de nuevas terapias para su tratamiento. El tejido adiposo (TA) ha pasado de considerarse solo un depósito de energía a ser relacionado con el mantenimiento de la homeostasis energética. Se divide en dos tipos, tejido adiposo blanco (TAB) y tejido adiposo marrón (TAM). El primero sirve como almacén de energía y el segundo produce calor debido al desacoplamiento de la cadena respiratoria resultando en un gasto energético incrementado. El TAB tiene la capacidad de reclutar células del fenotipo marrón en un proceso denominado pardeamiento. La actividad del TAM y el pardeamiento del TAB son componentes importantes del gasto energético y blancos terapéuticos para el tratamiento de la obesidad. GPR120 es un receptor de membrana para ácidos grasos poliinsaturados (PUFAs) que demostró promover la activación del TAM y el pardeamiento del TAB. El TAM es el tejido que expresa GPR120 principalmente y el estrés térmico causa una inducción en la expresión de GPR120 en los depósitos adiposos. Conjuntamente, la activación de GPR120 induce la actividad termogénica del TAM y pardeamiento del TAB. Inversamente, los ratones deficientes de GPR120 muestran una activación de la termogénesis disminuida tras la exposición al frío. Además, la activación de GPR120 ha mostrado inducir la diferenciación de adipocitos marrón y beige así como su activación termogénica. Dicha activación conlleva a la inducción en la expresión y liberación del factor de crecimiento fibroblástico-21 (FGF21) por el TA así como un aumento en los niveles en sangre. FGF21 es un factor hormonal capaz de inducir la termogénesis en el TA y de mejorar las condiciones metabólicas. Los animales deficientes de GPR120 muestran niveles de FGF21 disminuidos tras la exposición a frío mientras que la falta de FGF21 comprometió la inducción de la termogénesis tras la activación de GPR120 en ratones y adipocitos. Se concluyó que la activación de GPR120 induce la actividad termogénica de la grasa marrón y el pardeamiento de la grasa blanca a través de la inducción de FGF21.
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Sassatelli, Mathieu. "Synthèse de composés possédant un motif de type oxindole, inhibiteurs potentiels du récepteur de facteur de croissance de fibroblastes (FGFR1)." Phd thesis, Université Blaise Pascal - Clermont-Ferrand II, 2005. http://tel.archives-ouvertes.fr/tel-00683658.
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Les facteurs de croissance et leurs récepteurs sont surexprimés dans un grand nombre de cancers et ont un rôle très important dans la prolifération cellulaire. Nous nous sommes intéressés aux inhibiteurs compétitifs de l'ATP du domaine tyrosine kinase des récepteurs de facteurs de croissance, plus particuliérement du FGFR1, l'un des quatre récepteurs à activité tyrosine kinase des facteurs de croissance de fibroblastes. Les interactions FGF/FGFR sont impliquées dans le développement tumoral et dans la stimulation de l'angiogénèse. Ce récepteur constitue donc une cible privilégiée pour le développement de nouveaux agents anticancéreux. Dans la première partie bibliographique, les différents facteurs de croissance et leurs récepteurs, ainsi que le rôle de leurs interactions spécifiques dans le cycle cellulaire sont décrits. Les principales familles d'inhibiteurs des récepteurs de facteurs de croissance sont ensuite détaillées. Afin de concevoir un nouveau modèle d'inhiteurs de l'activité tyrosine kinase de ces récepteurs, principalement du FGFR1, nous nous sommes orientés vers trois familles de composés. La synthèse de ces composés est présentée dans la deuxième partie. La troisième partie, présente une étude de docking (fixation du ligand dans le site de fixation de l'ATP de l'enzyme cible) et de minimisation d'énergie par mécanisme moléculaire des complexes de certains des composés synthétisés dans le site de fixation de l'ATP du FGFR1. Cette étude a été mise en oeuvre afin de voir si ces molécules pouvaient présenter une bonne affinité pour ce site. Les activités antiprolifératives sur différentes lignées cellulaires des nouveaux produits préparés au cours de ce travail ont été déterminées, ainsi que l'activité inhibitrice de certains produits sur diverses kinases. Ces résultats sont présentés dans la quatrième partie
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Ozretić, Luka [Verfasser], Reinhard [Akademischer Betreuer] Büttner, and Catherina-Annika [Akademischer Betreuer] Niemann. "FGFR1-Amplifikation und Ko-Überexpression von c-MYC in oropharyngealen Plattenepithelkarzinomen / Luka Ozretić ; Akademische Betreuer: Reinhard Büttner, Catherina-Annika Niemann." Köln : Deutsche Zentralbibliothek für Medizin, 2019. http://d-nb.info/1177041391/34.
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Ozretić, Luka Verfasser], Reinhard [Akademischer Betreuer] [Büttner, and Catherina-Annika [Akademischer Betreuer] Niemann. "FGFR1-Amplifikation und Ko-Überexpression von c-MYC in oropharyngealen Plattenepithelkarzinomen / Luka Ozretić ; Akademische Betreuer: Reinhard Büttner, Catherina-Annika Niemann." Köln : Deutsche Zentralbibliothek für Medizin, 2019. http://d-nb.info/1177041391/34.
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Kröger, Jule [Verfasser], and Guido [Akademischer Betreuer] Sauter. "FGFR1 Amplifikationen weisen eine häufig homogene Verteilung beim Ösophaguskarzinom auf und sind assoziiert mit Plattenepithelkarzinomen / Jule Kröger ; Betreuer: Guido Sauter." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2017. http://d-nb.info/1140835254/34.
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Johnson, Sally Elaine. "Proliferating cell nuclear antigen (PCNA) and fibroblast growth factor receptor one (FGFR1) expression as indicators of rat satellite cell activation." Diss., The University of Arizona, 1993. http://hdl.handle.net/10150/186146.
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Rat satellite cells from young animals become activated and commence division sooner in culture than satellite cells from adult animals. Differences in the length of this lag period may be attributed to differences in expression of cell surface receptors, signal transduction or DNA replication capacity. To examine this period, an ELISA was developed to monitor proliferating cell nuclear antigen (PCNA) expression. Results indicated that PCNA is expressed earlier in cultures from young rats than in cultures from adult rats with an increase in PCNA levels occurring at 30 and 48 hours, respectively. Addition of basic fibroblast growth factor (bFGF), a mitogen for satellite cells, at the time of plating enhanced PCNA expression in young but not adult rat satellite cells. These results suggest that the adult cells may not express FGF receptors (FGFR) or that the receptor fails to generate a signal. Analysis of FGFR expression indicated that FGF receptors were present in satellite cells from young rats at 18 hours post-plating and in cells from adult rats at 42 hours post-plating. Western analysis demonstrated that the receptor present was the full length FGF receptor one (FGFR1). FGFR1 mediated the tyrosine phosphorylation of proteins with molecular weights of 150, 145, 90, 42 and 35 kDa upon addition of bFGF. The presence of a functional FGFR1 prior to PCNA expression suggests that the expression of FGFR1 can be used as a marker for entry of satellite cells into G₁ phase of the cell cycle. The ability of the cells from the young animals to become active sooner than their adult counterparts may be due to the length of time the adult cells have been quiescent. Depth of quiescence may be an important determinant in activation of satellite cells.
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Loyd, Christine M. "Hormonal Responses that Regulate the Metabolic Benefits of Exercise: The Contribution of the Melanocortin System and the Fibroblast Growth Factor 21 (FGF21) Signaling Pathway." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1421331671.
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Patry, Véronique. "Structure, localisation et fonctions des différentes formes du facteur de croissance fibroblastique basique (FGFb)." Toulouse 3, 1994. http://www.theses.fr/1994TOU30059.
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Le facteur de croissance fibroblastique basique (fgfb) est le prototype d'une famille de proteines de structures apparentees qui module les fonctions cellulaires telles que la proliferation, la differenciation et l'angiogenese. Il existe quatre formes du fgfb qui resultent de l'utilisation alternative de quatre codons d'initiation de la traduction: trois cug initiant des proteines de 210, 201 et 196 acides amines et un aug initiant une proteine de 155 acides amines (a. A. ). Des lignees permanentes de cellules d'ovaire de hamster chinois (cho) exprimant le bfgf de 210 ou de 155 a. A. Ont ete etablies. Par spectrometrie de masse en ionisation par electrospray, une modification post-traductionnelle sur la partie nh#2-terminale du fgfb de 210 a. A. A ete mise en evidence alors qu'aucune modification n'a ete detectee sur le bfgf de 155 a. A. Une analyse par la technique de fragmentation par irradiation a montre que le bfgf de 210 a. A. , localise dans le noyau, fait partie d'un complexe multiproteique d'environ 300 kda alors que le bfgf de 155 a. A. Cytoplasmique, est inclus dans un complexe proche de 100 kda. L'etude de la migration des cellules cho sauvages ou transfectees par le bfgf de 210 ou 155 a. A. A montre que seule la forme de 155 a. A. Stimule la migration. Toutes les formes de bfgf exogenes sont internalisees dans les cellules endotheliales, presentent un profil de degradation similaire et une activite mitogene identique. Une partie du bfgf internalise est transloque dans le noyau: le bfgf de 210 a. A. S'y accumule en quantite deux fois plus importante que la forme de 155 a. A. La substitution de la partie nh#2-terminale du bfgf de 210 a. A. (comprenant une nls) par le peptide de localisation nucleaire de l'antigene t de sv40, a montre que cette accumulation nucleaire ne faisait pas intervenir la nls, mais plutot un processus de retention dans le noyau par des sequences specifiques du bfgf de 210 a. A. De plus l'effet stimulateur des bfgf sur l'activateur du plasminogene est correle positivement avec l'accumulation nucleaire. Ainsi, a une structure, une localisation et une participation a un complexe multiproteique correspondent une fonction differente dans la cellule selon l'isoforme du fgfb
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Palcy, Sandrine. "Étude de l'implication des facteurs de croissance FGF1 et FGF2 dans les pathologies tumorales." Paris 12, 1994. http://www.theses.fr/1994PA120002.
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Les facteurs de croissance sont des polypeptides qui stimulent la proliferation cellulaire par l'intermediaire de recepteurs membranaires specifiques. Ces molecules sont l'objet de nombreuses etudes en cancerologie du fait de leur etroite relation avec les produits d'expression d'oncogenes. Le fgf1 et le fgf2 sont des facteurs multi-fonctionnels pouvant etre impliques dans la carcinogenese, aussi bien comme des facteurs angiogeniques que comme des facteurs capables d'assurer l'autonomie de la proliferation cellulaire. A travers l'etude de deux modeles tumoraux distincts, nous avons tente d'etablir une correlation entre l'etat neoplasique et la modification de l'expression tissulaire du fgf1 et du fgf2 ainsi que de leurs recepteurs membranaires specifiques. Dans le carcinome invasif de la vessie chez l'homme en comparaison avec la vessie humaine normale, nous avons observe des variations de la concentration tissulaire du fgf1 et du fgf2 ainsi que du nombre de sites recepteurs membranaires specifiques du fgf2. Ces observations suggerent l'hypothese d'un desequilibre dans le bilan des activites biologiques du fgf1 et fgf2 au sein du tissu vesical tumoral. La localisation specifique du fgf1 dans les cellules urotheliales tumorales semble indiquer que ce facteur joue un role preponderant dans les processus de transformation de l'urothelium. Dans le modele du chondrosarcome greffable chez le rat, nous avons ete dans l'impossibilite de detecter l'expression des arnms du fgf1 et du fgf2 ou la presence des proteines associees. La croissance du chondrosarcome chez le rat, au stade ou nous l'avons etudie, semble etre independante du niveau d'expression du fgf1 et du fgf2. L'etude de l'implication des fgf dans les pathologies tumorales est importante pour la comprehension de leurs mecanismes d'action. Malgre les multiples avantages des modeles in vivo, la complexite des interactions cellulaires existant au sein d'un tissu rend leur exploitation extremment delicate
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Mikołajka, Aleksandra. "Functional and structural studies of the FGFR1 oncogene partner protein and biochemical investigations of the retinoblastoma protein and its binding partners." [S.l.] : [s.n.], 2007. http://mediatum2.ub.tum.de/doc/614708/document.pdf.
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Murcia, Belmonte Verónica. "Análisis molecular de la interacción anosmina-1/FGFR1 y efectos de la sobreexpresión de anosmina-1 en el sistema nervioso central." Doctoral thesis, Universidad de Alicante, 2013. http://hdl.handle.net/10045/28039.
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Bouleau, Perez-Oyarzun Sylvina. "Etude de l'activité protectrice du FGF1 intracellulaire vis-à-vis de l'apoptose induite par p53." Versailles-St Quentin en Yvelines, 2006. http://www.theses.fr/2006VERS0015.
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La protéine oncosuppressive p53 et les facteurs de croissance tel que le FGF1 ont un rôle fondamental à l'interface entre cycle cellulaire, apoptose et survie. L'étude des relations entre ces deux protéines dans des fibroblastes embryonnaires et des cellules de type neuronal nous a permis de montrer que la protéine FGF1 inhibe l’activité pro-apoptotique de p53 par un mode d’action intracrine. La protéine FGF1 empêche la stabilisation et l’activation fonctionnelle de la protéine p53. Ainsi, l’action protectrice de FGF1 peut s’expliquer par sa capacité à inhiber l’activité transactivatrice de p53 vis-à-vis de gènes tels que bax (fibroblastes) et puma (neurones) qui codent pour des protéines pro-apoptotiques de la famille BCL-2, initiatrices de la voie mitochondriale de l’apoptoseThe p53 oncosuppresive protein and the growth factors, like FGF1, are essential to control the cell cycle and apoptosis. Study of the relationship between these two proteins, in embryo fibroblasts and sympathetic like neurons, had shown that FGF1 protein can inhibit the pro-apoptotic activity of p53 by an intracrine pathway. FGF1 factor inhibits p53 stability and its transcriptional activity, notably on bax (fibroblasts) and puma (neurons) genes. PUMA and NOXA are BH3-only pro-apoptotic proteins of the BCL-2 family that induce the mitochondrial pathway of apoptosis
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山内, 肇. "ゼブラフィッシュFgf21の造血因子としての役割とその作用メカニズムの解明." 京都大学 (Kyoto University), 2008. http://hdl.handle.net/2433/137160.
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Kurimchak, Alison. "The B55α/PP2A Holoenzyme in Cell Cycle Exit, Maturation/Differentiation, and Cancer." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/288430.
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Molecular Biology and GeneticsPh.D.
The cell cycle is negatively regulated by members of the pocket protein family, which consists of the tumor suppressor pRB and two closely related paralogs, p107 and p130. In their hypophosphorylated state, they are associated with E2F transcription factors which result in the repression of transcription of E2F-dependent genes that are required for cell cycle progression. The phosphorylation state of pocket proteins during the cell cycle is determined at least in part by an equilibrium between inducible CDKs and the serine/threonine protein phosphatase PP2A. Protein Phosphatase 2A (PP2A), is a serine/threonine phosphatase that functions as as a collection of trimeric holoenzymes. The trimeric PP2A holoenzyme is composed of the "A" scaffolding subunit, the "C" catalytic subunit, and a "B" regulatory subunit. The B subunit is the major determinant in substrate specificity and subcellular localization. Two holoenzymes consisting of the core PP2A dimer and either the B55α or PR70 regulatory subunits have been implicated in the activation of p107/p130 and pRB, respectively. While the phosphorylation state of p107 is very sensitive to forced changes of B55α levels in human cell lines, regulation of p107 in response to physiological modulation of PP2A/B55α has not been previously elucidated. In this thesis, I show that FGF1, which induces maturation and cell cycle exit in chondrocytes, triggers rapid accumulation of p107/PP2A/B55α complexes coinciding with p107 dephosphorylation without an increase in B55α protein expression in RCS cells. Reciprocal solution-based mass-spectrometry analysis identified the PP2A/B55α complex as a major component of a subset of p107 complexes, which also contain E2F/DPs, DREAM subunits and cyclin/CDK complexes. p107 is one of the major partners of B55α, which also associates with pRB in RCS cells. FGF1 induces dephosphorylation of p107, its translocation to the nucleus, remodeling of p107 complexes, and enhances its interaction with E2F4 and other p107 partners. Consistent with an essential role of B55α in the rapid activation of p107 in chondrocytes, limited ectopic expression of B55α results in marked dephosphorylation of p107, while B55α knockdown results in hyperphosphorylation. More importantly, limited knockdown of B55α dramatically delays FGF1 induced dephosphorylation of p107. Moreover, dephosphorylation of p107 in response to FGF1 treatment results in selective recruitment of p107 to regulated genes including CMYC. Our results suggest a model where FGF1 mediates rapid dephosphorylation and activation of p107 independently of the CDK activities that maintain p130 and pRB hyperphosphorylated for several hours post p107 dephosphorylation in maturing chondrocytes. Additionally, we provide preliminary evidence that PPP2R2A may act as a haploinsufficient tumor suppressor in prostate cancer cell lines. PPP2R2A is hemizygously deleted in various prostate cancer cell lines and tumor samples. We identified three cell lines that express less B55α the gene product of PPP2R2A, than cell lines that are reported to have both alleles intact. Furthermore, ectopic expression of B55α in PC3 cells results in a phenotype reminiscent of senescence, ultimately leading to cell death. These cells are unable to form colonies in soft agar and have increased DNA content and euploidy. Combined with their larger cell and nuclear size, this suggests that ectopic expression of B55α in PC3 cells results in endoreplication. Altogether these suggest that reduced B55α expression in these cells confers a growth advantage in PCa cell lines, which is extinguished when B55α is reintroduced, supporting the notion that hemizygous deletion of PPP2R2A in prostate tumors may help promote tumorigenesis.
Temple University--Theses
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Rodriguez-Enfedaque, Aida. "Régulation de l'apoptose mitochondriale par le facteur de survie FGF1 et l'inhibiteur de caspases zVAD-fmk." Versailles-St Quentin en Yvelines, 2009. http://www.theses.fr/2009VERS0038.
Full textAbstract:
L’apoptose est un processus physiologique de mort cellulaire essentiel à la survie des organismes pluricellulaires. L’objectif de ce travail a été d’étudier les effets de deux molécules : le facteur de survie FGF1 et l’inhibiteur des caspases zVAD-fmk sur l’apoptose dépendante de p53, un oncosuppresseur, régulateur clé de l’apoptose. Dans un premier temps, nous nous sommes intéressés à l’effet du FGF1 sur l’apoptose dépendante de p53 dans un modèle de cellules neuronales : les cellules PC12. Les résultats obtenus lors de ma thèse montrent que : (1) les FGF1 exogène et endogène (intracellulaire et nucléaire) inhibent l’apoptose dans les cellules PC12 en diminuant la phosphorylation et la stabilisation de p53, (2) la protéine FGF1 inhibe l’activité transcriptionnelle de p53 vis-à-vis de ses gènes cibles pro-apoptotiques puma et noxa, (3) le FGF1 inhibe l’activation de la caspase-3, effecteur de l’apoptose (4) pour la majorité des activités du FGF1 endogène, la présence de sa séquence de nucléarisation est déterminante. Dans un second temps, nous avons étudié l’effet de l’inhibiteur de caspases zVAD-fmk sur la voie mitochondriale de l’apoptose dans des fibroblastes embryonnaires de rongeurs. Les résultats obtenus montrent que : (1) le zVAD-fmk accélère l’apoptose dépendante de p53 et du TNF dans ces cellules, (2) les protéines Bax et Bak et la dépolarisation des membranes mitochondriales sont nécessaires pour cette accélération, (3) le zVAD-fmk inhibe classiquement les caspases executrices-3/7 et (4) de façon surprenante, le zVAD-fmk induit une augmentation du clivage et de l’activité de la caspase-9 et ne semble pas inhiber la caspase-8Apoptosis is a physiological cell death in multicellular organisms that is required for embryogenesis, metamorphosis, homeostasis and elimination of cells that are potentially detrimental to organism. Deregulations of apoptosis have been implicated in many pathologies. The main aim of this work is the study of the Fibroblasts Growth Factor I (FGFI) and the caspase inhibitor zVAD-fmk effects in p53-dependent apoptosis. First, we study the effect of FGF1 in p53-dependent apoptosis. As both factors have been involved in neuronal apoptosis, we realized our study in PC12 cells, a neuronal cellular model. Our results show that: (1) exogenous and endogenous (intracellular and nuclear) FGF1 inhibit p53 phosphorylation and stabilization and thus p53-dependent apoptosis, (2) FGF1 inhibits puma and noxa trans-activation induced by p53, (3) FGF1 inhibits caspases-3 cleavage and (4) the nuclear localization of endogenous FGF1 is required for its anti-apoptotic activities. Second, we study the effect of pancaspase inhibitor zVAD-fmk in mitochondrial apoptosis in rodent embryonic fibroblasts. Our results show that: (1) zVAD-fmk increases p53- and TNF-dependent apoptosis, (2) this acceleration of apoptosis by zVAD-fmk involved mitochondrial events (3) Bax and/or Bak are required for p53- and TNF-dependent apoptosis and for zVAD-fmk induced apoptosis acceleration, (4) zVAD-fmk inhibits caspases-3/7 activity and (5) surprisingly, zVAD-fmk increases caspases-9 cleavage and activity and does not seems to inhibit caspases-8