Dissertations / Theses on the topic 'Signalisation de la ghréline'
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Mousseaux, Delphine. "Etude pharmacologique de ligands de synthèse du récepteur des sécrétagogues de l'hormone de croissance (GHSR-1a) et voies de signalisation." Montpellier 1, 2005. http://www.theses.fr/2005MON13518.
Full textGhrelin is a predominantly gastric peptide hormone. It was first identified as a endogenous growth hormone secretagogue which binds to the GHS receptor type 1 a (GHSR-la). Apart from stimulating the secretion of growth hormone, ghrelin also stimulates appetite and causes weight gain. The work in this thesis firstly involved the in vitro study of new ligands for the GHSR-1a and secondly the study of the downstream signalling pathway through which the active GHSR-1a elicits its biological responses. This work has resulted in the discovery of a new series of ligands, which not only display high affinity for the GHSR-1a, but are equally active when tested in vivo in experiments using the rat. A patent application based on this series of ligands is currently under development. The work investigating the downstream signaling pathway of the active GHSR-la, suggests that Phospolipase C, Protein Kinase C (Epsilon) and ERK1/2 are involved. In addition, it appears that GHSR-1a signalling could play a role in the regulation of nuclear transcription factors
Qu, Mengdi. "Molecular mechanism underlying CaMK1D-dependent function in AgRP neurons." Electronic Thesis or Diss., Strasbourg, 2024. http://www.theses.fr/2024STRAJ029.
Full textDisruption of stress response mechanisms in organisms can lead to cellular dysfunction and diseases like metabolic syndrome. Energy balance is mainly regulated by the central nervous system (CNS), which integrates hormonal, neuronal, and dietary signals from various tissues. Dysfunction in this system is linked to obesity and metabolic syndrome, both precursors to type 2 diabetes (T2D). Our laboratory discovered that calcium/calmodulin-dependent protein kinase ID (CaMK1D), a gene associated with T2D, promotes ghrelin-mediated food intake in mice. However, CaMK1D signaling in NPY/AgRP neurons still remains questions. In this work, we proformed RNA sequencing using the GT1-7 hypothalamic cell line. To this end, we found that CalHM6 is a downstream target of CaMK1D signaling. CalHM6 mRNA levels were significantly upregulated in CaMK1D-/- cells and downregulated when CaMK1D was re-expressed. This was confirmed in vivo in the hypothalamus of CaMK1D-/- mice. CalHM6, likely a voltage-gated calcium channel, showed increased intracellular Ca2+ levels in response to ghrelin in CaMK1D-/- cells compared to CaMK1D+/+ cells using jGCamps method. Altogether, our work showed CalHM6 is a novel target of CaMK1D. High CaMK1D, leading to low CalHM6 expression, may enhance food intake and obesity by modulating calcium-dependent signaling in NPY/AgRP neuron
Marion, Candice. "Novel insights on ghrelin receptor signaling in energy homeostasis and feeding behavior using the GhsrQ343X mutant rat model." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB109.
Full textThe stomach-derived hormone acyl ghrelin promotes body weight gain, mostly in the form of fat mass, by means of several central and peripheral mechanisms mediated by the growth hormone secretagogue receptor (GHSR). The GHSR is a G protein-coupled receptor that, in addition to respond to acyl ghrelin, displays agonist-independent signaling through high constitutive activity and possibly heteromerization with dopamine receptors. Despite the potent biological properties of exogenous acyl ghrelin, the lack of animal models able to apprehend the complexity of the acyl ghrelin-GHSR system in vivo has been hampering the elucidation of its physiological roles. Indeed, genetic mouse models generated so far lack specificity either at the level of the hormone (not able to discriminate between acyl ghrelin versus desacyl ghrelin) and/or at the level of the GHSR (not able to discriminate between GHSR signaling modes). In this context, new models differentially affecting GHSR signaling pathways would represent valuable tools to decipher the acyl ghrelin-GHSR system in vivo. We therefore aimed at characterizing a new rat model carrying a point mutation in Ghsr that predicts truncation of a regulatory domain in the C-terminus, the GhsrQ343X mutation. In cellular models, this mutation was found to uncouple the GHSR from agonist-dependent receptor internalization and β-arrestin recruitment, while enhancing GHSR responsiveness in the G protein pathway. Accordingly, homozygous mutant GhsrM/M rats show enhanced responsiveness to exogenous GHSR agonists in terms of growth hormone release, food intake and locomotor activity. Physiological and behavioral exploration of GhsrM/M rats supports that the GhsrQ343X mutation is associated with increased body weight gain and adiposity independently of calorie intake, reduced whole-body fat oxidation, metabolic flexibility and glucose tolerance, without any critical impact on homeostatic feeding behavior. Moreover, given that circulating ghrelin levels are not increased by the GhsrQ343X mutation, the overall metabolic phenotype of GhsrM/M rats is consistent with enhanced GHSR sensitivity to the endogenous tone of acyl ghrelin. Furthermore, preliminary results suggest that the GhsrQ343X mutation could be associated with behavioral alterations related to reward and memory functions, through mechanisms that remain to be elucidated. Altogether, we propose the GhsrQ343X mutant rat model as a novel tool, more specific than knockout mouse models in its mechanism-of-action, to explore GHSR signaling across biological functions in vivo, and ultimately help in the design of efficient GHSR-targeting drugs
Lavoie, Stéphanie. "Les effets d'UCP2 dans l'homéostasie énergétique : modulation de la ghréline." Thesis, Université Laval, 2012. http://www.theses.ulaval.ca/2012/28642/28642.pdf.
Full textMaingot, Mathieu. "Conception et synthèse de ligands peptidomimétiques du récepteur de la ghréline." Thesis, Montpellier, 2015. http://www.theses.fr/2015MONTS110.
Full textGhrelin is a hormone of 28 amino acids, mostly synthesized in the stomach. Firstly identified as a growth hormone secretagogue, this peptide is also involved in food intake, blood glucose and in some processes related to addiction. Ghrelin effects are mediated by a G protein-coupled receptor: GHS-R1a (Growth Hormone Secretagogue Receptor). This receptor has a high constitutive activity and a complex intra-cellular signaling network via the activation of β-arrestin and different isoforms of G protein (Gq, Gi / o, G12 / 13). Given these multiple effects, ligands of GHS-R1a have a therapeutic interest.This thesis is devoted to the development of antagonists and inverse agonists of hGHS-R1a whose structure is based on the 3,4,5-trisubstituted 1,2,4-triazole scaffold. Thanks to a successive study of the various substituents of the peptidomimetic platform we identified antagonists with nanomolar affinity and inverse agonists with a significant efficiency. These compounds appear to be attractive candidates for in vivo studies on food intake or addiction models. On the other hand, a sophisticated pharmacological study, conducted on our compounds, has demonstrated that it is possible to obtain biased ligands based on the triazole motif. These results provide new informations about the functional selectivity of GHS-R1a. Thus, these data, combined with additional in vivo studies, could be useful for the design of new drugs with limited side effects
Lemarie, Fanny. "Impact de l'acide octanoïque alimentaire sur l'octanoylation de la Ghréline, chez le rat." Thesis, Rennes, Agrocampus Ouest, 2016. http://www.theses.fr/2016NSARI075/document.
Full textMedium chain fatty acids (MCFA) have been described as potentially beneficial for regulating human energetic balance. However, the recent discovery of the orexigenic ghrelin activation by octanoic acid revealed a new level of complexity in MCFA effects. Ghrelin must be octanoylated by the Ghrelin O-Acyltransferase (GOAT) to bind its pituitary receptor. Interestingly, the effects mediated by the post-translationally modified ghrelin seem opposed to MCFA known effects, increasing food intake and body weight. Development of GOAT inhibitors could then constitute a therapeutic strategy against obesity. MCFA are mainly provided by the diet, as their endogenous synthesis has only been described in lactating mammary glands. Dietary caprylic acid is then suspected to provide the GOAT enzyme with octanoyl- CoA co-substrates necessaryfor the acyl modification of ghrelin. My objective is to understand the discrepancy between the formerly described beneficial effects of dietary MCFAs on body weight loss and the C8:0 newly reported effect on appetite stimulation via ghrelin octanoylation. This thesis is divided into four parts: (1) Study of C8:0 physiological effects on ghrelin-GOAT axis, in rat, (2) Study of C8:0 gastric absorption by inhibition of preduodenal lipase, in young rat, (3) Study of C8:0 metabolism in gastric cells in vitro, (4) Preliminary study of GOAT activity in vitro
De, Vriese Carine. "Etude de l'expression, de la production et de la dégradation de la ghréline." Doctoral thesis, Universite Libre de Bruxelles, 2006. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210754.
Full textLa première partie de mon travail de thèse consistait en l’étude de la dégradation de la ghréline. La ghréline circule dans le sang principalement sous forme de des-acyl ghréline, une forme de ghréline dépourvue du groupement octanoyl qui ne se lie pas au GHS-R 1a. Peu d’études ont été réalisées sur le catabolisme de la ghréline. Les enzymes impliquées dans la dégradation de la ghréline étant des régulateurs importants de son activité biologique, le but de cette étude était d’identifier les sites de clivage et les enzymes impliquées dans la dégradation de la ghréline par du sérum, des sous-fractions plasmatiques et des homogénats de tissus. Nous avons montré qu’au contact de sérum humain et de rat, la ghréline est désoctanoylée, sans protéolyse. Dans le sérum humain, nous avons montré que la butyrylcholinestérase et la « platelet-activating factor acetylhydrolase » (PAF-AH), une phospholipase associée aux lipoprotéines de basse densité (LDL), sont impliquées dans ce phénomène (articles n°1 et n°2). En parallèle, nous avons montré que la ghréline peut être transportée dans la circulation sanguine par les lipoprotéines riches en triglycérides (TRL), les LDL, et les lipoprotéines de haute et de très haute densité (HDL et VHDL) (article n°2). Dans le sérum de rat, la désoctanoylation de la ghréline implique une carboxylestérase (article n°1). Au contact d’homogénats de tissus, la ghréline est dégradée à la fois par désoctanoylation et protéolyse N-terminale, suggérant la participation d’estérases et d’aminopeptidases. Nous avons identifié cinq sites de clivage dans la ghréline :entre les résidus Ser2-(acyl)Ser3 (dans l’estomac et le foie), (acyl ?)Ser3-Phe4 (dans l’estomac, le foie et le rein), Phe4-Leu5 (dans l’estomac et le rein), Leu5-Ser6 et Pro7-Glu8 (dans le rein) (article n°1).
La deuxième partie de mon travail de thèse consistait à étudier l’expression et la production de ghréline par différentes lignées leucémiques (HEL, HL-60, THP-1, SupT1), par des leucocytes poly- et mononucléés et par des plaquettes sanguines, et à étudier l’effet de la ghréline sur la prolifération cellulaire. Pour cela, nous avons mis au point des dosages radioimmunologiques (RIA) permettant de quantifier et de distinguer les formes octanoylées et non octanoylées de la ghréline, et nous avons caractérisé en détail les anticorps SB801 et SB969 obtenus. Par HPLC en phase inverse suivie des RIAs, nous avons mis en évidence la présence de ghrélines octanoylée et non octanoylée dans chaque population de cellules. Plus de 80 % de la ghréline produite est octanoylée dans les cellules HEL, les leucocytes et les plaquettes. Nous avons montré que la ghréline endogène stimule la prolifération des cellules HEL de façon autocrine impliquant un récepteur encore non identifié, distinct du GHS-R 1a (article n°3). La ghréline et la des-acyl ghréline inhibent la prolifération des leucocytes mononucléés mais sont dépourvues d’effet sur les cellules HL-60, THP-1 et SupT1. Malgré la présence du GHS-R 1a dans les leucocytes mononucléés, cet effet pourrait être médié par un récepteur différent puisque la des-acyl ghréline exerce le même effet que la ghréline sur la prolifération (article n°4).
Doctorat en sciences pharmaceutiques
info:eu-repo/semantics/nonPublished
François, Marie. "Étude de l'expression de la préproghréline et de la production d'autoanticorps dirigés contre la ghréline en relation au stress et à l'anxiété dans les modèles animaux d'anorexie et d'obésité et chez l'homme." Rouen, 2015. http://www.theses.fr/2015ROUENR03.
Full textLaprise, Patrick. "Signalisation et anoïkose musculaire." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0008/MQ56926.pdf.
Full textNapolitano, Tiziana. "Confidentiel." Thesis, Université Côte d'Azur (ComUE), 2017. http://www.theses.fr/2017AZUR4141.
Full textBrial, François. "Rôle du facteur de transcription HNF1α dans la promotion du diabète par l’intermédiaire d’hormones intestinales." Thèse, Université de Sherbrooke, 2014. http://hdl.handle.net/11143/9758.
Full textGourcerol, Guillaume. "Modulation peptidergique au cours de la stimulation électrique gastrique." Rouen, 2007. http://www.theses.fr/2007ROUES034.
Full textGastric electrical stimulation is a new therapy to relief symptoms of gastroparetic patients without affecting gastric emptying. In the present work, we first evidence that clinical improvement during this therapy was unrelated to gastric emptying. We next demonstrated in rats that gastric electrical stimulation could modulate hypothalamic corticotropin-releasing factor producing neurons, the later being vagal-independent. Then, this technique is likely to modulate central nervous system either by recruiting spinal afferent or though the release of gastric peptides in the bloodstream. Among them, ghrelin and urocortins are susceptible to explain such effect since they display significant effects on gastric motility and food intake. On the other hand, obestatin, encoded by the ghrelin gene, ihas no effect on feeding and digestive and does not represent a good candidate
Mear, Yves. "Implication de l'activité constitutive du récepteur de la ghréline dans la tumorigenèse des adénomes somatotropes." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM5102.
Full textPituitary tumors are most usual intracranial tumors. The somatotroph adenomas are characterised by a GH hypersecretion. The current treatments are based on somatostatinergic agonists. Unfortunately, there is steel 50% of patients, which remain insensitive to these treatments. The aim of our work was to find a pharmacological alternative to treat the patients resistant to the current therapies. Ghrelin stimulate pituitary GH release in vivo through GHS-R1a activation. Interestingly, this receptor transduces signal through an unusual high constitutive activity. Noteworthy, human somatotroph adenomas expressed a high level of GHS-R1a at both mRNA and protein level. We actually assess the implication of this constitutive activity in the tumorigenesis of the somatotroph adenomas. Firstly we demonstrated GHS-R1a functionality through its capacity to fixe endogenous ligand. Then we showed that treatment of human somatotroph adenomas primary cultures, with the GHS-R1a inverse agonist (MSP: Modified Substance P), induced a dose dependent decrease of GH secretion. To foremost investigate the transduction mechanisms underlying these results, we developed, from GH4C1 (rat somato-lactotroph tumoral cell line), stable monoclonal cell lines overexpressing human GHS-R1a (named MYST-Rg). Interestingly MYST-Rg cells exhibit relatively high basal activation of the IP3 pathway. GHS-R1a endogenous ligand (ghrelin) strengthens basal IP3 pathway activation of MYST-Rg cells. Noteworthy, the basal IP3 pathway activation can be lessened by MSP treatment. Thus, MSP could be a useful alternative to the current therapies of somatotroph adenomas
Picault, François-Xavier. "Signalisation apeline et adénocarcinomes coliques." Toulouse 3, 2013. http://thesesups.ups-tlse.fr/2407/.
Full textApelin, the endogenous ligand of the human G protein-coupled APJ receptor, is an angiogenic factor, which stimulates tumour growth by a paracrine effect on tumor neovascularisation. Our team also showed an upregulation of apelin gene expression in half of the human colon adenocarcinomas. The aim of my thesis was to determine the role of apelin signalling during colon carcinogenesis. I first confirmed by immunohistochemistry the overexpression of apelin peptide in the human colon adenocarcinomas. Then I showed for the first time that this overexpression occurred as soon as the adenoma stage. On adjacent sections, I observed the co-expression of APJ receptor with an identical temporal pattern of expression. These results therefore suggest the existence of an autocrine loop which might participate in the growth of colon tumours. In order to validate this hypothesis, we studied the expression of apelin and its receptor in several colorectal human cancer cell lines. In view of their high expression of apelin and apelin receptor, LoVo cells were selected for in vitro experiments. In this cell line, apelin induced Akt phosphorylation and adenylyl cyclase inhibition, thereby confirming the presence of the receptor at the plasma membrane as well as its functionality. Although apelin did not exert any mitogenic effect, it clearly acted as an anti-apoptotic factor. Indeed, the different apelin fragments protected LoVo cells from cell death induced by TNF-related apoptosis-inducing ligand (TRAIL) or the MG132 proteasome inhibitor. In addition, apelin inhibited caspase 3 cleavage, enzymatic activity of caspases 3 and 7 and PARP degradation induced by MG132. All these data clearly demonstrate that the activation of apelin signalling promotes an inhibition of apoptotic cell pathways which would increase tumour growth. The most prominent result was the inhibitory effect induced by the (F13A)apelin13 receptor antagonist on LoVo cell proliferation. Accordingly, co-expression of apelin and its receptor is the basis of a tumoral autocrine loop which should reinforce tumour growth. The co-existence of this autocrine effect on tumour and the paracrine effect on tumour vessels clearly emphasises the promising role of apelin signalling as a new therapeutic target in the treatment of human colon cancers
Stiévenard, Aliçia. "Investigation of the roles of ghrelin in experimental models of early stages of Parkinson’s disease : towards a clarification of ghrelin’s diagnostic and therapeutic potentials." Thesis, Lille 2, 2016. http://www.theses.fr/2016LIL2S041/document.
Full textParkinson’s disease (PD) is the second most frequent neurodegenerative disease in the world. It is characterized by motor symptoms such as bradykinesia, rigidity and resting tremor. Its definite diagnosis relies on the identification of specific neuropathological hallmarks at autopsy including severe neuronal death within the substantia nigra (SN) and the presence of Lewy bodies in the surviving neurons. PD progresses slowly and the first motor symptoms appear when more than 50% of the SN has degenerated. Therefore, the clinical diagnosis is established late in the course of the disease, thus restricting the therapeutic window for clinicians. In addition, the currently available therapeutic options can only temporarily alleviate PD motor symptoms. The challenges of current PD research are: 1) to anticipate the diagnosis and be able to identify the disease as early as possible, when the SN is still intact enough to implement a disease-modifying/neuroprotection strategy to prevent the appearance of motor symptoms, and 2) to improve current medications and/or develop new therapeutic strategies able to stop the disease before the motor phenotype is installed. The decade preceding PD clinical diagnosis is of particular interest since patients often complain about non-motor symptoms such as anosmia, depression or constipation. Moreover, recent evidences suggest that PD-characteristic lesions could first appear in the peripheral nervous system and slowly progress towards the brain. Thus PD earlier stages and their characteristics deserve better investigations using appropriate experimental models. In this regard, recent studies realized in animal and cellular models of advanced parkinsonism have suggested that ghrelin, an orexigenic peptide mainly produced in the stomach, could play a neuroprotective role in PD. Indeed, exposure to ghrelin has shown a protective effect against the neuronal death in animal and cellular models of parkinsonism. In addition, in a rodent model of parkinsonism, ghrelin was shown to alleviate the L-DOPA-induced worsening of gastro-intestinal symptoms, L-DOPA being the current main therapeutic option in PD. Moreover, ghrelin plasma concentrations have shown alterations in early stages of the disease in small cohorts of PD patients. We therefore hypothesized that ghrelin might play an important role in PD early stages and could serve as a biomarker and a neuroprotective agent in PD. In this context, the aim of my PhD was to investigate the roles of ghrelin in PD early stages using both in vitro and in vivo approaches.We first studied the effects of ghrelin in primary mesencephalic cells exposed to the pesticide rotenone, a potent inhibitor of mitochondrial complex I known for its association with PD. Contrary to the data of the literature, we show a dose and time-dependant deleterious effect of ghrelin on mesencephalic cells exposed to rotenone. This does not confirm the neuroprotective potential of ghrelin in our experimental conditions. In parallel, we investigated the potential of ghrelin as a biomarker in a rodent model of parkinsonism mimicking early stages of the disease after chronic oral exposure to low doses of rotenone. We first validated this model in our animal facility and confirmed that mice exposed to such a regimen develop progressive non-motor alterations but no dopaminergic neuronal death in the SN after 1.5 months. Our initial results do not show a modification of plasma ghrelin levels in rotenone-exposed mice at early stages of the pathological condition. However, confounding factors such as anxiety might have altered ghrelin levels. This should therefore be further ascertained in animals stratified for their anxiety levels and/or in longer exposures. In conclusion, these results challenge the suggested role of ghrelin as a disease-modifying agent in PD and set the bases for future investigations of ghrelin in the context of PD
Napolitano, Tiziana. "Gfi1 : une nouvelle cible pour la thérapie du diabète." Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2017. http://www.theses.fr/2017AZUR4141.
Full textThe mature pancreas consists of two main tissue types: the exocrine tissue, including acinar cells and a ductal tree, and the endocrine tissue. Acinar cells are dedicated to the synthesis of digestive enzymes, which are collected and conveyed to the duodenum by a ductal network running through the entire organ. Endocrine cells are organized into highly vascularized cell clusters, termed islets of Langerhans, which contain five cell subtypes, α-, β-, δ-, PP- and ε-cells secreting glucagon, insulin, somatostatin, pancreatic polypeptide and ghrelin, respectively. Classical genetic approaches have revealed much about individual factors regulating pancreatic development, however, we have yet to understand the regulatory network underlying pancreas formation and all the factors involved. Some of these factors are well known and studied but increasing researches revealed new and unknown factors involved in pancreas development and maturation. Among these, through in silico studies, we accumulated evidences suggesting a role of Gfi1 in pancreas cell development and specification. This protein, a zinc finger transcription factor, had previously been implicated in hematopoiesis, inner ear cell development, and in the maintenance of intestinal cell phenotypes. Here, we investigated the role of Gfi1 in the pancreas. Towards this goal, we generated a transgenic mouse line allowing Gfi1 inactivation exclusively in the pancreas. Altogether, our observations suggest that Gfi1 is required for the full maturation of pancreatic acinar cells. Importantly, we demonstrated that the sole loss of Gfi1 in the pancreas is sufficient to protect mice against two models of diabetes induction
Moulin, Aline. "Conception et synthèse de ligands du récepteur de la ghréline basés sur le motif 1,2,4-triazole." Montpellier 2, 2007. http://www.theses.fr/2007MON20038.
Full textMéquinion, Mathieu. "Altérations périphériques et centrales dans un modèle murin de restriction alimentaire chronique : rôle de la ghréline." Thesis, Lille 2, 2014. http://www.theses.fr/2014LIL2S055/document.
Full textChronic food restriction is one of the major features observed in anorexia nervosa (AN), especially in the restrictive type. This major eating disorder affects mainly teenager girls and young women. Additionally to the restriction behavior, important physical activity is observed in a large number of patients (40-80% of cases). This disease induces various physiological alterations that concern neuroendocrine, metabolic and bone (osteopenia, osteoporosis) pathways, which have dramatic consequences on the patient’s health. Moreover, many arguments suggest that AN could be considered like an "addictiv" disorder supported by an addiction to weight loss and/or food restriction or physical activity. It thus suggests modifications of the central dopaminergic reward system. Furthermore, whatever the origins or the causes of this disorder, AN leads to peripheral and central alterations that might be involved in an "adaptation" phase allowing patients surviving to these drastic conditions. For some patients, a phase of "chronicity" is described in which these physiological changes may worsen the patient conditions and contribute, when exhaustion is amplifying, to death. Our study points out ghrelin, an orexigenic hormone whose plasma concentrations are significantly increased in AN patients. Mainly secreted by stomach cells, it targets multiple peripheral organs as well as numerous neuronal structures in the brain. At the peripheral level, this hormone acts among others in the liver whose main function is the maintenance of glucose homeostasis. It acts also on the adipose tissue to promote its growth that is associated with lipid storage and on muscle resulting in a reduction of triglycerides stock. At the central nervous system level, ghrelin have various targets like the structures involved in the homeostatic as well as hedonic (motivation/reward) control of food intake through the hypothalamus and the meso-cortico-limbic system respectively.To study the involvement of ghrelin in the potential adaptive mechanisms, and even in the worsening of the disease, we have developed an animal model of chronic food restriction associated or not with physical activity, mimicking the physiological symptoms of AN. Our first objective was to characterize and to phenotype the mouse model by evaluating various physiological (metabolic, endocrine) factors in order to study in our second objective the role of ghrelin as a potential predictor of disease progression.We showed that our mouse model constitutes a pertinent model to study on a long term duration the physiological and central altérations described in the restrictive type AN. Moreover, we showed that moderate physical activity associated with food restriction had stabilizing effects on numerous metabolic parameters that may reduce an early exhaustion of energy stocks. Concerning the role of ghrelin in such model, its plasma concentrations were increased like in AN patients and were suggested to contribute to the adaptive regulation of energy metabolism
Ferland, Mélissa. "Préséniline 1 et voies de signalisation." Thesis, Université Laval, 2003. http://www.theses.ulaval.ca/2003/21021/21021.pdf.
Full textAffaticati, Emilien-Pierre. "Signalisation glutamatergique à la synapse immunologique." Paris 11, 2006. http://www.theses.fr/2006PA114837.
Full textL-glutamate, the major excitatory neurotransmitter, also plays a role in peripheral tissues. Immune T cells express glutamate receptors and communicate through immunological synapses. T cell receptor signaling precedes mature immunological synapse formation, raising questions about the precise role of the synaptic structure. We show here that L-glutamate acts as an immunotransmitter at synapses between dendritic cells and thymic developing T cells. DCs express glutamate-specific vesicular VGLUT transporters and release glutamte through Ca2+- dependent exocytosis. Thymic T cells express functional NMDA receptors modulating the Ca2+ signal and apoptosis induced by T cell-DC interaction. NMDAR is corecruited with PSD-95 to contact zones, suggesting a role for TCR signaling in shaping a functional glutamatergic synapse. We propose that the glutamate release by DCs may elicit focal responses mediated by GluR signaling in developing T cells
Marquette, Amélie. "Signalisation et oncogenèse dans le mélanome." Thesis, Paris Est, 2009. http://www.theses.fr/2009PEST0079.
Full textMelanoma, the most aggressive skin tumor, has become a major public health problem in many countries. Diagnosed early, it can be treated by surgical excision, but the prognosis for advanced melanoma is very poor because the tumor is resistant to all therapies used today. In order to develop new therapies to treat this tumor, we study the signaling pathways that play a major role in the proliferation, survival and differentiation of melanocytes and melanoma. These are the MAPK, PI3K pathway and the cyclic AMP (cAMP). We first demonstrated that some phosphodiesterases (PDEs; physiological inhibitors of cAMP pathway) are overexpressed in melanoma lines and thus inhibit the differentiation of these cells. Overexpression of PDEs is necessary for melanocyte transformation by oncogenic Ras when the reactivation of the cAMP pathway in melanoma lines inhibits their proliferation. These data suggest a therapeutic strategy that would aim to stimulate the differentiation of melanoma by reactivating the cAMP pathway could help to inhibit their proliferation. We have also shown that the protein kinase B-Raf, which is frequently mutated in melanoma, however, was inactivated in melanomas containing a mutation of Ras. We demonstrated that this inhibition was due to a downregulation of B-Raf by Erk substrate. Indeed, Erk phosphorylates B-Raf on its amino-terminal to prevent its interaction with Ras. This negative regulatory mechanism of B-Raf melanoma is forcing these lines to use isoform C-Raf. This work has implications for the treatment of melanoma. Indeed, if B-Raf is not used for the activation of MAPK in N-Ras mutated melanoma, the B-Raf inhibitors in clinical development will be ineffective in these cancers. We also demonstrated that a kinase inhibitor of B-Raf and C-Raf, which is in clinical development (Sorafenib), induces the activation of these kinases by heterodimerization in regulating their phosphorylation. These results reveal new mechanisms of regulation of proto-oncogene B-Raf and C-Raf, which could play an important role in the resistance of melanoma to Raf inhibitors, which are currently in clinical development
Pelletier, Joffrey. "AMPK, signalisation hypoxique et métabolisme tumoral." Electronic Thesis or Diss., Nice, 2014. http://theses.unice.fr/2014NICE4046.
Full textCells of solid tumors are often exposed to an environment deficient in oxygen, i.e. hypoxic. The Hypoxia-Inducible Factor-1 (HIF-1) is the major transcription factor involved in cellular adaptation to hypoxia. HIF-1 regulates a wide array of genes involved in angiogenesis, cellular metabolism or pH regulation. My thesis is organized into three axes around HIF-1 and metabolic reprogramming in hypoxia. I first studied Factor-Inhibiting HIF-1 (FIH), one of two oxygen sensors regulating HIF-1. We showed that FIH is essential for tumor development through inhibition of the HIF-1 transcriptional activity as well as through the suppression of the p53-p21 axis. I then studied the HIF-1-induced « shift » in cellular metabolism toward glycolysis, which generates a type of “glucose addiction”. We showed that paradoxically, tumor cells store glycogen in hypoxia through a HIF-1 dependant mechanism. Glycogen served as a reservoir of intracellular glucose, which allows hypoxic cells to survive periods of glucose starvation. Finally, I studied AMPK «the guardian of energy », and showed that surprisingly, this kinase is not necessary in maintaining a viable level of ATP when glycolysis is inhibited (by blockade of lactate export). However, as expected, AMPK protected cells during glucose starvation. Moreover, combined inhibition of the lactate transporter MCT4 and of AMPK reduced dramatically tumor development in a xenograft model, suggesting a crucial role for these two actors in the context of growth of tumor cells in a hostile environment. Taken together these results identified several potential drug targets involved in the metabolic plasticity of hypoxic cells
Pelletier, Joffrey. "AMPK, signalisation hypoxique et métabolisme tumoral." Phd thesis, Université Nice Sophia Antipolis, 2014. http://tel.archives-ouvertes.fr/tel-01067130.
Full textBlayo, Anne-Laure. "Conception et synthèse d'antagonistes du récepteur de la ghréline basés sur le motif 1,2,4-triazole 3,4,5-trisubstitué." Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20041.
Full textGhrelin, a peptidic hormone which is mainly synthesized in the stomach, is the endogenous ligand of the growth hormone secretagogue receptor named GHS-R1a. It is involved in numerous biological processes such as the growth hormone secretion and the control of energy homeostasis. Because of its orexigenic and adipogenic properties, ghrelin is a potent tool to control energy imbalance. Developing ghrelin receptor antagonists represents a promising strategy for the discovery of anti-obesity new drugs.This thesis is devoted to the development of ghrelin receptor antagonists based on a peptidomimetic scaffold: the 3,4,5-trisubstituted 1,2,4-triazole. Our aim is to combine ligand affinity and activity towards GHS-R1a with optimized properties which enable to promote a good oral bioavailability. We based our work on a rapid and efficient synthesis of our compounds to carry out detailed structure-activity and structure-property studies. By successively optimizing the different positions around the triazole scaffold, interesting compounds were obtained. We have thus identified receptor antagonists which exhibit sufficient microsomal stability and satisfactory membrane permeability to consider in vivo studies
Legrand, Romain. "Effets modulateurs des immunoglobulines plasmatiques sur les hormones peptidiques impliquées dans la régulation du comportement alimentaire." Rouen, 2016. http://www.theses.fr/2016ROUENR02.
Full textNowadays, food intake disorders are a major public health problem. In those patients, a modification of their food intake regulation is observed. Plasmatic levels of ghrelin, the main orexigenic hormone, are impared in those diseases. Moreover, in obese patients, ghrelin injections are more efficient on food intake than in normal persons suggesting a better transport of this hormone in the blood circulation. Ghrelin reactive auto-antibodies could be responsible for this transport improvement. In this thesis work, the implication of the ghrelin reactive auto-antibodies was studied in food intake disorders. An affmity increase for ghrelin was identified in ghrelin reactive auto-antibodies from obese patients. It was responsible for a ghrelin effects improvement by a better transport due to the fixation increase and a better protection from its degradation. In anorexia, opposite changes were observed. Moreover, the co-injection of ghrelin with immunoglobulins from obese patients or mice stimulated more efficiently food intake and was beneficial against the anorectic phenotype in a murine model of anorexia. So, the implication of the ghrelin reactive auto-antibodies in the physiopathology of food intake disorders and their potential interest in the treatment of anorexia was demonstrated. The hedonic control of the food intake was also studied in this thesis. Indeed, the influence of a-MSH, an anorectic peptide, was studied by microdialysis on the dopamine liberation in lateral hypothalamic area and the nucleus accumbens
Lucas, Nicolas. "Étude du rôle des immunoglobulines plasmatiques dans la modulation du signal anorexigène porté par l'α-MSH sur le récepteur aux mélanocortines de types 4 : implication dans la physiopathologie des troubles du comportement alimentaire et de l'obésité." Rouen, 2016. http://www.theses.fr/2016ROUENR03.
Full textObesity (OB) and eating disorders (ED) are major health problems which pathophysiological mechanisms are not well understood. Humans naturally display auto-antibodies that are reactive with a-MSH and ghrelin, two key regulatory hormones implicated in the satiety and hunger pathways, respectively. The present work aimed at analysis of immunoglobulins (Ig) autoantibodies directed against these peptides for their possible role in the appetite dysfunctions found in these diseases. Because the melanocortin receptor type 4 (MC4R) is critical to mediate a-MSH anorexigenic effects, we first characterized the impact of anti-a-MSH IgG from immunized rabbits or ED and OB patients on activation of MC4R expressing cells in vitro. We found that anti-a-MSH IgG display an allosteric effect on MC4R signaling which is altered in ED and OB. Moreover novel chronic neuropeptide chronic delivery tool in the brain was developed which opens further opportunities for the study of long-term effects of peptides molecules on feeding behavior. Furthermore the characterization of ghrelin-reactive IgG affinity kinetic proprieties was found to depend on nutritional status. Taken together these data helped to integrate autoantibodies in the regulation of both orexigenic and anorexigenic pathways involvement in the pathophysiology of ED and OB
Girard, Alexia. "Régulations croisées entre signalisation lipidique et signalisation dépendant des nucléotides cycliques dans l'activation lymphocytaire : rôle de l'acide phosphatidique." Lyon, INSA, 1997. http://theses.insa-lyon.fr/publication/1997ISAL0129/these.pdf.
Full textMitogenic activation of human peripheral blood mononuclear cells (PBMC) rapidly increased both the IntraceUular phosphatidic acid (PA) level and cyclic nucleotide phosphodiesterase (POE) activity. In addition, PA directly stimulated PDE activity in an acellular system. Thus, the mitogenic properties of PA might be due to its ability to lower cAMP levels, a negative effector of lymphocyte activation, through PDE activation. This work shows that the mitogenic lectin Concanavalin A (Con A) significantly increases PA production in PBMC by a PIIPLC/DAG-Kinase pathway after 5 min of stimulation. When PA production, POE activities and cAMP levels were simultaneously determined in the same cells following activation by several mitogens, significant positive correlations could be established between PA level and PDE activities. Furthermore, agents able to impair the PA increase were also able to prevent the PDE activation. Finally, a modest but significant diminution of cAMP level was observed in response to mitogens. In a second part, we considered the relationship between PA and the mitogenic response in cells that were enriched with the arachidonic acid oxygenated metabolite, 12-HETE, involved in ageing. Given the 1ntimitogenic effect of 12-HETE for various types of cells including lymphocytes, and its reported inhibitory properties towards DAG-Kinase, we wondered whether an accumulation of 12-HETE in blood cells might result in an altered production of PA. On the contrary, 12-HETE was found to potentiate the PA formation induced by Con A, by a mechanism involving a PLD. This PLD activation does not involve PKC, but protein tyrosine-kinases; were found to be implicated. Finally, we demonstrated the presence of low-affinity binding sites for 12-HETE on PBMC, possibly linked to aG protein-coupled receptor
Girard, Alexia Prigent Annie-France. "Régulations croisées entre signalisation lipidique et signalisation dépendant des nucléotides cycliques dans l'activation lymphocytaire rôle de l'acide phosphatidique /." Villeurbanne : Doc'INSA, 2005. http://docinsa.insa-lyon.fr/these/pont.php?id=zakaroff-girard.
Full textMoretti, Julien. "Déubiquitinations dans la voie de signalisation Notch." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2011. http://tel.archives-ouvertes.fr/tel-00726110.
Full textAtindéhou, Roger B. "Dividende, signalisation du risque et réaction boursière." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq25375.pdf.
Full textTrinquand, Amélie. "Leucémies Aigues Lymphoblastiques T et signalisation TCR." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05S008.
Full textT-cell acute lymphoblastic leukemias (T-ALL) are rare lymphoid neoplasms characterized by the proliferation of T lymphoblasts arrested at specific stages of maturation. Leukemic transformation of maturating thymocytes is caused by a multistep pathogenesis involving numerous genetic abnormalities that drive normal T cells into uncontrolled cell growth and clonal expansion. Depending on immunogenetic, T-ALLs are classified in 3 groups: immature, cortical (blocked around b-selection) and mature (CD3/TCR+) T-ALL. My work was to determine if activation and TCR signalling are involved in the biology of this disease. We demonstrate in T-ALL that, irrespective of the complex oncogenic abnormalities underlying tumor progression, experimentally induced, persistent TCR signalling has anti-leukemic properties and enforces a molecular and phosphoproteomic program resembling thymic negative selection, a major developmental event in normal T cell development. Using mouse models of T-ALL, we show that induction of TCR signalling by high affinity self-peptide/MHC or treatment with monoclonal antibodies to the CD3e chain (anti-CD3) causes massive leukemic cell death. Importantly, anti-CD3 treatment hampered leukemogenesis in mice transplanted with either mouse or patient-derived T-ALLs. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of TCR-expressing T-ALL patients and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells. Besides, I studied frequency and prognostic impact of anomalies concerning pre-TCR/TCR signalling in a large cohort of adult T-ALL included in GRAALL trials. RAS/MAPK and PI3K/PTEN/AKT pathways are involved in pre-TCR/TCR signalling and are reported as deregulated in pediatric T-ALL. I identified deletion/mutation loss-of-function of PTEN (12%) and activating mutations of KRAS/N-RAS (11%) in 23% of patients. These anomalies predict poor outcome and abrogate the good prognosis of NOTCH1/FBXW7 mutations. We proposed a purely genetic stratification of patients based on N/F/RAS/PTEN status, identifying low-risk patients (51%) with N/F mutations without RAS/PTEN anomalies and high-risk patients (49%) composed by the remaining cohort. This stratification will be used for the next protocol of adult-T-ALL
Gomez, Cédric. "Molécules de signalisation neuronale et développement osseux." Lyon 1, 2006. http://www.theses.fr/2006LYO10130.
Full textAmour, Julien. "Cardiomyopathie diabétique et voies de signalisation adrénergiques." Paris 6, 2007. http://www.theses.fr/2007PA066125.
Full textMoretti, Julien. "Deubiquitinations dans la voie de signalisation Notch." Paris 6, 2011. http://www.theses.fr/2011PA066365.
Full textSartelet, Hervé. "Glycosylphosphatidylinositol et inositolphosphate glycanne, ancrage et signalisation." Reims, 1996. http://www.theses.fr/1996REIMS024.
Full textVirard, François. "Trafic, maturation et signalisation proapoptotique de TLR3." Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10337.
Full textLE, MELLAY VERONIQUE. "Signalisation membranaire des steroides dans les osteoblastes." Paris 6, 1998. http://www.theses.fr/1998PA066549.
Full textQueiroux, Clothilde. "Signalisation moléculaire dans la symbiose Frankia-aulne." Thesis, Lyon 1, 2009. http://www.theses.fr/2009LYO10228.
Full textNitrogen is essential for cells development. It's one of the limiting factors of plant growth. The only abundant source of this component is the atmosphere which contains 80 % of dinitrogen, but this form can only be assimilated by some prokaryotes. These microorganisms are able to fix atmospheric nitrogen under freeliving condition or in symbiosis with some plants. Thus, they provide nitrogen substrates to the plant in the form of ammonium, and in return the plant provides carbon substrates from photosynthesis. It is an association with reciprocal profits for both partners. There are two major nitrogen-fixing symbioses: rhizobial symbiosis, which involves various Proteobacteria and actinorhizal symbiosis, which involves the Actinobacterium, Frankia. Bacteria enter plant root cells and develop a new organ, the nodule where nitrogen fixation takes place. Molecular bases are well characterized for rhizobial symbiosis, whereas little is known about the actinorhizal symbiosis. This fact is in part due to absence of genetic tools for Frankia. However, early steps of the interaction show some similarities. These two bacteria are able to induce root hair deformation by secreting a deforming factor, Nod factor in most rhizobial symbioses and a noncharacterized factor in the actinorhizal symbiosis. The aim of this thesis was to determine if molecular dialogue between plant and bacteria is based on universal components. This work used two approaches. One was targeted on nodC-like gene from Frankia alni ACN14a. We tried to characterize their function. Another used trancriptomic microarrays in Frankia. This technique allowed us to compare transcripts from 2 conditions: free-living cells and symbiosis. A last approach focused on aromatic compounds in Frankia. We wanted to determine if Frankia was able to use different aromatic compounds to grow. Indeed, a lot of aromatic compounds are involved in plant-bacteria interaction such as plant defense
Navet, Benjamin. "Homéogènes Dlx, signalisation RANK/RANKL et ostéosarcomes." Thesis, Nantes, 2016. http://www.theses.fr/2016NANT1018/document.
Full textOsteosarcoma (OS), the most common malignant primary bone tumor, is characterized by an osteoid formation occasionally associated with osteolysis. De-spite therapeutic advances, the 5-years survival rate remains low (30% in case of metastasis or drug-resistance). New therapeutic approaches targeting the tumor cell and its environment are needed. Presented studies focused on potential pro-tumor factors namely Dlx genes and a key signaling pathway of the bone environment (RANKL / RANK) that may influence tumor aggressiveness. The OS is an osteo-blastic tumor and Dlx family was chosen due to its in-volvement in osteoblastogenesis. RANKL / RANK path-way was selected as it constitutes a main element in the coupling between osteoblasts and osteoclasts. A link between Dlx genes and RANK signaling was suspected. Dlx1, Dlx4 and Rank genes are not normally ex-pressed in osteoblasts but are present in the OS cell lines. Dlx and Rank expression modulations were real-ized to assess the impact on tumor cells. RANK / RANKL signaling involvement in the tumor microenvi-ronment was analyzed. Disruption of remodeling is in favor of the tumor taking part in the establishment of a vicious circle between tumor and environment. This work established the involvement of Dlx, espe-cially DLX4 to which a new coding transcript has been characterized. However, additional studies are needed. Regarding the RANK / RANKL signaling, it turns out that beyond the vicious circle, leading to tumor initiation stage, the RANK expression by the tumor proves to be pro-metastatic elements
Restagno, Damien. "Contribution à l’étude du choc septique à l’aide de modèles animaux : de l’immunoparalysie à la cachexie." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1096.
Full textDuring sepsis, the organism is subjected to an infection. Its first immunological response will be an inflammation which is the source of numerous immunological and physiological modifications.This massive inflammation will be compensated almost simultaneously: the organism set a compensatory anti-inflammatory response in order to alleviate the deleterious effects of the release of pro-inflammatory cytokines on the organ, whether they are distant or not from the infectious site. This so called beneficial response actually turns out to be a real scourge for the host. Indeed this compensatory anti-inflammatory response is sustainable and will overtake the inflammation leading to a protracted immunoparalysis. This infection-induced immunosuppression is responsible for an increase in patients’ susceptibility to secondary nosocomial infections.Another compensatory mechanism called proteolysis will be set in response to the massive inflammation. This protein breakdown induces a supply of nutrients which are essentials for the organism. The furnished amino acids originate from skeletal muscles and in case of sepsis or any inflammatory disease, the organism is overrun. Therefore, proteolysis persists, leading to an important muscle wasting, named cachexia.Setting up a murine model of sepsis induced through a cecal ligation and puncture allowed the identification of several mechanisms involved in immunoparalysis. We point out a consistent and sustainable anti-inflammatory response with a lymphocyte anergia (reduced number and proliferative ability), and an increase of the total number of regulatory T cells. We also highlighted a bacterial load-dependent and cytokines-dependent mortality following a secondary pulmonary infection with Pseudomonas aeruginosa.Thanks to this model we also characterized septic cachexia. Despite several descriptions, formal evidences of cachexia during sepsis were lacking. Thus, the important weight loss of our animals, but especially their muscular loss after 13 days and their reduced fiber cross sectional areas could be used as a basis to an investigation of ubiquitin ligases pathway, the major actors of proteolysis. Beside classical MAFbx and MuRF1, many other ubiquitin ligases were upregulated during sepsis
Stiévenard, Aliçia. "Investigation of the roles of ghrelin in experimental models of early stages of Parkinson’s disease : towards a clarification of ghrelin’s diagnostic and therapeutic potentials." Electronic Thesis or Diss., Lille 2, 2016. http://www.theses.fr/2016LIL2S041.
Full textParkinson’s disease (PD) is the second most frequent neurodegenerative disease in the world. It is characterized by motor symptoms such as bradykinesia, rigidity and resting tremor. Its definite diagnosis relies on the identification of specific neuropathological hallmarks at autopsy including severe neuronal death within the substantia nigra (SN) and the presence of Lewy bodies in the surviving neurons. PD progresses slowly and the first motor symptoms appear when more than 50% of the SN has degenerated. Therefore, the clinical diagnosis is established late in the course of the disease, thus restricting the therapeutic window for clinicians. In addition, the currently available therapeutic options can only temporarily alleviate PD motor symptoms. The challenges of current PD research are: 1) to anticipate the diagnosis and be able to identify the disease as early as possible, when the SN is still intact enough to implement a disease-modifying/neuroprotection strategy to prevent the appearance of motor symptoms, and 2) to improve current medications and/or develop new therapeutic strategies able to stop the disease before the motor phenotype is installed. The decade preceding PD clinical diagnosis is of particular interest since patients often complain about non-motor symptoms such as anosmia, depression or constipation. Moreover, recent evidences suggest that PD-characteristic lesions could first appear in the peripheral nervous system and slowly progress towards the brain. Thus PD earlier stages and their characteristics deserve better investigations using appropriate experimental models. In this regard, recent studies realized in animal and cellular models of advanced parkinsonism have suggested that ghrelin, an orexigenic peptide mainly produced in the stomach, could play a neuroprotective role in PD. Indeed, exposure to ghrelin has shown a protective effect against the neuronal death in animal and cellular models of parkinsonism. In addition, in a rodent model of parkinsonism, ghrelin was shown to alleviate the L-DOPA-induced worsening of gastro-intestinal symptoms, L-DOPA being the current main therapeutic option in PD. Moreover, ghrelin plasma concentrations have shown alterations in early stages of the disease in small cohorts of PD patients. We therefore hypothesized that ghrelin might play an important role in PD early stages and could serve as a biomarker and a neuroprotective agent in PD. In this context, the aim of my PhD was to investigate the roles of ghrelin in PD early stages using both in vitro and in vivo approaches.We first studied the effects of ghrelin in primary mesencephalic cells exposed to the pesticide rotenone, a potent inhibitor of mitochondrial complex I known for its association with PD. Contrary to the data of the literature, we show a dose and time-dependant deleterious effect of ghrelin on mesencephalic cells exposed to rotenone. This does not confirm the neuroprotective potential of ghrelin in our experimental conditions. In parallel, we investigated the potential of ghrelin as a biomarker in a rodent model of parkinsonism mimicking early stages of the disease after chronic oral exposure to low doses of rotenone. We first validated this model in our animal facility and confirmed that mice exposed to such a regimen develop progressive non-motor alterations but no dopaminergic neuronal death in the SN after 1.5 months. Our initial results do not show a modification of plasma ghrelin levels in rotenone-exposed mice at early stages of the pathological condition. However, confounding factors such as anxiety might have altered ghrelin levels. This should therefore be further ascertained in animals stratified for their anxiety levels and/or in longer exposures. In conclusion, these results challenge the suggested role of ghrelin as a disease-modifying agent in PD and set the bases for future investigations of ghrelin in the context of PD
Fouillade, Charles. "Voie de signalisation Notch3 dans les artères cérébrales." Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05T043.
Full textNotch3 encodes a transmembrane receptor primarily expressed in arterial smooth muscle cells. Human and mouse genetics studies demonstrated that Notch3 is a key player in physiology and diseases of small vessels. Studies in mice revealed that Notch3 is required to generate functional arteries in regulating arterial differentiation, maturation of vascular smooth muscle cells and myogenic tone. Cerebral Autosomal Dominant Arteriopathy with Subcortical infarcts and Leukoencephalopathy (CADASIL) is the most frequent hereditary small vessels disease in human adults caused by NOTCH3 mutations. Pathogenic mutations lead to an odd number of cysteine residues within the NOTCH3 extracellular domain. Data from the laboratory suggest a model that invokes novel pathogenic roles from the mutant NOTCH3 protein. The main goals of this work are: 1°) To determine if there is small vessels disease caused by modification of Notch3 activity 2°) To identify Notch3 effectors involved in development and maturation of cerebral arteries We identified a novel heterozygous missense mutation (L1515P) in the heterodimerization domain of NOTCH3 in a patient with cerebral small vessel distinct from CADASIL. In vitro analysis showed that the L1515P mutant exhibits increased canonical NOTCH3 signaling in a ligand-independent manner. Biochemical analysis suggests that the mutation renders NOTCH3 hyperactive through destabilization of the heterodimer. Transcriptome analysis using tail arteries of Notch3-/- and Notch3+/+ mice identified a core set of 17 novel Notch3-regulated genes confirmed in tail or brain arteries. Postnatal deletion of RBP-Jκ in smooth muscle cells recapitulated the structural, functional, and molecular defects of brain arteries induced by Notch3 deficiency. Transient in vivo blockade of the Notch pathway with γ-secretase inhibitors uncovered, in addition to Notch3, 6 immediate responders, including the voltage-gated potassium channel Kv1.5, which opposes to myogenic constriction of brain arteries, and the glutamate receptor-interacting protein-2, with no previously established role in the cerebrovasculature. We identified a vascular smooth muscle cell isoform of Grip2. We showed that Notch3-RBP-Jκ specifically regulates this isoform. Finally, we found that cerebral arteries of glutamate receptor-interacting protein-2 mutant mice, which express an N-terminally truncated glutamate receptor-interacting protein-2, exhibited selective attenuation of pressure-induced contraction. In conclusion, we have demonstrated the existence of a NOTCH3 activating mutation associated with small vessels disease in human. Our results show that, in the context of cerebral arteries maturation, Notch3 functions are mediated by CSL/RBPJK transcription factor. We have identified several new Notch3 effectors and validated Grip2 as a novel regulator of myogenic tone in cerebral arteries. One can expect that mutations in these Notch3-regulated genes could be responsible of some monogenic form of small vessel diseases of the brain
Phaneuf, Francis. "Implication de l'ubiquitination dans la signalisation de TRPC6." Mémoire, Université de Sherbrooke, 2013. http://hdl.handle.net/11143/6350.
Full textRossi, Anne-Lise. "Nouveaux régulateurs de la signalisation TLR2-NF-kB." Phd thesis, Université René Descartes - Paris V, 2013. http://tel.archives-ouvertes.fr/tel-01016690.
Full textSimonot, Cédric. "Contribution à l'étude des voies de signalisation mitochondriale." Lyon 1, 1997. http://www.theses.fr/1997LYO1T246.
Full textHyvert, Yann. "Signalisation par les récepteurs Toll chez la Drosophile." Université Louis Pasteur (Strasbourg) (1971-2008), 2007. http://www.theses.fr/2007STR13184.
Full textMammalian TLRs play an important role in the immune defence by activating and regulating the immune response. In Drosophila, Toll is the only member of the Toll receptors family, which has been characterized as a regulator of the immune response in Drosophila after infection by fungi or Gram-positive bacteria. For the other members 18W to Toll-9 little is known about their function. This work presents four aspects of the immunobioloy of those receptors. It as been shown that the prodomain of the cytokine Spätzle has an important and unexpective role in the activation of the Toll receptor. The study of Toll-5 shows that it does not interact with Toll or with Toll-9. The work on the characterization of Weckle, a new component of the Toll pathway, is presented. Toll-9 presents sequence similarities with the mammalian TLRs. It has been shown that it plays a role in the epithelial defence of the midgut. The study of the signalling pathways activated by 18W and Toll-8 is also described
Markov, Gabriel. "Evolution de la signalisation stéroïdienne chez les Métazoaires." Thesis, Lyon, École normale supérieure, 2011. http://www.theses.fr/2011ENSL0634/document.
Full textNuclear receptor mediated steroid signaling is involved in many processes in metazoandevelopment, such as puberty in vertebrates, molting in insects and entry into infective stage in some parasitic nematodes. Understanding those phenomena is important regarding public health, agronomical and conservation biology issues. This necessitates to know and to explore the interactions between the evolution of steroid-binding receptors and steroid-synthesizing pathways. My work was articulated around three major parts. First, using the historical expertise of the laboratory, I updated the relationships between nuclear receptors that are involved in steroid binding, but also from all those that are involved in steroidogenesis regulation, in order to elucidate when and in which context this machinery has arisen. Second, using a classical comparative genomic approach, I showed that the steroidogenetic enzymes have appeared independently by duplication from xenobiotic-metabolizing enzyme with a wider range of substrate specificity.Third, I explored the relationships between metabolic pathways using tools from comparative anatomy. This has confirmed and completed the previous results, showing that steroidogenetic pathways have evolved with the pattern of cholesterol degradation pathways.The synthesis of all these results has led to an evolutionary model where hormonal signaling in bilaterian animals has been inherited from the detoxification of dietary sterols. This model may explain the coupling between nutrient accumulation and sexual maturation, and also the link between metabolic disorders and endocrine disruption due to environmental chemicals or drugs
Chaves-Almagro, Carline. "Signalisation apeline : nouvelle cible thérapeutique de l'adénocarcinome pancréatique ?" Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30246/document.
Full textApelin, the endogenous ligand of the human G-protein coupled receptor, APJ, is a key regulator of cardiovascular system, notably during physiological and tumor angiogenesis. Using a cancer profiling array approach, our team clearly showed that apelin gene is overexpressed in one third of the human carcinomas, with the highest frequency (2/3) in pancreatic cancers. Thus, the aim of my PhD project was to characterize apelin signaling function during pancreatic carcinogenesis. Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and the discovery of biomarkers and new therapeutic targets is of crucial interest for this cancer since this cancer is diagnosed too late and there is no effective therapy. By an immunohistochemistry approach on human PDAC slides (49 patients), we show that apelin and APJ are strongly expressed by pancreatic tumor cells. In order to characterize apelin and APJ spatio-temporal expression during pancreatic carcinogenesis, we have studied their expression by immunohistochemistry in genetically engineered mouse models of PDAC. In the K-ras mouse model (Lox-Stop-Lox-K-rasG12D/+/Pdx1-Cre) which recapitulates early stages of the disease, and in the KPC mouse model (Lox-Stop-Lox- K-rasG12D/+ ; Lox-Stop-Lox-Trp53 R172H/+/Pdx1-Cre) which develops PDAC until invasive stages, our results demonstrate that apelin and its receptor are expressed by tumor cells since the first steps of carcinogenesis. In order to study apelin signaling function, we have characterized signal transduction pathways activated by apelin in MiaPaCa human pancreatic cancer cell line endogenously expressing apelin and APJ as observed in vivo. In these cells, apelin induces transient activation of ERKs and p70S6 Kinase, a sustained Akt activation and an inhibitory phosphorylation of GSK3 thus allowing Beta-catenin stabilization. Interestingly, my results demonstrate that the MAPK pathway activation apelin induced is Gi protein dependent. Conversely, long term stimulation of PI3K/Akt pathway is G protein independent but instead involves receptor internalization. Moreover, apelin positively regulates on one hand c-myc and cyclin D1 protein levels, both of them being implicated in cell proliferation and on the other hand, intracellular protein content of Hexokinase 2 in order to ensure high glycolytic flux which is essential for tumor cells energy supply. These results are in agreement with cellular effects that we observed since apelin stimulates proliferation, glucose uptake and migration of tumor cells which are essentials properties for tumor progression. Accordingly, apelin and APJ overexpression in PDAC and the effects of this signaling pathway on tumor cells make of this ligand/receptor couple a new potential therapeutic target for pancreatic cancer treatment
Leroy, Benjamin. "Etude et développement d'un système de signalisation holographique." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS126.
Full textThis work has focused on the design and realization of a planar lighting device based on plasmonic structures, for a 633nm operation. This device will be able to convert a coherent incident light into a uniform output beam over the surface of the device, collimated and with a predefined angle with respect to the plane of the device. To achieve this feature, the proposed solution is the use of an array of dielectric waveguides to distribute the light over the surface, and silver nanostructures chains coupled to the waveguides and dimensioned as antennas to retransmit the light out of the plane. The work carried out has highlighted the control of the coupling between the waveguide and the silver nanostructures chain, modulated by several parameters in a range between 10% and 90%: the number of particles, particle size, distance between the guide and the particles. By playing on the period of the chain, it is possible to obtain an out-of-plane radiation, with an angle determined by the diffraction gratings formula. Elementary emitters, consisting of a guide and particle chains, were manufactured in a clean room and characterized on a guided wave optical bench with Fourier plane projection set-up. The experimental radiation patterns are in agreement with the simulations one. First results have also experimentally confirmed the possibility of modulating the waveguide-chain coupling by modifying the dimensions of the particles. Finally, the waveguide network has been dimensioned for an 1 cm² surface and manufactured with projection lithography. The linear losses measured in the waveguides are of the order of 5 dB / mm. Several optimizations can be made to improve the quality of the guides. From the experimental data obtained and the beam propagation simulations, a realistic configuration of the lighting device including the number and positioning of the transmitters on the waveguide network has been proposed. All the works carried out validate the chosen approach
Martinerie, Laëtitia. "Signalisation minéralocorticoïde et homéostasie hydrosodée du nouveau-né." Paris 11, 2010. http://www.theses.fr/2010PA11T048.
Full text