Tesi sul tema "Receptor, IGF Type 2"
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1
O'Reilly, Kathryn Elizabeth. "Integration of mtor and IGF-1 signaling : feedback upregulation of survival pathways in human cancer cells /". Access full-text from WCMC:, 2007. http://proquest.umi.com/pqdweb?did=1296100571&sid=11&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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2
Luey, Brendan Charles. "Targeting the type 1 IGF receptor in oestrogen-responsive breast cancer". Thesis, University of Newcastle upon Tyne, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709848.
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3
Godefroy, Anastasia. "Nouvelle stratégie d'enzymothérapie substitutive ciblant le récepteur du mannose 6-phosphate pour les maladies lysosomales". Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT030.
Testo completoAbstract (sommario):
Les maladies lysosomales forment un groupe hétérogène d’une cinquantaine d’affections qualifiées de « rares ». Actuellement, seulement 9 maladies lysosomales disposent d’un traitement spécifique, principalement par enzymothérapie substitutive, mais les effets bénéfiques sont souvent limités. Le manque de ciblage pour le Récepteur du Mannose 6-Phosphate (RM6P), responsable de l’internalisation dans les lysosomes, expliquerait en partie cette efficacité modérée des enzymes thérapeutiques. Dans ce contexte, nous avons développé une approche de ciblage innovante basée sur des Analogues synthétiques du Mannose 6-Phosphate fonctionnalisés sur l’Aglycone (appelés AMFA) afin de répondre aux besoins non satisfaits par les traitements actuels.Les travaux de cette thèse portent principalement sur la maladie de Pompe, myopathie causée par la déficience d’une enzyme lysosomale, l’Alpha Glucosidase Acide (GAA), responsable de la conversion du glycogène en glucose. Afin d’améliorer l’adressage de l’enzyme thérapeutique aux lysosomes via le RM6P, nous avons fonctionnalisé la GAA recombinante humaine (rhGAA) avec les AMFA. Nos études sur la forme adulte de la maladie ont démontré une augmentation significative de l’internalisation et pour la première fois, chez des souris âgées modèles de la maladie, une restauration de la santé musculaire et une amélioration significative de la fonction motrice ont été observées (article 1). Nous nous sommes ensuite intéressés aux propriétés de la rhGAA-AMFA. Nous avons démontré que l’efficacité de la rhGAA-AMFA n’était pas uniquement due à une meilleure internalisation mais également à une meilleure maturation intracellulaire de l’enzyme (article 2). En effet, nos résultats ont démontré que chez les patients atteints de la maladie de Pompe, il existe une surexpression des phosphatases acides ACP2 et ACP5. Ces phosphatases peuvent détruire le signal mannose 6-phosphate (M6P) naturellement présent sur l’enzyme, ce qui interrompt sa maturation en forme active. L’AMFA, contrairement au M6P, est insensible à cette dégradation et assure donc la stabilité de l’adressage de l’enzyme in vitro, mais également in vivo.L’ensemble de ces résultats suggèrent que le greffage des AMFA sur des enzymes recombinantes représente une nouvelle solution thérapeutique pour le traitement de la maladie de Pompe et potentiellement pour le traitement d’autres maladies lysosomalesLysosomal diseases form a heterogeneous group of about fifty rare diseases. At present, only 9 lysosomal diseases have a specific treatment, mainly by enzyme replacement therapy but the beneficial effects appear often limited. The lack of targeting for the Mannose 6-Phosphate Receptor (M6PR), responsible for internalization into the lysosomes, would partly explain this moderate efficiency of the therapeutic enzymes. In this context, we have developed an innovative targeting approach based on Mannose 6-Phosphate Synthetic Analogues Functionalized at the Aglycone position (called AMFAs) to address the unmet needs of current treatments.The work of this thesis focuses mainly on Pompe disease which is a myopathy caused by the deficiency of a lysosomal enzyme, Acid Alpha Glucosidase (GAA), responsible for the conversion of glycogen into glucose. In order to improve the targeting of the therapeutic enzyme to lysosomes via the M6PR, we have functionalized the human recombinant GAA (rhGAA) with the AMFAs. Our studies on aged mice model of the adult form of the disease have demonstrated a significant increase of the enzyme internalization and for the first time, the restoration of muscle health and the significant improvement in motor function (article 1). We then investigated the properties of rhGAA-AMFA. We have proved that the effectiveness of rhGAA-AMFA is not only due to a better cell uptake but also to a more complete intracellular processing of the enzyme (article 2). Indeed, our results demonstrated that in myoblasts of patients affected by Pompe disease there is an overexpression of ACP2 and ACP5 acid phosphatases. These phosphatases can destroy the mannose 6-phosphate signal (M6P) naturally present on the enzyme, therefore possibly interrupting its processing into the active form. AMFA, unlike M6P, is insensitive to this degradation and thus ensures the stability of enzyme addressing in vitro, but also in vivo.All together, these results suggest that the grafting of the AMFAs on recombinant enzymes represents a new therapeutic solution for the treatment of Pompe disease and potentially for other lysosomal diseases
4
Vincent, Karla Kristine. "Transactivation of Beta 2 Adrenergic Receptor by Bradykinin type 2 Receptor via heterodimerization". Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/37117.
Testo completoAbstract (sommario):
Although a long standing convention maintained that G Protein Coupled Receptors (GPCRs) exist in the plasma membrane solely as monomers, substantial work over the last two decades has demonstrated that these ubiquitous receptors can and in many cases, preferentially, exist as homodimers, heterodimers, or higher order oligomers. Often, two GPCRs of the same class heterodimerize; it is less common for two GPCRs of different signaling pathways to interact. The work presented here studied the physical and functional interaction of two GPCRs from discrete classes, the Beta 2 Adrenergic Receptor (β2AR), a Gαs-coupled receptor, and Bradykinin type 2 Receptor (Bk2R), a Gαq coupled receptor. These data show that Bk2R and β2AR are physically coupled when heterologously expressed in Xenopus oocytes, and in pheochromocytoma (PC12) cells and in freshly isolated murine ventricular myocytes, two systems that endogenously express these receptors. This physical coupling led to functional consequences in heterologous and endogenous expression systems, as Bk2R was able to transactivate β2AR signaling via its direct interaction with the receptor. Furthermore, coexpression of Bk2R shifted the dose response curve of β2AR for its selective agonist rightward in Xenopus oocyte electrophysiology experiments, suggesting the presence of Bk2R negatively affected β2AR native pharmacology. Up to thirty minutes of either bradykinin (BK) or isoproterenol exposure did not change the relative amount of Bk2R/β2AR heterodimer in PC12 cells, a rat adrenal medulla tumor cell line that endogenously expresses these receptors. Despite the obvious signaling consequences, the Bk2R/β2AR heterodimer accounted for only 10% of the total β2AR protein detected and 20% of the total Bk2R protein detected. When other Bk2R-specific ligands were also tested to examine the extent of β2AR transactivation, our data showed that both Lys-des-Arg-Bradykinin, a Bk2R partial agonist and NPC 567, a Bk2R antagonist, transactivated β2AR to the same extent as BK. Taken together, our data provide a novel mode of receptor regulation and signaling via Bk2R/β2AR heterodimerization. Because a large percentage of therapeutics target GPCRs, a greater understanding of how a GPCR heterodimer functions could be beneficial for targeting new drugs and refining existing drugs. Understanding the Bk2R/β2AR heterodimer provides a new perspective on the myriad of fucntional consequences that occur when a GPCR is activated.
5
Hower, Amy Elizabeth. "Receptor Functions of the Receptor-Type Protein Tyrosine Phosphatase PTPRO". Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/303.
Testo completoAbstract (sommario):
Protein tyrosine phosphorylation regulates many aspects of cell growth and differentiation. Since cellular tyrosine phosphorylation levels are controlled by the antagonizing actions of the protein tyrosine kinases (PTKs) and the protein tyrosine phosphatases (PTPs), these enzymes play a direct role in regulating processes as diverse as oncogenesis and neuronal development. In particular, the transmembrane group of PTPs, known as the receptor-type protein tyrosine phosphatases (RPTPs), has been linked to regulation of axon growth and guidance during development and regeneration. The regulation of activity of these RPTPs is of clear importance, yet the fundamental mechanisms underlying this regulation are poorly understood. While extracellular ligands are well known to dimerize and activate the receptor protein tyrosine kinases, the extent to which RPTP regulation parallels this scenario is largely unknown. We have examined the dimerization state and the relationship this state has with the phosphatase activity of the neuronal RPTP, PTPRO. We have found that PTPRO, a Type III RPTP, can exist in a dimerized state, likely regulated by disulfide linkages in the intracellular domain. Ligand addition to a chimeric PTPRO increases dimerization of the transmembrane and intracellular domains. Ligand addition to the chimeric PTPRO also decreases its phosphatase activity towards artificial peptides and a putative substrate, TrkC, a protein also known to be important in neuronal development. PTPRO's regulation of TrkC may be physiologically relevant as the proteins can be co-precipitated from transfected cells and PTPRO's dephosphorylation of TrkC is efficient compared to that of other RPTPs. The decrease in PTPRO's activity upon ligand-induced dimerization was unexpected as dimerization of a structurally-similar RPTP family member suggested the opposite functional outcome. This work suggests a complex relationship between dimerization and activity for the Type III RPTPs, which include PTPRO. The results presented in this dissertation will extend the current knowledge on RPTP functions and the cellular processes they regulate.
6
Patel, Dhaval Subhas. "Analysis of the daf-2 insulin/igf-1 receptor gene in Caenorhabditis elegans". Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445066/.
Testo completoAbstract (sommario):
The daf-2 gene is a key regulator of growth, metabolism and longevity in the nematode Caenorhabditis elegans. The DAF-2 receptor functions in a pathway that is analogous to mammalian insulin/insulin-like growth factor signalling and determines whether animals proceed with full reproductive development or arrest in a long-lived diapausal state known as the dauer larva. Temperature-sensitive hypomorphic mutants of daf-2 constitutively arrest as dauers when raised at non-permissive temperatures. At permissive temperatures the animals develop into adults that are long-lived compared to wild-type adults. These alleles of daf-2 can be separated into two distinct classes (1 and 2) based on their pleiotropic phenotypes. In addition to their phenotypic differences, the two classes also differ in their epistatic interactions with other genes involved in dauer formation, suggesting that the DAF-2 receptor has multiple signalling outputs. In this thesis I have investigated the nature of the daf-2 allele class difference using a range of methods, including sequence analysis and homology modelling of mutant receptors. This generated the prediction that signalling flux through the receptor is a determinant of the class difference, with class 2 alleles having an asymmetrical alteration in signal transduction through DAF-2. Experimental testing of these predictions suggest that some phenotypes such Eat and Unc may be associated with asymmetrical signalling, while others such as early larval arrest may be correlated with a reduction in receptor level at the plasma membrane. A comparative analysis of the DAF-2 receptor with its homologues from Caenorhabditis briggsae, Caenorhabditis remanei and the parasitic nematode Brugia malayi suggests the large C-terminal extension in the Caenorhabditis species, which shorter in Brugia and not present in vertebrates, is an adaptive trait that has evolved by exon duplication for rapid growth and development and may contribute to the shortevity of these species. In addition, I have also performed an analysis of ins-7 and ins-35, two putative ligands of DAF-2 that are differentially regulated by the transcription factor DAF-16, using RNAi. Knockdown of both these genes lead to slight lifespan extension (10-20%) at 20 °C in all genetic backgrounds and slight suppression (-10%) at 25 °C in long-lived daf-2 mutant backgrounds compared to controls. This suggests that INS peptides may function as agonists a 20 °C and antagonists at 25 °C, and that this behaviour may be independent of their transcriptional regulation.
7
Hatcher-Solis, Candice N. "PHARMACOLOGICAL IMPLICATIONS OF ADENOSINE 2A RECEPTOR- DOPAMINE TYPE 2 RECEPTOR HETEROMERIZATION". VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4458.
Testo completoAbstract (sommario):
G protein-coupled receptors (GPCRs) are heptahelical, transmembrane proteins that mediate a plethora of physiological functions by binding ligands and releasing G proteins that interact with downstream effectors. GPCRs signal as monomers, complexes of the same receptor subtype (homomers), or complexes of different receptor subtypes (heteromers). Recently, heteromeric GPCR complexes have become attractive targets for drug development since they exhibit distinct signaling and cell-specific localization from their homomeric counterparts. Yet, the effect of heteromerization on the pharmacology of many GPCR homomers remains unknown. Therefore, we have undertaken the task to examine the effect of heteromerization on Gs signaling through the adenosine 2A receptor (A2AR) and Gi signaling through the dopamine type 2 receptor (D2R) since the A2AR-D2R heteromer is an emerging therapeutic target for Parkinson’s disease (PD). We examined the effect of heteromerization on A2AR and D2R homomeric signaling using electrophysiology and the Xenopus laevis oocyte heterologous expression system. G protein-coupled inwardly rectifying potassium channels (GIRKs) were used as reporters for Gi signaling because activation leads to direct Gbeta-gamma (Gβγ)-mediated stimulation of the GIRK current. We also coupled GIRK channels to Gs signaling by overexpressing Gαs and signaling throughGαsβγ. Our electrophysiological assay is innovative because it allows us to optimize the conditions of heteromerization and directly observe GPCR signaling at the G protein level. Our data demonstrate that heteromer formation alone decreases dopamine-elicited Gi signaling through the D2R and CGS-21680-elicited Gs signaling through the A2AR. Furthermore, this reciprocal antagonism was predominately due to changes in efficacy versus potency. We also examined crosstalk observing that applying agonists or antagonists to the adjacent receptor further modulate this inhibition with the combination of agonists and antagonists relieving inhibition. Mutating the A2AR-D2R heteromer interface abrogated all of the aforementioned ligand-induced effects on G protein signaling through the A2AR-D2R heteromer. We are currently aiming to validate our results from the oocyte experiments with an in vivo model. Our data further elucidate the effect of various ligands on G protein signaling through the A2AR- D2R heteromer, which may facilitate future studies that examine A2AR-D2R heteromer signaling.
8
Phillips, Timothy Trevor. "A study of metabotropic glutamate receptor type 2". Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624330.
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9
DE, DOMENICO EMANUELA. "Role of type-2 cannabinoid receptor in reproduction". Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2016. http://hdl.handle.net/2108/202948.
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10
Daws, Michael Rory. "Hormone responsiveness in breast cancer cell growth : the role of the type I IGF receptor". Thesis, University of Newcastle Upon Tyne, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284225.
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11
Sophocleous, Antonia. "Role of type 2 cannabinoid receptor in bone metabolism". Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/5940.
Testo completoAbstract (sommario):
Cannabinoid receptors play an important role in regulating bone mass and bone turnover. Studies in our laboratories have shown that young mice lacking type 1 cannabinoid receptor (CNR1-/-) had increased bone mass and were resistant to ovariectomy-induced bone loss. Other workers have reported that type 2 cannabinoid receptor knockout mice (CNR2-/-) develop age-related osteoporosis. The aim of this PhD thesis was to further investigate the role of CNR2 in bone metabolism in vitro and in vivo, using genetic and pharmacological approaches. This study showed that CNR2-/- mice had normal bone mass and bone turnover at 3 months of age, but following ovariectomy, CNR2-/- mice were partially protected from bone loss, because of a mild defect in osteoclast formation and bone resorption. In keeping with this, studies in vitro showed that RANKL-stimulated bone marrow cultures from CNR2-/- mice had fewer osteoclasts than cultures from wild type littermates. The CNR2-selective antagonist/inverse agonist AM630, inhibited osteoclast formation in wild type bone marrow cultures in vitro and prevented ovariectomy-induced bone loss in wild type mice in vivo. In contrast, osteoclast cultures from CNR2-/- mice were resistant to the inhibitory effects of AM630 at low concentrations and CNR2-/- ovariectomised mice did not respond to its protective effects at low doses, consistent with a CNR2- mediated effect. These results indicate that CNR2 regulates bone loss under conditions of increased bone turnover, such as ovariectomy, by affecting osteoclast differentiation and function. CNR2-deficient mice developed accelerated age-related osteoporosis and by 12 months of age they had a significant reduction in osteoblast numbers and bone formation, whereas osteoclast numbers remained comparable to wild type littermates. In agreement with this, osteoblasts derived from bone marrow of CNR2-/- mice had reduced PTHstimulated alkaline phosphatase activity and ability to form bone nodules, when compared with wild type cultures. The CNR2-selective agonist, HU308, stimulated bone nodule formation in wild type calvarial osteoblast cultures in vitro and reversed ovariectomy-induced bone loss in wild type mice in vivo. HU308 had blunted effects on bone nodule formation in cultures from CNR2-/- mice and no significant effects on ovariectomy-induced bone loss in CNR2-/- mice, indicating a CNR2-mediated effect. These studies demonstrate that CNR2 protects against age-related bone loss by mainly enhancing osteoblast differentiation and bone formation. In conclusion, type 2 cannabinoid receptors protect from bone loss by maintaining bone remodelling at balance. In addition, type 2 cannabinoid receptor agonists show evidence of anabolic activity, whereas antagonists/inverse agonists show evidence of antiosteoclastic activity in vitro and in vivo.
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Netherland, Courtney Denise. "Role of Type 2 Cannabinoid Receptor (CB2) in Atherosclerosis". Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etd/1392.
Testo completoAbstract (sommario):
Atherosclerosis is a macrophage-dominated nonresolving inflammatory disease of the arterial wall. Macrophage processes, including apoptosis, influence lesion development in atherosclerosis. Cannabinoids, compounds structurally related to Δ9-tetrahydrocannabinol (THC), the active ingredient in marijuana, exert their effects through cannabinoid receptors, CB1 and CB2. Cannabinoid treatment, THC or Win55,212-2, reduces atherosclerosis in ApoE-null mice by a mechanism thought to involve CB2. However, the exact role of CB2 in atherosclerosis remains unclear. We found that CB2-null macrophages are resistant to oxysterol/oxLDL-induced apoptosis leading us to hypothesize that CB2 may modulate macrophage apoptosis in atherosclerosis. To determine the functions of CB2 in atherosclerosis, we fed low density lipoprotein receptor-null (Ldlr-/-) and Ldlr-/- mice genetically deficient in CB2, an atherogenic diet for 8 and 12 weeks. CB2 deficiency did not significantly affect aortic root lesion area after 8 or 12 weeks; however, after 12 weeks, CB2-deficient lesions displayed increased lesional macrophage and smooth muscle cell (SMC) content and a ~2-fold reduction in lesional apoptosis. CB2-deficienct lesions also displayed reduced collagen content and elevated elastin fiber fragmentation that was associated with elevated levels of the extracellular matrix degrading enzyme, matrix metalloproteinase 9 (MMP9). These results demonstrate that although CB2 signaling does not affect atherosclerotic lesion size it does modulate lesional apoptosis, cellularity and ECM composition. Ldlr-/- and CB2-deficient Ldlr-/- mice were also subjected to daily treatments with Win55,212-2, a synthetic cannabinoid, over the last 2 weeks of an 8 week atherogenic diet to identify CB2-dependent and CB2-independent effects of cannabinoid receptor stimulation on atherosclerosis. Win55,212-2 did not affect hypercholesterolemia, aortic root lesion area, lesional macrophage infiltration, or ECM composition in either genotype but did significantly reduce total plasma triglyceride levels and lesional SMC content, independent of CB2. Surprisingly, lesional apoptosis was dose-dependently repressed by Win55,212-2 in Ldlr-/- mice by a CB2-dependent mechanism. All together, these results support the suggestion that CB2 may be a target for novel therapies aimed at modulating lesional apoptosis and cellularity to increase lesion stability and reduce the vulnerability to rupture.
13
Vasilcanu, Radu. "Regulation of insulin-like growth factor-1 receptor expression and signaling /". Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-244-6/.
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14
Strömberg, Thomas. "The regulation of growth and survival in human multiple myeloma cells by IGF-I receptor signaling /". Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3586.
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15
Knowlden, Janice M. "Role of insulin-like growth factor-type 1 receptor (IGF-IR) signalling in tamoxifen-resistant breast cancer". Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/55695/.
Testo completoAbstract (sommario):
The aim of the first part of this thesis was to determine the role played by IGF-IR in mediating the growth of EGFR-positive tamoxifen-resistant variants of MCF-7 Tam-R and T47D T47D-R breast cancer cell lines. The results identify a general tamoxifen-resistant mechanism whereby the autocrine release and action of IGF-II, mediated through the IGF-IR, plays a significant and crucial supporting role in regulating basal EGFR/MAPK signalling and cell proliferation and this occurs via a c-SRC-dependent mechanism in both Tam-R and T47D-R cells. The latter aim of this thesis was to determine further mechanisms of cross-talk between EGFR and IGF-IR in a range of EGFR-positive cancer cell lines. These studies identified a novel physical interaction between the EGFR and IRS-1 in each of these cell lines. In Tam-R breast and LNCaP prostate cancer cells, recruitment of IRS-1 by EGFR limited the availability of IRS-1 to associate with IGF-IR, thus inhibiting IGF-IR signalling capacity. Blockade of EGFR activity with gefitinib allowed re-association of IRS-1 with IGF-IR and re-establishment of IGF-IR signalling, the dominant growth regulatory mechanism of gefitinib resistance in Tam-R cells. Thus, gefitinib played an active role in limiting its own efficacy in these cells by promoting activation of a resistance pathway. Importantly, induction of this pathway by gefitinib could be abrogated by co-treatment with an IGF-IR inhibitor. Such findings identify the IGF-IR as a potential therapeutic target for the treatment of both tamoxifen-resistant and gefitinib-resistant breast and prostate cancers.
16
Long, Li. "Regulation of tumor cell invasion and metastasis by the type I insulin-like growth factor receptor (IGF-1R)". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0018/NQ44499.pdf.
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Marsh, Andrew. "Characterisation of the type I IGF receptor binding surfaces of insulin-like growth factor 1 using protein engineering". Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245705.
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de, Bock Charles Edo St George Clinical School UNSW. "Novel protein interactors of urokinase-type plasminogen activator receptor". Awarded by:University of New South Wales. St George Clinical School, 2005. http://handle.unsw.edu.au/1959.4/23009.
Testo completoAbstract (sommario):
The plasminogen activator (PA) system plays an important role in cell adhesion, migration and invasion, and may require the coordinated expression of various proteins. The human urokinase-type plasminogen activator (uPA) receptor (uPAR) is a central protein component of the PA system. By binding its ligand uPA, uPAR can direct proteolysis of the extracellular matrix. Also, it is now apparent that uPAR can initiate proteolytic independent signal transduction to influence angiogenesis, inflammation, wound repair and tumour progression. To determine whether any novel proteins interacted with uPAR, a yeast two-hybrid screening analysis was undertaken using alternate uPAR domain constructs as baits. These included full-length three domain uPAR (uPAR-DIDIIDIII), two domain uPAR (uPAR-DIIDIII), and each individual uPAR domain (uPAR-DI, uPAR-DII and uPAR-DIII). A number of proteins were identified as putative candidate interactors for the alternate constructs, with two of special interest for uPAR-DIDIIDIII. These were the heat shock protein Mrj, and the extracellular matrix protein fibulin-2. The protein Mrj was shown to bind uPAR both in vitro and in vivo using GST-pull down and co-immunoprecipitation assays respectively. The GST-pull down assay identified the interaction between Mrj and uPAR dependent on the C-terminal domain of Mrj and DI of uPAR. Using in vivo co-immunoprecipitation analysis, Mrj also bound to uPAR. Preliminary data suggest the association between uPAR and Mrj may play a role in the regulation of apoptosis. In regard to the uPAR interactor of fibulin-2, a calcium dependent binding interaction with uPAR was identified using the GST-pull down assay. However due to the large molecular weight and stringent conditions needed to solubilise fibulin-2, it was not possible to co-immunoprecipitate both uPAR and fibulin-2. Together, the identification of both Mrj and fibulin-2 amongst other candidate interactors of uPAR presented here provides further insight into the intricate relationship between uPAR and other proteins which may influence a range of biological functions.
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Fulmer, Makenzie. "Role of Cannabinoid Receptor Type 2 (CB2) in Late Stage Atherosclerosis". Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etd/3328.
Testo completoAbstract (sommario):
Atherosclerosis is a chronic inflammatory disorder of medium and large vessels. Immune signaling and dyslipidemia are two of several processes which influence lesion development in atherosclerosis. Cannabinoids, such as those found in marijuana, exert their effects through two cannabinoid receptors, CB1 and CB2. Recent studies using CB2 knockout mice and CB2-selective ligands have shed light on a protective role of CB2 in early stages of atherosclerosis. However, the role of CB2 in advanced stages of atherosclerosis remains unclear. To determine if CB2 plays a role in advanced atherosclerotic lesion composition and progression, we investigated the effects of systemic CB2 gene deletion on advanced atherogenesis in Ldlr-null mice fed an atherogenic high fat diet (HFD) for 20-24 weeks. CB2 deficiency did not significantly affect aortic root lesion area, however, CB2-/- mice had a significant increase (~1.9 fold) in the percentage of abdominal aorta surface occupied by lesion. CB2-/- mice also displayed increased lesional macrophage content (~2.3 fold) and an unstable phenotype characterized by significantly reduced smooth muscle cell/macrophage ratio and increased matrix metalloproteinase-9 activity and mineralization. These results suggest that although CB2 does not affect the size of atherosclerotic lesions, it does modulate the cellular and extracellular matrix composition and promotes a stable phenotype. CB2+/+ and CB2-/- mice were also subjected to treatments with either CB2-selective agonist, JWH-015, or antagonist, SR144528, over the last four weeks of a 24 week atherogenic diet to identify the effects of CB2 stimulation on calcification of advanced lesions. No change was observed in body weight or cholesterol in response to either treatment. SR144528 reduced triglycerides and mineralization of aortic root lesions in CB2+/+ mice only. Aortic Runx2 and osteopontin were increased in response to JWH-015 by a CB2-dependent mechanism. Administration of synthetic cannabinoids in an ex vivo organ culture of CB2+/+ aortas revealed increased vascular calcification in response to CB2 blockade and decreased vascular calcification in response to CB2 activation. All together, these results support a protective role for CB2 in late stages of atherosclerosis and suggests that drugs targeting CB2 may be beneficial in the treatment of advanced atherosclerosis by affecting osteogenic mechanisms implicated in the mineralization of lesions.
20
Girnita, Ada. "Targeting insulin-like growth factor-1 receptor in cancer /". Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-041-9/.
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21
Rodríguez, Eduardo. "Virion- and VAP-receptor recognition in the human adenovirus type 2 system". Lund : Lund University, 1998. http://catalog.hathitrust.org/api/volumes/oclc/68945080.html.
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Moir, Michael. "The Design and Synthesis of Novel Selective Cannabinoid Receptor Type 2 Ligands". Thesis, The University of Sydney, 2019. https://hdl.handle.net/2123/21946.
Testo completoAbstract (sommario):
The cannabinoid type 2 receptor (CB2R) is involved in the pathophysiology of numerous diseases. It is believed that in response to injury or damage, activation of CB2Rs triggers protective mechanisms for the resolution of inflammation and its associated symptoms. While many selective CB2R ligands have demonstrated promising results in pre-clinical animal models, no CB2R-based therapeutics are currently used in the clinic. Therefore, there is a grave need to develop novel, more efficacious and safer drugs that target the CB2R. Using a known pyrazolylidene benzamide agonist as a lead compound we systematically investigated the validity of a preliminary pharmacophore model. A library of heteroaromatic benzamides was prepared to explore how the heteroaromatic core influences functional activity. It was found that the –ylidene amide functionality of the lead compound is imperative for functional activity. To further investigate this, we prepared a library of analogues with varied linkage moieties between the heteroaromatic core and substituted phenyl group. This study culminated in the discovery of a novel pyrazolotriazine agonist with low nanomolar potency and complete selectivity over the CB1R. In recent years, synthetic cannabinoids have become a popular alternative to recreational cannabis use. We decided to use these simple scaffolds to design selective CB2R agonists as potential therapeutic drugs. Movement of the amide substituent of non-selective indole 3-carboxamide synthetic cannabinoids to the 2-position was demonstrated to be a simple and general strategy to abolish CB1R activity. Likewise, the use of a 7-azaindole scaffold in conjunction with judicious choice of substituents was shown to be a reliable way to design CB2R selective agonists. Allosteric modulation of the CB2R is thought to pose a number of advantages over orthosteric activation. A recent report of the first synthetic allosteric modulator of the CB2R inspired our efforts to develop novel allosteric modulators. Scaffold hopping from the 2-pyridone core of the lead compound led to a small library of potential modulators. The in vitro evaluation of these compounds is currently in progress.
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Mercado-Matos, Jose R. "A Mechanistic Investigation of Insulin Receptor Substrate 2 Function in Breast Cancer Progression". eScholarship@UMMS, 2017. http://escholarship.umassmed.edu/gsbs_diss/918.
Testo completoAbstract (sommario):
The advancement of cancer treatment depends on understanding the biological processes that contribute to disease progression. The spread of tumor cells from the primary site to distant organs is the biggest obstacle to efficacious treatment. The insulin receptor substrate (IRS) proteins IRS1 and IRS2 are cytoplasmic adaptor proteins that organize signaling events downstream of the Insulin receptor (IR) and the Insulin-like growth factor receptor 1 (IGF1R). Both of these receptors have been implicated in cancer progression. The IRS proteins share a significant level of homology and are both capable of recruiting and activating phosphatidylinositol-3 kinase (PI3K). Despite these similarities, signaling through IRS1 and IRS2 leads to distinct tumor cell outcomes in vitro and in vivo. In vitro, IRS1 regulates cell proliferation and growth and IRS2 regulates metabolism, survival and invasion. In vivo, Irs2 is a positive regulator of tumor metastasis, whereas Irs1 does not promote metastasis. The major objective of this thesis work was to further the understanding of the mechanism by which IRS2 signaling regulates tumor progression.
To investigate how IRS-1 and IRS-2 regulate distinct tumor cell outcomes, I examined the involvement of the microtubule cytoskeleton in IRS-dependent signaling. I determined that IRS2-mediated AKT activation is dependent upon an intact microtubule cytoskeleton, whereas IRS1-mediated AKT signaling occurs independently of microtubules. As a result, drugs that disrupt microtubules promote apoptosis in cells that signal through IRS2, but cells that signal through IRS1 are resistant to the effects of microtubule disruption. However, AKT inhibition sensitizes IRS1-dependent cells to apoptotic cell death upon microtubule disruption. From a clinical perspective, my studies identify IRS2 as a potential biomarker for the response of breast cancer patients to anti-microtubule drug therapy. To investigate further the mechanism of IRS2 contributions to tumor progression, I employed a mutagenesis approach to identify structural requirements of IRS2 for its function. I established that the ability of IRS2 to activate PI3K is necessary for its regulation of both invasion and tumor initiating cell (TIC) self-renewal. I also identified two independent regions within the IRS2 C-terminus that are required for invasion and self-renewal, respectively. Characterization of the invasion-promoting region identified BMP2-induced protein kinase (BMP2K) as an interacting protein. Suppression of BMP2K expression in mammary tumor cells disrupts IRS2-mediated tumor cell invasion. Taken together, my work advances the understanding of how IRS2 contributes to breast cancer progression and provides a molecular understanding for the development of novel approaches for the treatment of breast cancer and other malignancies that rely upon IRS2.
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Vasilcanu, Daiana. "IGF-1R inhibition : a tool for functional studies of insulin-like growth factors family in malignant cells /". Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-643-3/.
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Ehrnborg, Christer. "Growth hormone in athletes /". Göteborg : Department of Internal Medicine, Institute of Medicine, The Sahlgrenska Academy at Göteborg University, 2007. http://hdl.handle.net/2077/4709.
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26
Stumpf, Alexander [Verfasser]. "Cannabinoid type 2 receptor-mediated cell type-specific self-inhibition in hippocampal and cortical neurons / Alexander Stumpf". Berlin : Freie Universität Berlin, 2019. http://d-nb.info/1190087871/34.
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Colón, Eugenia. "Autocrine and paracrine regulation of Leydig cell survival in the postnatal testis /". Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-275-0/.
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Metcalfe, Beverly Lynn. "Defining the role of the angiotensin ii type 2 receptor in cardiovascular disease". [Gainesville, Fla.] : University of Florida, 2004. http://wwwlib.umi.com/cr/ufl/fullcit?p3136977.
Testo completoAbstract (sommario):
Thesis (Ph.D.)--University of Florida, 2004.Typescript. Title from title page of source document. Document formatted into pages; contains 136 pages. Includes Vita. Includes bibliographical references.
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Bhandari, R. N. B. "Characterization of a cell adhesion receptor on rat lung alveolar type 2 cells". Thesis, Imperial College London, 1988. http://hdl.handle.net/10044/1/46962.
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30
Chu, Yatson. "Herpes simplex virus type 2 regulates the IFN-gamma receptor expression and function". Thesis, University of Ottawa (Canada), 2003. http://hdl.handle.net/10393/26460.
Testo completoAbstract (sommario):
This study shows that HSV-2 can cause down-regulation in IFN-gammaR expression on the monocyte surface in both HSV-2 seropositive and seronegative patients. The objective of this work is to examine and explain the mechanisms involved in the viral down-regulation of IFN-gammaR. The first question I tried to answer was whether humoral factors might participate in this down-regulation. Humoral factors were not involved in this phenomenon. Next, cell-to-cell interactions were examined. T, B or natural killer cell depletion experiments were conducted in peripheral blood mononuclear cells of both HSV2 seropositive and seronegative patients. The results suggest that NK cells and T cells but not B cells were involved in the IFN-gammaR downregulation in HSV-2 seropositive patients. In addition, purified monocytes also demonstrated IFN-gammaR down-regulation after HSV-2 exposure in seropositive patients. I concluded that, in HSV-2 seropositive patients, NK cells may have an inhibitory effect and T cells may have a facilitatory role in the down-regulation of IFN-gammaR. (Abstract shortened by UMI.)
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Franklin, Zara Jane. "Evaluation and characterisation of novel glucagon receptor antagonists for type 2 diabetes therapy". Thesis, University of Ulster, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.588499.
Testo completoAbstract (sommario):
Glucagon receptor antagonism is becoming a key target area for type 2 diabetes treatment. This thesis evaluates the potential of novel peptide-based glucagon receptor analogues for type 2 diabetes therapy. Structural modifications of the well established glucagon analogue, desHis1Glu9-glucagon, was used to develop novel glucagon analogues. All peptide analogues were resistant to DPP-4 degradation and effectively antagonised glucagon-mediated cAMP production and insulin secretion when tested in vitro. desl-lis'Glu'-glucagon had a duration of biological action of 8 h and effectively antagonised glucagon-mediated glucose and insulin release in vivo. Mid-chain acylation of desl-lis'Glu/-glucagon did not hinder acute antagonistic properties and prolonged the duration of biological action to 24 h. An additional y-glutamyl Iinker in combination with acylation resulted in similar biological activity. C-terminal acylation also effectively antagonised acute glucagon-mediated glucose production in vivo. However, a C-terminal miniPEGylated version did not exhibit antagonistic properties. In general C-terminal modifications resulted in analogues with reduced acute biological activity indicating that mid-chain acylation was more effective. Pro4 substitution for Gly" without G1u9 replacement also resulted in reduced biological efficacy in relation to antagonising glucagon-mediated actions. However, Pro4 substitution did not hinder the activity of desl-lis'Glu'i-glucagon, emphasising the important role of Glu9 in biological activity. C-terminal acylation of this Pro4 analogue reduced its acute action in animals. However, chronic administration of non-acylated and mid-chain acylated forms of this Pr04 analogue improved metabolic status in high fat fed mice. Furthermore, chronic administration of the non-acylated Pro4 analogue exhibited similar beneficial effects as exendin-4 in high fat fed mice, but additive effects of combined administration were not evident. This thesis demonstrates that peptide-based glucagon antagonists exhibit prominent anti-diabetic effects in animal models of obesity-diabetes, and illustrates the necessity to further establish peptide-based glucagon receptor antagonists for type 2 diabetes therapy
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Ma, Ching-man, e 馬靜雯. "Molecular epidemiology and characterization of the receptor binding ofporcine circovirus type 2 (PCV2)". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B38227204.
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Li, K. "Interactions of complement receptor type 2 with C3d and factor H with C3u". Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/769696/.
Testo completoAbstract (sommario):
Complement receptor type 2 (CR2, CD21) is a cell surface protein that links the innate and adaptive immune response through its binding to C3d, a cleavage fragment of the major complement component C3. Factor H (FH) is a major plasma protein that is the major regulator of the activity of C3b in the alternative pathway. FH binds to C3u, which is formed from C3 by hydrolysis, and C3u shows functional similarities to C3b. In this thesis, X-ray scattering, analytical ultracentrifugation and constrained modelling were used to determine solution structures and interactions of CR2 with C3d and FH with C3u. Structural studies reveal that the overall CR2 structure is unaffected by change in ionic strength or when C3d is bound to it. Unbound C3d exists in monomerdimer and monomer-trimer equilibria in low salt buffer, but as a monomer only in physiological buffer. The CR2-C3d interaction is not formed in physiological salt conditions, but was observed in low salt conditions. The solution structure and selfassociation of C3u were investigated. C3u underwent weak salt-dependent dimerisation, similar to that for C3d. Modelling showed that the functionally-important TED/CUB domains in the C3d part of C3u were extended away from the rest of the C3u structure. This TED/CUB conformation is intermediate between those of C3 and C3b. C3u and FH were observed to interact as 1:1 and 2:1 complexes in a salt-dependent manner. The modelling of the interaction showed that no major conformational changes occurred in C3u or FH, and suggested that C3u binds separately to FH at two independent sites. These results provide new insights in the activation of C3 and the complement regulatory activity of CR2 and FH.
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Souto, Maior Mourão Sá D. "Characterisation of the C-type lectin receptor CLEC-2 : expression, ligands and functions". Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1302407/.
Testo completoAbstract (sommario):
Myeloid cells express a plethora of C-type lectin receptors (CLR) that can regulate inflammatory responses. Dectin-1 belongs to a sub-family of CLRs that possesses an extracellular C-type lectin domain (CTLD) and a single YxxL intracellular motif (hemITAM) that allows signalling via Syk kinase and induction of downstream functions. Based on consensus sequences for the CTLD and hemITAM, we identified CLEC-2 as a dectin-1-like receptor. CLEC-2 was previously characterised as a Syk-coupled platelet receptor able to induce platelet aggregation when targeted by the snake venom rhodocytin and by cells expressing the endogenous protein podoplanin. I generated monoclonal antibodies against mouse CLEC-2 and found that CLEC-2 is also expressed on lymphoid and myeloid cells, including dendritic cells (DC). Notably, treatment with LPS increases CLEC-2 expression by myeloid cells and synergises with CLEC-2 signaling to induce increased secretion of IL-10 but not IL-12. This increased IL-10 production is also observed in the serum of mice administered with anti-CLEC-2 mAb and LPS, and is dependent on the presence of macrophages and DCs. Furthermore, I generated a CLEC-2 conditional KO mouse line that will provide a tool to study CLEC-2 function in myeloid cells in vivo. Collectively, these data indicate that CLEC-2 expression is not restricted to platelets and that it plays a role on the vascular development and modulation of TLR responses.
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Seta, Koichi. "Study on mechanisms for angiotensin 2 type 1 receptor-mediated tyrosine kinase activation". Kyoto University, 2008. http://hdl.handle.net/2433/135926.
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Goto, Masahisa. "Growth-Dependent Induction of Angiotensin II Type 2 Receptor in Rat Mesangial Cells". Kyoto University, 2001. http://hdl.handle.net/2433/150550.
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37
Sehat, Bita. "SUMO and ubiquitin; the yin and yang of IGF-1R function /". Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-360-3/.
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Rosengren, Linda. "Targeting the GH/IGF-1 axis with novel, small molecule inhibitors /". Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-346-7/.
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Bode-Rhoads, Michelle Lynn. "Regulation of the growth hormone receptor, insulin-like growth factor (IGF) I and IGF binding protein 2 in reproductive tissues of dairy cattle during lactation and associated effects on fertility". free to MU campus, to others for purchase, 2004. http://wwwlib.umi.com/cr/mo/fullcit?p3164490.
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Digirolamo, Douglas J. "Growth hormone signaling and action in osteoblasts". Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2009r/digirolamo.pdf.
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Boulle, Nathalie. "Analyse du système des insulin-like growth factors (IGF) et du fibroblast growth factor-2 (FGF-2) dans la tumorigenèse corticosurrenalienne". Paris 11, 2000. http://www.theses.fr/2000PA11T006.
Testo completoAbstract (sommario):
Dans les tumeurs corticosurrénaliennes, des anomalies de la région 11p15 et une surexpression du gène d'IGF-11 sont contemporaines de l'acquisition du phénotype malin. Nous montrons que la surexpression du gène IGF-11 dans les tumeurs corticosurrénaliennes malignes s'accompagne d'une traduction efficace de la protéine, majoritairement sous forme de précurseurs d'IGF-11. Ces mêmes tumeurs surexpriment de manière spécifique IGFBP-2, protéine de liaison des IGF fréquemment associée à la prolifération tumorale. La caractérisation de la lignée H295R, dérivée d'un carcinome surrénalien, montre que celle-ci surexprime IGF-11 et IGFBP-2 et constitue un bon modèle in vitro d'ét•ude de la tumorigénèse corticosurrénalienne. Cette lignée a permis de démontrer qu'IGF-11 était impliqué dans la prolifération des cellules tumorales corticosurrénaliennes via le récepteur de type 1 des IGF. L'intérêt de I'IGFBP-2 plasmatique en tant que marqueur circulant des tumeurs corticosurrénaliennes malignes a été évalué. Nous montrons que les taux d'IGFBP-2 plasmatique s'élèvent spécifiquement chez les patients porteurs de tumeurs malignes mais que cette élévation survient à lin stade avancé de la maladie (stade métastatique), indiquant la faible sensibilité d'IGFBP-2 et son intérêt limité comme marqueur des carcinomes surrénaliens. Les effets de FGF-2 sur les cellules tumorales corticosurrénaliennes ont également été étudiés. Nos résultats montrent que FGF-2 a un effet prolifératif sur les cellules H295R mais que paradoxalement, il inhibe l'expression du système des IGF par ces cellules. L'inhibition d'IGFBP-2 se fait au niveau transcriptionnel, alors que celle d'IGF-11 est post-transcriptionnelle, par inhibition de la maturation des précurseurs d'IGF-11. Ainsi, si IGF-11 a un rôle indiscutable au stade tardif de la tumorigénèse corticosurrénalienne, différents facteurs sont susceptibles de moduler son expression (FGF-2) ou son activité (IGFBP-2) au sein du tissu tumoralLn adrenocortical tumors, malignant phenotype is associated with abnormalities at the 11p15 locus and overexpression of the IGF-11 gene. Here, we show that IGF-11 mRNA is efficiently translated and that malignant adrenocortical tumors contain large amounts of IGF-11 protein, mainly in its prohormone form. The same tumors exhibit a high content in IGFBP-2 protein, an IGFBP being frequently expressed in tumor cells. The H295R cell line, which is derived from a human adrenal carcinoma, express high levels of both IGF-11 and IGFBP-2 and represents a suitable in vitro model to study adrenocortical tumorigenesis. Using this cell line, we could demonstrate that IGF-11 is involved in the proliferation of adrenocortical tumor cells, after binding to the type 1 IGF receptor. The interest of plasma IGFBP-2 as a marker for adrenocortical carcinoma was evaluated. Our results show that high levels of IGFBP-2 are specifically detected in the plasma of patients with malignant adrenocortical tumors. However, the increase in IGFBP-2 levels occur at a late stage of tumor progression (metastatic stage). This indicates a poor sensitivity for plasma IGFBP-2, which may limit its interest as a tumor marker. We also studied the effects of FGF-2 on adrenocortical tumor cells. Our results indicate that FGF-2 is mitogenic for H295R cells, although it inhibits the expression of both IGF-11 and IGFBP-2 by these cells. The inhibition of IGFBP-2 expression occur at the transcriptional levels. Ln contrast, FGF-2 inhibits the secretion and the last steps of maturation of the IGF-11 precursor. Altogether, these results suggest that in malignant adrenocortical tumors, various factors may modulate the expression (FGF-2) or the effects (IGFBP-2) of IGF-11 on adrenocortical tumor cells
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Adachi, Yuichiro. "Angiotensin 2 type 2 receptor deficiency exacerbates heart failure and reduces survival after acute myocardial infarction in mice". Kyoto University, 2006. http://hdl.handle.net/2433/144310.
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Ruch, Claudia. "Structure / function analysis of the extracellular domain of vascular endothelial growth factor receptor-2 (VEGFR-2) /". Zürich : ETH/PSI, 2007. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=17030.
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Ma, Ching-man. "Molecular epidemiology and characterization of the receptor binding of porcine circovirus type 2 (PCV2)". Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B38227204.
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Surovy, André Martin. "Toll like Receptor 2 is highly expressed in lesions of Acne Inversa and colocalizes with C-type Lectin Receptor expression /". Bern : [s.n.], 2007. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Pickel, Lara Michelle. "Study of the role of the Angiotensin II (Ang II) type 2 receptor (AT[subscript]2) in lung tumorigenesis". Thesis, Manhattan, Kan. : Kansas State University, 2008. http://hdl.handle.net/2097/788.
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47
Cosaceanu, Daria. "The use of IGF-IR inhibitors in cancer therapy - a potential approach for sensitizing tumor cells to ionizing radiation /". Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-911-4/.
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Ribeiro, Tamaya Castro. "Análise da expressão e do silenciamento do receptor tipo 1 do fator de crescimento semelhante à insulina em tumores adrenocorticais humanos". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5166/tde-16032015-161040/.
Testo completoAbstract (sommario):
Introdução O sistema dos fatores de crescimento semelhantes à insulina (IGF) desempenha importante papel no crescimento e desenvolvimento celular normal. Hiperexpressão do gene IGF1R tem sido demonstrada em diversos tumores, sugerindo que a expressão deste receptor represente um pré-requisito fundamental para transformação celular. Nosso grupo de pesquisa demonstrou o aumento de expressão de IGF1R em tumores adrenocorticais pediátricos. Objetivos: Induzir o silenciamento do gene IGF1R por siRNA na linhagem de tumor adrenocortical humano NCI H295R, bem como avaliar os efeitos in vitro por meio da análise de proliferação celular e apoptose desta linhagem celular. Adicionalmente, avaliar a expressão de IGF-1R e de microRNAs relacionados a sua transcrição em tumores adrenocorticais humanos. Pacientes e métodos: A linhagem celular de carcinoma adrenocortical humano NCI H295R foi cultivada e submetida ao tratamento com 2 siRNAs específicos para IGF-1R. Todos os experimentos foram realizados em quatro grupos: (1) células não tratadas com siRNA, (2) células tratadas com siRNA # 1, (3) células tratadas com siRNA # 2 e (4) células tratadas com o siRNA controle negativo. A expressão gênica e proteica de IGF-1R foram determinadas por meio das técnicas de PCR em tempo real e Western Blot, respectivamente. Os efeitos do silenciamento de IGF-1R in vitro foram avaliados por ensaios de proliferação celular e análise de atividade de caspases. Além disso, 202 pacientes com tumor adrenocortical foram selecionados para o estudo de expressão proteica de IGF-1R por imunohistoquímica. Para avaliação de expressão de microRNAs relacionados à expressão de IGF-1R (miR-100, 375, 145 e 126) por PCR em tempo real foram selecionados 32 pacientes dos 202 disponíveis. Resultados: A expressão de IGF-1R foi significantemente diminuída nas células tratadas com siRNA # 1 e siRNA # 2. Os valores relativos de RNA mensageiro de IGF1R diminuíram aproximadamente 50% e as análises de Western Blot revelaram uma redução de 30% na proteína de IGF-1R. A diminuição de expressão foi acompanhada por uma redução de 40% na taxa de crescimento celular in vitro e um aumento de 45% das taxas de apoptose. A análise de expressão dos microRNAs 100, 375, 145 e 126 demostrou que a expressão de IGF-1R não se correlaciona com a expressão destes RNAs pequenos. Adicionalmente, a análise de expressão proteica de IGF-1R em tumores adrenocorticais humanos revelou que expressão forte (20%) de IGF-1R foi mais comum em carcinomas de adultos. Além disso, a imunolocalização do IGF-1R nos carcinomas (19%) foi mais frequentemente nuclear em relação aos adenomas de adultos. Conclusões: Os dados obtidos reforçam a importância de IGF-1R nas vias tumorigênicas das neoplasias malignas do córtex da glândula suprarrenal. A inibição deste receptor foi capaz de inibir o crescimento tumoral in vitro por meio da redução das taxas de proliferação celular e aumento da apoptose em linhagem celular de carcinoma adrenocortical humano. Além disso, a expressão proteica nuclear de IGF-1R foi mais comum entre os carcinomas, sugerindo representar um marcador biológico desta neoplasiaIntroduction: The insulin-like growth factor (IGF) system plays a key role in normal cell growth and development. IGF1R overexpression has been demonstrated in several tumors suggesting that its expression is a prerequisite for cell transformation. We demonstrated IGF1R overexpression in pediatric adrenocortical tumors. Objectives: To induce IGF1R silencing by siRNA in a human adrenocortical cell line NCI H295R and evaluate its effects on cell proliferation and apoptosis. Additionally, evaluate the expression of IGF-1R protein and microRNAs related to its transcription in human adrenocortical tumors. Patients and methods: The human adrenocortical tumor cell line NCI H295R was cultured and treated with 2 specific IGF1R siRNA. All experiments were carried out in four groups: (1) untreated NCI H295R cells, (2) NCI H295R cells transfected with specific IGF1R siRNA # 1, (3) NCI H295R cells transfected with specific IGF1R siRNA # 2 and (4) NCI H295R cells transfected with a negative control. IGF-1R gene and protein expression was determined by the techniques of real-time PCR and Western blot, respectively. We assessed the effects of IGF-1R silencing on cell proliferation and apoptosis. Moreover, 202 patients with adrenocortical tumors were selected for the study of IGF-1R protein expression by immunohistochemistry. In the analysis of microRNAs that are related to IGF1R (miR-100, 375, 145 e 126) by real time PCR, 32 out 202 patients were selected. Results: IGF-1R levels were significantly decreased in cells that were treated with IGF-1R siRNA # 1 and siRNA # 2. The relative values of IGF1R mRNA decreased approximately 50% and Western blot analysis revealed a 30% of reduction in IGF-1R protein. Downregulation of this gene was accompanied by a reduction in 40% of cell growth in vitro and an increase in 45% of apoptosis. The analysis of microRNAs demonstrated that IGF1R expression is not correlated with the expression of these small RNAs. Additionally, the analysis of IGF-1R protein expression in human adrenocortical tumors revealed that strong expression (20%) of IGF-1R was more common in adult carcinomas. Moreover, the nuclear IGF-1R was more frequent in carcinomas diagnosed in adults (19%) when compared to adenomas. Conclusions: These data demonstrate the importance of IGF-1R in tumorigenic pathways of malignant neoplasms of the adrenocortical gland. IGF-1R silencing could inhibit tumor growth in vitro by reducing cell proliferation and increasing apoptosis in a cell line of human adrenocortical carcinoma. Furthermore, nuclear IGF-1R expression was more frequent in carcinomas diagnosed in adults, suggesting that IGF-1R may be a biological marker of this neoplasia
49
Girnita, Leonard. "Growth factor pathways in human cancer : functional and therapeutic implications /". Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-307-4.
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Xie, Yuntao. "The biological role and clinical impact of SYT-SSX fusion gene and IGF-1R in synovial sarcoma /". Stockholm, 2002. http://diss.kib.ki.se/2002/91-628-5298-1.
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