Guanylyl cyclase receptors: Targets for medical intervention
鸟苷酸环化酶受体:医疗干预的目标
基本信息
- 批准号:7989868
- 负责人:
- 金额:$ 3.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-12-03 至 2010-02-28
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdipocytesAdipose tissueAmericasAngioplastyAnimalsArteriesAtherosclerosisBody WeightBreedingC-Type Natriuretic PeptideCell LineCellsChondrocytesClinicComplementDietDiseaseDwarfismEatingEmbryoFatty acid glycerol estersFibroblastsFigs - dietaryGTP-Binding ProteinsGenesGeneticGenetic ModelsGenomeGenomicsGuanylate CyclaseHealthHippocampus (Brain)HypertensionHypertrophyImmunoprecipitationIn VitroInhibition of Cell ProliferationInterventionKnock-outKnockout MiceLesionLifeLigandsLipolysisLiverLiver diseasesMediatingMedicalMembraneMolecularMolecular TargetMusNon-Insulin-Dependent Diabetes MellitusNucleic Acid Regulatory SequencesObesityPathway interactionsPhenotypePhosphorylationPhosphorylation SitePhysiologicalPrincipal InvestigatorProceduresProtein DephosphorylationProtein KinaseProtein phosphataseProteinsProtocols documentationReceptor ActivationReceptor GeneReceptor SignalingRegulationResearchResearch PersonnelRisk FactorsRoleSchemeSerumSeveritiesSignal PathwaySignal TransductionSmall Interfering RNASphingosine-1-Phosphate ReceptorTherapeuticTissuesTransgenesTransgenic OrganismsTranslationsWorkWound HealingYeastsadipocyte differentiationanalogatrial natriuretic factor receptor Bautocrinebasebonedentate gyrusdesensitizationestablished cell linehigh riskhuman diseasein vivoknock-downmouse modelparacrinepeptide Apolypeptide Cprogramspromoterreceptorreceptor expressionresearch studyresponserestenosissphingosine 1-phosphatesubcutaneousyeast two hybrid system
项目摘要
We will define the functions of GCB (NPR-B), a membrane guanylyl cyclase receptor activated by the local
paracrine/autocrine ligand, C-type natriuretic peptide (CNP). GCB is highly expressed in chondrocytes,
adipocytes and fibroblasts; GCB activation usually leads to an inhibition of cell proliferation and hypertrophy.
We recently identified sphingosine-1 -phosphate (S1P) as a potent, effective and highly specific GCB
desensitization factor. The first specific aim concentrates on the molecular pathway by which S1P
specifically induces GCB desensitization. These studies are important in that CNP, which acts as an
antagonist to S1P, is strongly implicated as having an important role in tissue remodeling, including
atherosclerosis, restenosis following angioplasty, and even liver disease. Mouse genetic models, siRNA and
interaction trap screens (immunoprecipitation, yeast two hybrid, Sos-Ras) will define proteins that mediate
the S1P-induced desensitization of GCB. In preliminary research we have already identified various
candidate GCB-associated proteins. These proteins will themselves be used in interaction trap screens to
define other molecules within the S1P-GCB desensitization pathway. Desensitization of GCB is ultimately
regulated by dephosphorylation of the receptor, and therefore the protein kinase/protein phosphatase
responsible for GCB regulation will be purified, identified and mechanisms of regulation determined. We also
have disrupted the GCB gene, and then corrected a severe dwarfism by expression of GCB specifically in
chondrocytes in the null background. These GCB animals contained almost no fat compared to wild-type
littermates. Therefore, the second specific aim concentrates on the functional roles of GCB in fibroblasts and
adipocytes. We will compare the effects of various treatments (in vitro and in vivo) on fibroblast and
adipocyte function, with particular emphasis on the role of GCB in tissue remodeling after wounding and in
adipocyte differentiation. The proposed studies will have significant and substantial implications in human
disease, since one of the largest health problems in America is obesity, often caused by an over-abundance
of fat cells. Obesity is a high risk factor for non insulin-dependent diabetes and hypertension. Thus, the
proposed research impacts on some of our most important medical issues, including wound repair,
atherosclerosis, restenosis following angioplasty, and a host of diseases associated with obesity.
我们将定义GCB (NPR-B)的功能,GCB是一种由局部激活的膜观基环化酶受体
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JOSEPH P ALBANESI其他文献
JOSEPH P ALBANESI的其他文献
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{{ truncateString('JOSEPH P ALBANESI', 18)}}的其他基金
Guanylyl cyclase receptors: Targets for medical intervention
鸟苷酸环化酶受体:医疗干预的目标
- 批准号:
7333226 - 财政年份:2006
- 资助金额:
$ 3.3万 - 项目类别:
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