Functional analysis of differentiation through PPARg

通过 PPARg 进行分化的功能分析

• 批准号: 6743642
• 负责人: WENLI YANG
• 金额: $ 4.73万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6743642
• 关键词: 3T3 cells; SDS polyacrylamide gel electrophoresis; adipocytes; affinity chromatography; autoradiography; cell differentiation; cofactor; electrospray ionization mass spectrometry; green fluorescent proteins; hormone receptor; hormone regulation /control mechanism; peroxisome proliferator activated receptor; phosphorylation; postdoctoral investigator; protein kinase; thermogenesis; western blottings; yeast two hybrid system

DESCRIPTION (provided by applicant): PPARgamma is a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear hormone receptor (NHR) superfamily of ligand-dependent transcription factors. It plays an important role in a number of pathways including in adipose differentiation, glucose homeostasis, atherosclerosis, and cancer. PPARgamma has a dominant effect in induction of adipose differentiation upon ligand activation. A major portion of this adipogenic activity is regulated by the N-terminal region of PPARgamma, a domain whose function is poorly characterized in PPARgamma and in the nuclear receptor family in general. The N-terminal region is also phosphorylated in response to growth factor stimulation, which in turn modulates PPARgamma activity. The proposed research aims to define and characterize the role of this domain in the regulation of PPARgamma function. Since this region contains adipogenic activity lacking or reduced in other PPAR isoforms, this work will also be important in defining functional specificity between different nuclear receptors that bind to the same DNA sequences. An adipogenic cofactor PGC-2 binds to this region and enhances transcriptional and adipogenic activities of PPARgamma. The function of PGC-2 will be characterized in detail. Secondly, novel factors that bind specifically to the PPARgamma N-terminus that regulate its function will be identified using biochemical methods. In addition, factors that associate with the N-terminus in a phosphorylation-dependent manner will also be isolated.

描述（由申请人提供）：Ppargamma是核激素受体（NHR）超家族的过氧化物酶体增殖物激活受体（PPAR）的成员。它在许多途径中起着重要作用，包括脂肪分化，葡萄糖稳态，动脉粥样硬化和癌症。 ppargamma在配体激活时脂肪分化的诱导具有主要作用。这种掺杂活性的主要部分受Ppargamma的N末端区域的调节，Ppargamma的N末端区域在Ppargamma和核受体家族中的功能较差。 N末端区域还响应生长因子刺激而被磷酸化，这反过来又调节了Ppargamma活性。拟议的研究旨在定义和表征该领域在PPARGAMMA功能调节中的作用。由于该区域包含其他PPAR同工型中缺乏或降低的掺杂活性，因此该工作对于定义与相同DNA序列结合的不同核受体之间的功能特异性也很重要。掺杂辅助辅因子PGC-2与该区域结合，并增强ppargamma的转录和成脂活性。 PGC-2的功能将详细表征。其次，将使用生化方法鉴定与调节其功能的PPARGAMMA N端的新因素。此外，还将分离以磷酸化依赖性方式与N末端相关的因素。