P3: REGULATION OF PPARGAMMA IN ADIPOCYTES BY THE UBIQUITIN-PROTEASOME SYSTEM

P3：泛素-蛋白酶体系统对脂肪细胞中 PPARGAMMA 的调节

• 批准号: 8167951
• 负责人: ZELPHA ELIZABETH FLOYD
• 金额: $ 20.58万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167951
• 关键词: Adipocytes; Area; Cells; Computer Retrieval of Information on Scientific Projects Database; Diabetes Mellitus; Enzymes; Funding; Goals; Grant; Institution; Ligands; Ligase; Link; Metabolic; Modification; PPAR gamma; Play; Post-Translational Protein Processing; Proteins; Recommendation; Regulation; Research; Research Personnel; Resources; Role; Source; Stream; Suggestion; System; Ubiquitin; United States National Institutes of Health; insight; lipid biosynthesis; multicatalytic endopeptidase complex; research study; response; ubiquitin-protein ligase

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A. Specific Aims In March 2009, the external reviewers indicated that our project "has the potential to reveal new mechanistic insights" into the regulation of PPARgamma and that our initial screen of ubiquitin E3 ligases has identified "E3 ligases that appear to influence steady state levels of PPARgamma within cells". The reviewers also advised that "successfully competing for an R01 in this area is likely to require narrowing the focus to one or two enzymes that play functional roles in PPARgamma action". A primary concern continued to be linking PPARgamma ubiquitylation and degradation to PPARgamma transcriptional function or a down-stream metabolic alteration. Recommendations for achieving these goals centered on continuing our experiments with the E3 ligases by focusing on one or two ligases, determining whether the effect of the E3 ligase on PPARgamma protein levels is direct or indirect and considering the effect of the selected E3 ligase on adipogenesis. In addition, the reviewers recommended we focus on ubiquitin proteasome modification of PPARgamma as a regulated posttranslational modification of PPARgamma. In response to the reviewers' suggestions, we pursued the following aims: Specific Aim 1: Complete the secondary screen to identify ubiquitin E3 ligases that regulate PPARgamma protein levels in mature adipocytes. Specific Aim 2: Examine the effect of the selected ligase or ligases on ligand-enhanced ubiquitylation and proteasome-dependent degradation of PPARgamma. Specific Aim 3: Determine the effect of the identified ligase or ligases on adipogenesis.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 A. 具体目标 2009 年 3 月，外部评审员指出，我们的项目“有可能揭示 PPARgamma 调节的新机制见解”，并且我们对泛素 E3 连接酶的初步筛选已识别出“似乎影响 PPARgamma 稳态水平的 E3 连接酶”细胞”。 审稿人还建议，“在这一领域成功竞争 R01 可能需要将焦点缩小到在 PPARgamma 作用中发挥功能作用的一两种酶”。 主要关注点仍然是将 PPARgamma 泛素化和降解与 PPARgamma 转录功能或下游代谢改变联系起来。 实现这些目标的建议集中于继续我们的 E3 连接酶实验，重点关注一种或两种连接酶，确定 E3 连接酶对 PPARgamma 蛋白水平的影响是直接还是间接，并考虑所选 E3 连接酶对脂肪生成的影响。 此外，审稿人建议我们重点关注 PPARgamma 的泛素蛋白酶体修饰，作为 PPARgamma 的受调节翻译后修饰。 根据审稿人的建议，我们追求以下目标： 具体目标 1：完成二次筛选，以确定调节成熟脂肪细胞中 PPARgamma 蛋白水平的泛素 E3 连接酶。 具体目标 2：检查所选连接酶对配体增强的泛素化和 PPARgamma 蛋白酶体依赖性降解的影响。 具体目标 3：确定已鉴定的一个或多个连接酶对脂肪生成的影响。