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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 A.具体目标 2009年3月，外部评审员指出，我们的项目“有可能揭示新的机制见解”，以调节PPARgamma，我们的泛素E3连接酶的初步筛选已经确定了“E3连接酶，似乎影响稳态水平的PPARgamma细胞内”。 评审员还建议，“在这一领域成功竞争R 01可能需要将焦点缩小到在PPARgamma作用中发挥功能作用的一种或两种酶”。 一个主要的问题仍然是连接PPARgamma泛素化和降解PPARgamma转录功能或下游代谢改变。 实现这些目标的建议集中在继续我们的E3连接酶实验，通过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的还是间接的，并考虑所选E3连接酶对脂肪形成的影响。 此外，综述者建议我们关注PPARgamma的泛素蛋白酶体修饰，将其作为PPARgamma的一种受调控的翻译后修饰。 为回应检讨者的建议，我们致力达致以下目标： 具体目标1：完成二次筛选以鉴定在成熟脂肪细胞中调节PPARgamma蛋白水平的泛素E3连接酶。 具体目标二：检查所选的一种或多种连接酶对配体增强的PPARgamma泛素化和蛋白酶体依赖性降解的影响。 具体目的3：确定所鉴定的一种或多种连接酶对脂肪形成的影响。