Ubiquitin-dependent regulation of PPARgamma

PPARγ 的泛素依赖性调节

基本信息

批准号：
7188564
负责人：
ZELPHA ELIZABETH FLOYD
金额：
$ 7.14万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7188564
关键词：
2,4-thiazolidinedione 26S proteasome Adipocytes Adipose tissue Adult Affect Age Aging Antidiabetic Drugs Attention Awareness Cardiovascular Diseases Cellular biology Cessation of life Chronic Chronic Disease Complex Cultured Cells Development Disease Energy Metabolism Fatty acid glycerol esters Foundations Future Gene Expression Regulation Genes Goals Health Health Care Costs Hypertension In Vitro Incidence Insulin Insulin Resistance Interferon Gamma Receptor Beta Chain Learning Leptin Ligands Link Lysine Maintenance Measures Mediating Medical Metabolic syndrome Modeling Modification Molecular N-terminal Non-Insulin-Dependent Diabetes Mellitus Nuclear Hormone Receptors Numbers Obesity Overweight PPAR gamma PPARgamma2 Participant Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pharmacological Treatment Phosphoenolpyruvate Carboxylase Play Population Post-Translational Protein Processing Process Proteasome Inhibition Proteins Proteolysis Public Health Pus Range Rate Regulation Reporter Research Risk Factors Role Signal Transduction Stroke System Therapeutic Thiazolidinediones Ubiquitin Ubiquitination United States adipocyte biology adipocyte differentiation aging population blood glucose regulation improved insulin sensitivity lipoprotein lipase member multicatalytic endopeptidase complex mutant novel therapeutics obesity treatment receptor receptor function research study therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Obesity is a primary risk factor for type 2 diabetes, metabolic syndrome and cardiovascular diseases such as hypertension. These chronic disorders are predicted to increase with the aging population. Adipose tissue expresses high levels of the peroxisome proliferator-activated receptor, PPARgamma, the master switch in adipose cell formation. Recent studies show that modulation of PPARgamma levels improves insulin sensitivity and protects against insulin resistance associated with aging. Our recent studies indicate that regulation of PPARgamma levels by the ubiquitin-proteasome system is linked to the control of PPARgamma activity. In addition, we have learned that SUMO-1 modification of PPARgamma in the N-terminal ligand-independent activation (AF-1) domain affects PPARgamma stability and activity. We hypothesize that ubiquitin-dependent degradation is an important regulator of PPARgamma activity in adipocytes and that the N-terminal AF-1 domain of PPARgamma is a determinant of PPARgamma ubiquitin-proteasome mediated degradation. Our goals in this proposal are to define the region of PPARgamma that is required for the regulated degradation of PPARgamma and to examine the relationship between SUMOylation of PPARgamma at lysine 107 and modification of PPARgamma by ubiquitin. Our long-term goal is to further the development of PPARgamma-directed therapeutics in the treatment of obesity-related disorders by understanding how PPARgamma protein levels are regulated. In Specific Aim 1, we will define the region of PPARgamma that is recognized by the ubiquitin-proteasome system. These studies will focus on the AF-1 or AF-2 activation domains of PPARgamma2. In specific aim 2, we will examine the relationship between SUMOylation of lysine 107 and ubiquitylation of PPARgamma2 and how this relates to PPARgamma activity. Information obtained from examining the molecular mechanisms regulating PPARgamma protein levels may provide new therapeutic targets in treating obesity, type 2 diabetes, and related cardiovascular diseases.

描述（由申请人提供）：肥胖是 2 型糖尿病、代谢综合征和高血压等心血管疾病的主要危险因素。预计这些慢性疾病会随着人口老龄化而增加。脂肪组织表达高水平的过氧化物酶体增殖物激活受体 PPARgamma，它是脂肪细胞形成的主开关。最近的研究表明，调节 PPARgamma 水平可以提高胰岛素敏感性，并防止与衰老相关的胰岛素抵抗。我们最近的研究表明，泛素蛋白酶体系统对 PPARgamma 水平的调节与 PPARgamma 活性的控制有关。此外，我们还了解到 SUMO-1 对 PPARgamma 的修饰在 N 端配体独立激活中 (AF-1) 结构域影响 PPARgamma 稳定性和活性。我们假设泛素依赖性降解是脂肪细胞中 PPARgamma 活性的重要调节因子，并且 N 末端 PPARgamma 的 AF-1 结构域是 PPARgamma 泛素蛋白酶体介导的降解的决定因素。我们在本提案中的目标是定义 PPARgamma 调节降解所需的 PPARgamma 区域，并检查 PPARgamma 在赖氨酸 107 处的 SUMO 化与泛素对 PPARgamma 的修饰之间的关系。我们的长期目标是通过了解 PPARgamma 蛋白水平的调节机制，进一步开发 PPARgamma 导向疗法，用于治疗肥胖相关疾病。在具体目标 1 中，我们将定义泛素-蛋白酶体系统识别的 PPARgamma 区域。这些研究将集中于 PPARgamma2 的 AF-1 或 AF-2 激活域。在具体目标 2 中，我们将研究赖氨酸 107 的 SUMO 化与 PPARgamma2 的泛素化之间的关系，以及这与 PPARgamma 活性的关系。通过研究调节 PPARgamma 蛋白水平的分子机制获得的信息可能为治疗肥胖、2 型糖尿病和相关心血管疾病提供新的治疗靶点。