Ubiquitin-dependent regulation of PPARgamma

描述（由申请人提供）：肥胖是2型糖尿病、代谢综合征和心血管疾病（如高血压）的主要风险因素。预计这些慢性疾病将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，脂肪细胞形成的主开关。最近的研究表明，PPARgamma水平的调节可改善胰岛素敏感性，并防止与衰老相关的胰岛素抵抗。我们最近的研究表明，通过泛素-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修饰的PPARgamma在N-末端不依赖配体激活 （AF-1）结构域影响PPARgamma的稳定性和活性。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， PPARgamma的AF-1结构域是PPARgamma泛素-蛋白酶体介导降解的决定因素。我们的目标是确定PPARgamma降解所需的区域，并研究PPARgamma在赖氨酸107处的SUMO化与泛素修饰PPARgamma之间的关系。我们的长期目标是通过了解PPARgamma蛋白水平是如何调节的，进一步开发PPARgamma导向的治疗肥胖相关疾病的疗法。在具体目标1中，我们将定义由泛素-蛋白酶体系统识别的PPARgamma区域。这些研究将集中于PPARgamma 2的AF-1或AF-2激活结构域。在具体目标2中，我们将研究赖氨酸107的SUMO化和PPARgamma 2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症、2型糖尿病和相关心血管疾病提供新的治疗靶点。

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.