ANALYSIS OF LIPOLYTIC TRAFFICKING IN FAT AND MUSCLE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 脂质的储存和动员是基本的细胞过程，其失调有助于许多疾病，包括糖尿病，动脉粥样硬化和心肌病。 我们的中心假设是，调节脂解涉及脂肪酶和共激活剂的有序运输到由特定脂滴支架蛋白组织的专门的脂滴结构。我们预期，控制异位脂质清除的特定分子相互作用的知识将使我们能够设计促进这种活性的小分子的筛选，其长期目标是确定用于治疗肥胖相关脂毒性的先导化合物。 我们的实验室正在研究脂肪和肌肉中脂肪分解的细胞和分子机制。 我们和其他人已经表明，脂肪酸从储存的甘油三酯的动员涉及特定的蛋白质运输到液滴表面。 有直接数据表明PAT蛋白（perilipin/ADRP/TIP 47）在组织脂解蛋白运输中的核心作用，间接数据表明这发生在专门的脂滴或大脂滴的结构域上。 此外，除了蛋白质运输，脂解的激活似乎涉及液滴表面的结构变化，如微滴形成。我们相信，应用3D扫描电镜和透射电镜技术开发的NCMIR将允许前所未有的分析，如果这个动态和重要的细胞器。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The storage and mobilization of lipid are fundamental cellular processes, and its dysregulation contributes to numerous diseases including diabetes, atherosclerosis and cardiomyopathy. Our central hypothesis is that regulated lipolysis involves the orderly trafficking of lipases and co-activators to specialized lipid droplet structures that are organized by specific lipid droplet scaffold proteins. We anticipate that knowledge of the specific molecular interactions that control ectopic lipid clearance will allow us to devise screens for small molecules that promote this activity, with the long term goal of identifying lead compounds for treatment of obesity-related lipotoxicity. Our lab is investigating cellular and molecular mechanisms of lipolysis in fat and muscle. We and others have shown that that mobilization of fatty acids from stored triglyceride involves specific trafficking of proteins to the droplet surface. There are direct data demonstrating the central role of PAT proteins (perilipin/ADRP/TIP47) in organizing lipolytic protein trafficking and indirect data that indicating that this occurs on specialized lipid droplets or domains of large lipid droplets. Furthermore, in addition to protein trafficking, activation of lipolysis appears to involve structural changes in the droplet surface, such as microdroplet formation. We believe that application of the 3D SEM and TEM techniques developed by NCMIR would allow unprecedented analysis if this dynamic and important organelle.