Analysis of Lipolytic Trafficking in Muscle

描述(由申请人提供)： 脂类的储存和动员是基本的细胞过程。在哺乳动物中，脂肪组织作为一种特殊的脂肪缓冲，以甘油三酯的形式储存多余的能量，以游离脂肪酸(FFA)的形式进行全身动员。尽管如此，几乎所有的细胞都有储存和动员游离脂肪酸的能力；事实上，对于某些组织来说，游离脂肪酸可以提供代谢能量的主要来源。过量的FFA会扰乱细胞功能，这种过程被称为“脂毒性”，被认为是肥胖导致糖尿病和心血管疾病的主要途径。从理论上讲，脂肪组织中FFA的全身性供应过多，或者外周组织中FFA的储存和动员失衡，都可能导致脂毒性。因此，从机制上理解细胞如何同化、动员和引导游离脂肪酸是一个重要的生物学问题，对健康和疾病具有广泛的影响。我们的长期目标是提供对细胞脂肪分解的机械性理解，从而确定治疗肥胖和糖尿病的新的治疗干预点。我们假设，肌肉中的细胞内脂肪分解是由特定蛋白质在特定脂滴表面的有序运输控制的。这项工作将定义发生脂解的细胞内位置，测试动态蛋白质-蛋白质相互作用的特定模型，并确定这些相互作用在体外和体内的功能影响。

DESCRIPTION (provided by applicant): The storage and mobilization of lipids are fundamental cellular processes. In mammals, adipose tissue functions as a specialized lipid buffer that stores excess energy as triglyceride for systemic mobilization as free fatty acids (FFA). Nonetheless, virtually all cells have the ability to store and mobilize FFA; indeed, for some tissues FFA can provide the major source of metabolic energy. Excessive FFA can disrupt cellular function in a process that has been termed 'lipotoxicity," which is thought to be a major means by which obesity contributes to diabetes and cardiovascular disease. In theory, lipotoxicity can be brought about by excessive systemic supply of FFA from adipose tissue, or by an imbalance in FFA storage and mobilization in peripheral tissues. Thus, a mechanistic understanding of how cells assimilate, mobilize and channel FFA is an important biological question with broad implications for health and disease. Our long term goal is to provide a mechanistic understanding of cellular lipolysis so as to identify novel points of therapeutic intervention for the treatment of obesity and diabetes. We hypothesize that intracellular lipolysis in muscle is controlled by the orderly trafficking of specific proteins at the surface of specialized lipid droplets. This work will define the intracellular sites where lipolysis occurs, test specific models of dynamic protein- protein interactions, and determine the functional impact of those interactions in vitro and in vivo.