Analysis of Lipolytic Trafficking in Muscle

描述（由申请人提供）： 脂质的储存和动员是基本的细胞过程。在哺乳动物中，脂肪组织作为一种专门的脂质缓冲器，将多余的能量储存为甘油三酯，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FFA的能力;事实上，对于某些组织，FFA可以提供代谢能量的主要来源。过量的FFA会在一个被称为“脂毒性”的过程中破坏细胞功能，这被认为是肥胖导致糖尿病和心血管疾病的主要手段。理论上，脂肪毒性可由脂肪组织中FFA的过量全身供应或外周组织中FFA储存和动员的不平衡引起。因此，了解细胞如何吸收、动员和引导FFA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解的机制理解，以便确定治疗肥胖和糖尿病的治疗干预的新点。我们推测，肌肉细胞内的脂解是由特定的脂滴表面的特定蛋白质的有序运输控制的。这项工作将确定脂肪分解发生的细胞内位点，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.