Massive Cardiac Endocytosis and Ectosome Shedding

摘要 该项目的重点是心脏信号通路，其中脂代谢，耦合到 线粒体活性状态，通过内吞作用促进大量肌膜内化 (修复)和/或大量胞外体脱落(MASS)到细胞外间隙。这个 内吞途径依赖于脂肪酸代谢和 细胞质酰基辅酶A，用来使许多肌膜蛋白脂化。 脱落途径主要依赖于溶血磷脂酰胆碱的产生， 心肌细胞中其受体的激活，以及随后的扰乱 单层之间的肌膜磷脂。这两种机制似乎都依赖于 肌膜内有序膜结构域的产生 促进独特的蛋白质-蛋白质相互作用和功能。这两种机制都是 预计在发生的膜重塑中发挥主要作用 缺血/再灌注损伤，以及涉及的主要慢性退行性疾病 氧化应激。使用在这些通路上有缺陷的多个小鼠系，以及 操纵药物的个体反应，我们将分析其共性和 这些途径的独特特征，确定基本的分子参与者，因素 果断地推动肌膜修复或混乱，并更准确地定义 修补和混乱的生理和病理作用。该项目将提供洞察力 转化为基本的细胞调控机制，对 了解发达国家的主要死因。

ABSTRACT This project focuses on cardiac signaling pathways in which lipid metabolism, coupled to mitochondrial activity state, promote massive sarcolemma internalization via endocytosis (MEND) and/or massive ectosome shedding (MESS) to the extracellular space. The endocytosis pathway depends on fatty acid metabolism and the generation of cytoplasmic acyl-coenzyme A that is used to lipidate numerous sarcolemmmal proteins. The shedding pathway depends primarily on the generation of lysophosphatidylcholine, the activation of its receptors in the cardiac myocyte, and subsequent scrambling of sarcolemmal phospholipids between monolayers. Both mechanisms appear to depend on the generation of ordered membrane domains within the sarcolemma which then facilitate unique protein-protein interactions and functions. Both mechanisms are expected to play major roles in membrane remodeling that occurs in ischemia/reperfusion injury, as well as in major chronic, degenerative diseases involving oxidative stress. Using multiple mice lines with deficiencies in these pathways, as well as drugs to manipulate individual reactions, we will analyze the commonalities and distinctive traits of these pathways, identify the essential molecular players, factors that decisively push the sarcolemma to MEND or MESS, and define more precisely the physiological and pathological roles of MEND and MESS. The project will provide insight into fundamental cell regulatory mechanisms that have a high impact for an understanding of the leading causes of death in the developed world.