MECHANISMS OF RENAL TUBULAR EPITHELIAL CELL INJURY

描述：（改编自申请人的摘要）-本项目的目标 建议是阐明ATP的代谢和生物化学效应 消耗，负责的主要功能后果， 肾小管上皮细胞亚致死性损伤。 申请人会 重点关注亚致死性损伤的两个功能后果： 细胞-基质粘附，导致活细胞从 基底膜和细胞-细胞粘附丧失，随后受损 紧密连接功能。 他们将研究亚致死的影响 细胞骨架的三种成分上的损伤， 在维持正常的紧密连接功能中起重要作用， 细胞-基质粘附; i）肌动蛋白细胞骨架ii）粘附斑，和 iii）粘附连接。 本申请的基本假设是： i）ATP耗竭的代谢后果导致组织解体 这反过来又导致结构变化， 粘附连接和粘附斑的功能损害，ii） 肌动蛋白细胞骨架的丢失是造成这些效应的原因， 肌动蛋白结合蛋白酪氨酸磷酸化的失调 在粘附连接和粘附斑块内，和iii） 防止酪氨酸磷酸化变化的干预措施 与ATP耗竭相关的功能性后果将改善 亚致死性损伤 具体目标是确定代谢 ATP耗竭的后果，导致结构紊乱， 肌动蛋白细胞骨架，以检查ATP耗竭对酪氨酸的影响 包括粘附斑和粘附蛋白的蛋白质的磷酸化 连接，并检查这些改变的磷酸化事件的作用， 亚致死性损伤的功能性后果

DESCRIPTION: (Adapted from the applicant's abstract) - The goals of this proposal are to elucidate the metabolic and biochemical effects of ATP depletion that are responsible for the major functional consequences of sublethal injury in renal tubular epithelial cells. The applicants will focus on two functional consequences of sublethal injury: loss of cell-matrix adhesion with resultant detachment of viable cells from the basement membrane and loss of cell-cell adhesion with consequent impairment of tight junction function. They will examine the effects of sublethal injury on three components of the cell cytoskeleton that are known to play an important role in maintaining normal tight junction function and cell-matrix adhesion; i) The actin cytoskeleton ii) the adhesion plaque, and iii) the adherens junction. The hypotheses underlying this application are: i) That the metabolic consequences of ATP depletion lead to disorganization of the actin cytoskeleton which in turn results in structural changes and function impairment of the adherens junctions and adhesion plaques, ii) that loss of the actin cytoskeleton is responsible for these effects by causing dysregulation of tyrosine phosphorylation of actin-binding proteins present within the adherens junctions and adhesion plaques, and iii) that interventions that prevent the changes in tyrosine phosphorylation associated with ATP depletion will ameliorate the functional consequences of sublethal injury. The specific aims are to identify the metabolic consequences of ATP depletion that result in structural disorganization of the actin cytoskeleton, to examine the effects of ATP depletion on tyrosine phosphorylation of proteins comprising the adhesion plaque and adherens junction, and to examine the role of these altered phosphorylation events in the functional consequences of sublethal injury.