Role of myosin 1e in podocyte biology and renal filtration

描述（由申请人提供）：为了改善慢性肾脏疾病的预防和治疗，这是美国和世界范围内主要的公共卫生问题，有必要确定正常肾小球功能所必需的蛋白质。鉴定对肾小球滤过至关重要的蛋白质将有助于查明导致肾功能障碍的疾病途径的分子靶点。本研究项目的目的是确定肌动蛋白依赖分子运动肌球蛋白1e （myo1e）在正常肾功能和肾脏疾病发展中的作用。Myosin 1e在肾小球足细胞中表达，这是一种在选择性肾滤过中起关键作用的特化肾上皮细胞。我们发现myo1e基因敲除小鼠可以存活，但在肾小球滤过和组织方面存在严重缺陷。本项目的重点是鉴定myo1e在足细胞中的细胞内功能，并分析myo1e在维持正常肾滤过中的作用。这些研究将有助于确定肌e活动的变化如何促进肾脏疾病的进展。我们提出了一个假设，即肌运动活动是其在正常足细胞功能中的作用所必需的。为了检验这一假设，我们将追求以下具体目标。目的1。分析myo1e突变对足细胞功能的影响。在这个目的中，我们将确定肌运动活动在足细胞迁移和细胞形状调节中的作用。目标2。确定足细胞内的信号通路如何受到myo1e活性丧失的影响，并分析足细胞信号传导对myo1e运动功能的调节。目标3。检测myo1e突变体对缺乏myo1e小鼠肾小球滤过缺陷的修复能力。

DESCRIPTION (provided by applicant): In order to improve prevention and treatment of chronic kidney disease, a major public health concern in the US and worldwide, it is essential to identify proteins that are necessary for normal glomerular functions. Identification of proteins that are critical for glomerular filtration will help pinpoint molecular targets of disease pathways that lead to renal dysfunction. The goal of this research project is to identify the roles of an actin-dependent molecular motor myosin 1e (myo1e) in normal kidney functions and in development of kidney disease. Myosin 1e is expressed in glomerular podocytes, specialized kidney epithelial cells that play a critical role in selective renal filtration. We have found that myo1e knockout mice are viable but exhibit severe defects in glomerular filtration and organization. This project focuses on identification of the intracellular functions of myo1e in podocytes and analysis of the role of myo1e in maintaining normal renal filtration. These studies will help determine how changes in myo1e activity may contribute to progression of kidney disease. We propose a hypothesis that myo1e motor activity is required for its role in normal podocyte functions. In order to test this hypothesis, we will pursue the following specific aims. Aim 1. Analyze the effects of mutations in myo1e on its functions in podocytes. In this aim we will determine the role of myo1e motor activity in regulation of podocyte migration and cell shape. Aim 2. Determine how intracellular signaling pathways in podocytes are affected by the loss of myo1e activity and analyze regulation of myo1e motor functions by podocyte signaling. Aim 3. Test the ability of myo1e mutants to rescue the defects in glomerular filtration in mice lacking myo1e.