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（美国和全球主要的公共卫生问题）的预防和治疗，必须鉴定正常肾小球功能所必需的蛋白质。确定对肾小球滤过至关重要的蛋白质将有助于确定导致肾功能不全的疾病途径的分子靶点。本研究项目的目标是确定肌动蛋白依赖性分子运动肌球蛋白1e（myo1e）在正常肾功能和肾脏疾病发展中的作用。肌球蛋白1e在肾小球足细胞中表达，肾小球足细胞是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基因敲除小鼠是可行的，但表现出严重的肾小球滤过和组织缺陷。本项目主要研究足细胞中myo1e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活性的变化如何促进肾脏疾病的进展。 我们提出了一个假设，myo1e运动活动是必需的，其作用在正常的足细胞功能。为了检验这一假设，我们将追求以下具体目标。目标1。分析myo1e基因突变对足细胞功能的影响。在这个目标中，我们将确定在足细胞迁移和细胞形状的调节中，肌运动活性的作用。目标二。确定足细胞的细胞内信号通路如何受到myo1e活性丧失的影响，并分析足细胞信号对myo1e运动功能的调节。目标3。测试myo1e突变体挽救缺乏myo1e的小鼠肾小球滤过缺陷的能力。

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.