Role of myosin 1e in podocyte biology and renal filtration

肌球蛋白 1e 在足细胞生物学和肾滤过中的作用

• 批准号: 8517103
• 负责人: Mira Krendel
• 金额: $ 33.58万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517103
• 关键词: Actins; Adult; Affect; Apoptosis; Binding; Binding Proteins; Biological Assay; Biology; Cell Shape; Cell membrane; Cells; Chronic Kidney Failure; Complex; Cytoskeleton; Defect; Development; Disease; Disease Pathway; Endocytosis; Epithelial Cells; Exhibits; Filtration; Focal Segmental Glomerulosclerosis; Foot Process; Functional disorder; Future; Gene Delivery; Glomerular Capillary; Goals; Growth Factor; In Vitro; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Lead; Link; Measures; Mediating; Membrane; Microfilaments; Modeling; Molecular; Molecular Motors; Molecular Target; Motor; Motor Activity; Mus; Mutation; Myosin ATPase; Pathogenesis; Pathway interactions; Play; Point Mutation; Prevention; Proteins; Proteinuria; Public Health; Regulation; Renal function; Renal glomerular disease; Research Project Grants; Role; SH3 Domains; Signal Pathway; Signal Transduction; Stress Fibers; Structure; Testing; Variant; base; cell growth; cell motility; genetic regulatory protein; glomerular filtration; glomerular function; improved; in vitro testing; in vivo; kidney epithelial cell; migration; morphometry; mutant; optical traps; podocyte; protein protein interaction; response; slit diaphragm; tool

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.

描述（由申请人提供）：为了改善慢性肾病的预防和治疗，慢性肾病是美国和全世界主要的公共卫生问题，有必要鉴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。该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，肾小球足细胞是一种特殊的肾上皮细胞，在选择性肾滤过中发挥着关键作用。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表现出严重缺陷。该项目重点鉴定足细胞中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 myo1e 活性的变化如何导致肾脏疾病的进展。 我们提出一个假设，即 myo1e 运动活动是其在正常足细胞功能中发挥作用所必需的。为了检验这一假设，我们将追求以下具体目标。目标 1. 分析 myo1e 突变对其在足细胞中功能的影响。为此，我们将确定 myo1e 运动活动在足细胞迁移和细胞形状调节中的作用。目标 2. 确定足细胞中的细胞内信号传导途径如何受到 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. 测试 myo1e 突变体修复缺乏 myo1e 的小鼠肾小球滤过缺陷的能力。