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）：为了改善慢性肾脏疾病的预防和治疗，这是美国和全球范围内的主要公共卫生问题，必须识别正常肾小球功能所必需的蛋白质。鉴定对于肾小球滤过至关重要的蛋白质将有助于确定导致肾功能障碍的疾病途径的分子靶标。该研究项目的目的是确定依赖肌动蛋白的分子运动肌球蛋白1E（MyO1E）在正常肾脏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，专门的肾上皮细胞中表达，在选择性肾脏过滤中起关键作用。我们发现MyO1E敲除小鼠是可行的，但在肾小球过滤和组织中表现出严重的缺陷。该项目的重点是鉴定肌细胞中MyO1E的细胞内功能，并分析MyO1E在维持正常肾脏过滤中的作用。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发展。 我们提出了一个假设，即MyO1E运动活动在正常足细胞功能中的作用是必需的。为了检验这一假设，我们将追求以下特定目标。 AIM 1。分析MyO1E突变对足细胞功能的影响。在此目标中，我们将确定MyO1E运动活性在调节足细胞迁移和细胞形状的作用。 AIM 2。确定足细胞中细胞内信号通路如何受到MyO1E活性丧失的影响，并通过足细胞信号传导分析MyO1E运动功能的调节。 AIM 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。