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

基本信息

批准号：
10587345
负责人：
Mira Krendel
金额：
$ 67.49万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587345
关键词：
ATP Hydrolysis Actins Adhesions Affect Amino Acids Animal Model Award Binding Biochemical Biology Cell Adhesion Cell membrane Cells Chronic Kidney Failure Cytoskeletal Modeling Cytoskeletal Proteins Cytoskeleton Defect Dialysis procedure Dimensions Disease End stage renal failure Endocytosis Epithelial Cells Etiology Filtration Focal and Segmental Glomerulosclerosis Functional disorder Genes Genomics Histologic In Vitro Inherited Injury Kidney Kidney Diseases Kidney Transplantation Knockout Mice Lipids Measures Mechanics Methods Microfilaments Missense Mutation Molecular Motors Motor Motor Activity Movement Mutation Myosin ATPase Nephrotic Syndrome Pathogenesis Pathway interactions Patients Peptides Persons Phosphatidylinositols Process Proteins Proteinuria Public Health Regulation Renal Replacement Therapy Renal function Renal glomerular disease Role Shapes Steroid-resistant idiopathic nephrotic syndrome Tail Testing Therapeutic Variant Waste Products Work cohort fluid flow glomerular basement membrane glomerular filtration glomerulosclerosis in vitro activity in vivo insight mechanical properties migration mouse model novel podocyte preservation protective effect restoration

ATP Hydrolysis Actins Adhesions Affect Amino Acids Animal Model Award Binding Biochemical Biology Cell Adhesion Cell membrane Cells Chronic Kidney Failure Cytoskeletal Modeling Cytoskeletal Proteins Cytoskeleton Defect Dialysis procedure Dimensions Disease End stage renal failure Endocytosis Epithelial Cells Etiology Filtration Focal and Segmental Glomerulosclerosis Functional disorder Genes Genomics Histologic In Vitro Inherited Injury Kidney Kidney Diseases Kidney Transplantation Knockout Mice Lipids Measures Mechanics Methods Microfilaments Missense Mutation Molecular Motors Motor Motor Activity Movement Mutation Myosin ATPase Nephrotic Syndrome Pathogenesis Pathway interactions Patients Peptides Persons Phosphatidylinositols Process Proteins Proteinuria Public Health Regulation Renal Replacement Therapy Renal function Renal glomerular disease Role Shapes Steroid-resistant idiopathic nephrotic syndrome Tail Testing Therapeutic Variant Waste Products Work cohort fluid flow glomerular basement membrane glomerular filtration glomerulosclerosis in vitro activity in vivo insight mechanical properties migration mouse model novel podocyte preservation protective effect restoration

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项目摘要

Modified Project Summary/Abstract Section Disruption of normal glomerular filtration is one of the key causes of end-stage renal disease, leading to the need for renal replacement therapy. Myosin 1e (Myo1e) is a cytoskeletal protein that is highly expressed in the glomerular epithelial cells (podocytes) and is involved in many processes important for podocyte function, such as actin assembly regulation, endocytosis, and regulation of cell adhesion. Mutations in MYO1E are found in patients with chronic kidney disease, highlighting its role in maintaining glomerular filtration barrier. In this project we will examine the role of Myo1e activity in supporting podocyte cytoskeletal organization and normal kidney function and test the hypothesis that activation of Myo1e can help protect podocytes from injury and preserve normal glomerular filtration. In Aim 1 we will analyze how disease-associated mutations affect Myo1e functions and activity using a combination of cell-based and in vitro (biochemical) methods. In Aim 2 we will determine the mechanism of autoinhibition of Myo1e activity. In Aim 3 we will test how Myo1e activity helps maintain podocyte integrity and whether activation of Myo1e will have a protective effect on kidney function.

修改的项目摘要/摘要部分正常肾小球过滤的破坏是终末期肾脏疾病的关键原因之一，导致需要进行肾脏替代疗法。肌球蛋白1E（MyO1E）是一种细胞骨架蛋白，在肾小球上皮细胞（足细胞）中高度表达，并且参与了许多对足细胞功能重要的过程，例如肌动蛋白组装调节，内吞作用和细胞粘附调节。在患有慢性肾脏疾病的患者中发现了MyO1E中的突变，突出了其在维持肾小球滤过屏障中的作用。在该项目中，我们将研究MyO1E活性在支持足细胞细胞骨架组织和正常肾脏功能中的作用，并检验以下假设：MyO1E的激活可以帮助保护足细胞免受损伤并保留正常的肾小球滤膜。在AIM 1中，我们将分析与疾病相关的突变如何使用基于细胞和体外（生化）方法的组合影响MyO1E的功能和活性。在AIM 2中，我们将确定MyO1E活性自身抑制的机制。在AIM 3中，我们将测试MyO1E活动如何有助于维持足细胞完整性，以及Myo1e的激活是否对肾脏功能具有保护作用。