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：
9176093
负责人：
Mira Krendel
金额：
$ 53.73万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9176093
关键词：
Actins Animal Model Architecture Area Award Binding Binding Proteins Biological Biology Bundling Cell Adhesion Cell-Cell Adhesion Cells Chemicals Chronic Kidney Failure Cues Data Development Diagnosis Dialysis procedure End stage renal failure Endocytosis Environment Equilibrium Event Exocytosis Filtration Focal Segmental Glomerulosclerosis Functional disorder Generations Genomics Goals Human Hypertension Image In Vitro Injury Kidney Kidney Transplantation Link Maintenance Mechanics Mediating Membrane Microfilaments Modeling Molecular Motor Motor Activity Mus Mutation Myosin ATPase Patients Phosphorylation Play Positioning Attribute Post-Translational Protein Processing Property Proteins Public Health Recovery Regulation Renal function Research Role Signal Transduction Structure Surface Testing Transcriptional Regulation Work Wound Healing base biophysical techniques cohort environmental adaptation glomerular filtration in vivo innovation podocyte prevent protein complex protein protein interaction research study slit diaphragm transcriptomics

项目摘要

Chronic kidney disease is a major public health concern in the US and worldwide. Myosin 1e (Myo1e), an actin-dependent motor protein expressed in glomerular visceral epithelial cells (podocytes), is necessary for normal glomerular filtration in humans and mice. Myo1e is one of the components of the slit diaphragms, protein complexes that connect adjacent podocytes and play a key role in selective protein filtration in the glomerulus. Inactivating mutations in Myo1e are associated with focal segmental glomerulosclerosis (FSGS), one of the leading causes of end stage renal disease. In this proposal, we will determine how actin-dependent motor activity of Myo1e contributes to the maintenance of normal glomerular architecture and functions. We hypothesize that Myo1e is necessary for podocyte adaptation to the changes in their environment, including changes caused by high blood pressure and other pathological conditions, via its role in regulating membrane tension and slit diaphragm stability. In this application, we propose to study the role of Myo1e in tension generation and slit diaphragm turnover using innovative biophysical and cell biological approaches. In Aim 1, we will determine how Myo1e-mediated tension regulates podocyte activity and allows podocytes to adapt to the changing environment within the glomerulus under normal and pathological conditions. In Aim 2, we will dissect Myo1e role in regulating slit diaphragm assembly and turnover. In Aim 3, we will analyze the mechanisms responsible for regulation of Myo1e expression and activity. These studies will help determine how mutations in Myo1e contribute to development of FSGS and provide better understanding of the regulation of podocyte structure and function.

慢性肾病是美国的一个主要公共卫生问题全世界。肌球蛋白 1e (Myo1e)，一种肌动蛋白依赖性运动蛋白，表达于肾小球脏层上皮细胞（足细胞），是正常肾小球的必需细胞人类和小鼠的过滤。 Myo1e是狭缝隔膜的组件之一，连接相邻足细胞并在选择性中发挥关键作用的蛋白质复合物肾小球中的蛋白质过滤。 Myo1e 的失活突变与局灶节段性肾小球硬化症 (FSGS)，终末期的主要原因之一肾脏疾病。在本提案中，我们将确定 Myo1e 的肌动蛋白依赖性运动活动如何有助于维持正常的肾小球结构和功能。我们假设 Myo1e 对于足细胞适应其变化是必需的环境，包括高血压和其他病理引起的变化条件下，通过其调节膜张力和狭缝隔膜稳定性的作用。在这个应用中，我们建议研究Myo1e在张力产生和狭缝中的作用使用创新的生物物理和细胞生物学方法进行隔膜翻转。瞄准 1，我们将确定 Myo1e 介导的张力如何调节足细胞活性并允许足细胞在正常情况下适应肾小球内不断变化的环境病理状况。在目标 2 中，我们将剖析 Myo1e 在调节狭缝隔膜中的作用装配和周转。在目标 3 中，我们将分析负责的机制 Myo1e 表达和活性的调节。这些研究将有助于确定如何 Myo1e 的突变有助于 FSGS 的发展并提供更好的了解足细胞结构和功能的调节。