Role of myosin 1e in podocyte biology and renal filtration

修改项目摘要/摘要部分 正常肾小球滤过的破坏是终末期肾病的关键原因之一，导致需要肾脏替代治疗。肌球蛋白1 e（Myo 1 e）是一种在肾小球上皮细胞（足细胞）中高度表达的细胞骨架蛋白，参与足细胞功能的许多重要过程，如肌动蛋白组装调节、内吞作用和细胞粘附调节。MYO 1 E的突变在慢性肾脏疾病患者中发现，突出了其在维持肾小球滤过屏障中的作用。在这个项目中，我们将研究Myo 1 e活性在支持足细胞骨架组织和正常肾功能中的作用，并测试Myo 1 e的激活可以帮助保护足细胞免受损伤和保持正常肾小球滤过的假设。在目标1中，我们将使用基于细胞和体外（生物化学）方法的组合来分析疾病相关突变如何影响Myo 1 e功能和活性。在目标2中，我们将确定Myo 1 e活性的自抑制机制。在目标3中，我们将测试Myo 1 e活性如何帮助维持足细胞的完整性，以及Myo 1 e的激活是否会对肾功能产生保护作用。

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.