Role of myosin 1e in podocyte biology and renal filtration

慢性肾脏疾病在美国是一个主要的公共卫生问题， 全世界。肌球蛋白1e(Myo1e)是一种肌动蛋白依赖的运动蛋白，在 肾小球内脏上皮细胞(足细胞)，是正常肾小球所必需的 在人类和小鼠体内的过滤。Myo1e是缝隙横隔膜的组件之一， 连接相邻足细胞的蛋白质复合体，在选择 肾小球内的蛋白质过滤。Myo1e基因的失活突变与 局灶节段性肾小球硬化(FSGS)是终末期的主要原因之一 肾脏疾病。 在这项提案中，我们将确定Myo1e的肌动蛋白依赖的运动活性是如何 有助于维持正常的肾小球结构和功能。我们 假设Myo1e是足细胞适应其基因变化所必需的 环境变化，包括高血压等引起的病理改变 条件，通过其调节膜张力和狭缝隔膜稳定性的作用。在这 应用，我们建议研究Myo1e在张力产生和缝隙中的作用 使用创新的生物物理和细胞生物学方法进行横隔膜翻转。在AIM 1，我们将确定Myo1e介导的张力如何调节足细胞活动并允许 足细胞在正常和正常情况下适应肾小球内不断变化的环境 病理情况。在目标2中，我们将剖析Myo1e在调节裂隙横隔膜中的作用 装配和周转。在目标3中，我们将分析负责 Myo1e的表达和活性的调节。这些研究将有助于确定 Myo1e基因突变有助于FSGS的发展并提供更好的 了解足细胞结构和功能的调节。

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.