Role of Calpains in Podocyte Biology

项目摘要 慢性肾脏病（CKD）通常会导致肾功能不可逆的恶化， 终末期肾病（ESKD）CKD已成为一个严重的公共卫生问题， 来自USRDS的数据显示，美国有2000万患者患有CKD。作为 继发于足细胞功能障碍的肾小球疾病占所有CKD的80%以上，这是一种严重的慢性肾病。 用分子和遗传学方法鉴定足细胞发育、维持和修复的机制 可能提供新的治疗靶点最近的证据表明肾小球损伤的重要作用 因钙蛋白酶激活而加剧使用无偏筛选，我们已经确定Pfn1，作为潜在的关键 基因来维持肾小球滤过屏障的完整性。人足细胞中PFN1的缺失导致 多核细胞，钙增加和钙蛋白酶2激活。因此，在目标1中，我们将定义 Pfn1的缺失如何通过表征足细胞功能障碍的基本机制 新产生的基因敲除小鼠。在目标2中，我们将描述Capn 2稳定足细胞功能的作用。 并进一步研究Pfn1和Capn2之间的联系。我们的小鼠疾病模型为 进一步明确Pfn1和Capn2在形成和维持完整肾小球滤过中的作用 屏障

Project Summary Chronic kidney disease (CKD) often leads to irreversible deterioration of kidney function that often progresses to End Stage Kidney Disease (ESKD). CKD has emerged as a serious public health issue and data obtained from the USRDS reveals that the number 20 million patients in the United States suffer from CKD. As glomerular diseases secondary to podocyte dysfunction account for greater than 80% of all CKD, an intensive molecular and genetic approach to identify mechanisms for podocyte development, maintenance and repair may provide new therapeutic targets Recent evidence suggests an important role of glomerular injury exacerbated by calpain activation. Using a unbiased screen, we have identified Pfn1, as potentially a critical gene to maintain the integrity of the glomerular filtration barrier. Loss of PFN1 in human podocytes resulted in multinucleated cells, increased calcium, and calpain 2 activation. Therefore, In Aim 1, we will define the fundamental mechanisms on how loss of Pfn1 contributes to podocyte dysfunction through characterizing the new generated knockout mice. In Aim 2, we will characterize the role of Capn2 to stabilize podocyte function and further investigate the link between Pfn1 and Capn2. Our mouse models of disease provide impetus to further define the role of Pfn1 and Capn2 in the formation and maintenance an intact glomerular filtration barrier.