Role of Calpain in Podocyte Injury

 描述（由申请人提供）：慢性肾脏疾病（CKD）通常导致肾功能不可逆恶化，进展为终末期肾脏疾病（ESKD）。CKD已成为严重的公共卫生问题，从USRDS获得的数据显示，到2015年，美国ESKD新发病例的数量预计将超过700，000例患者。由于继发于足细胞功能障碍的肾小球疾病占所有ESKD的90%，因此详细的分子和遗传方法来确定足细胞发育和修复的机制可能会为我们开发治疗药物和靶点提供新的见解。最近的证据表明，细胞基质相互作用在足细胞健康和疾病期间是至关重要的，并且由蛋白酶如钙蛋白酶调节。为了进一步确定重要性，我们还确定了足细胞calapin活性诱导内质网应激（ER应激），这是一种保护细胞免受病理刺激的适应性过程。在我们的初步数据中，我们证明了足细胞损伤后显著的talin1蛋白水解和ER应激的激活，这两者都被钙蛋白酶的药理学抑制所减弱。在目标1中，我们将定义并进一步表征足细胞特异性钙蛋白酶活性在调节细胞基质调节中的重要性。在目标2中，我们将研究钙蛋白酶激活导致内质网应激的机制，以及它如何导致足细胞功能障碍。通过完成这些目标，我们将有机会进一步扩大我们的钙蛋白酶调节及其在足细胞稳态下游效应的知识。

 DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) often leads to irreversible deterioration of renal function that progresses to End Stage Kidney Disease (ESKD). CKD has emerged as a serious public health problem and data obtained from the USRDS reveals that the number of new cases of ESKD in the United States is projected exceed 700,00 patients by 2015. As glomerular diseases secondary to podocyte dysfunction contribute up to 90% of all ESKD, a detailed molecular and genetic approach to identify mechanisms for podocyte development and repair may give us new insights for developing therapeutic agents and targets. Recent evidence suggests that cell matrix interactions are critical during podocyte health and disease, and are regulated by proteases, such as calpain. To further determine the importance, we have also identified that podocyte calapin activity induces endoplasmic reticulum stress (ER stress), an adaptive process put in place to protect cells from pathologic stimuli. In our preliminary data, we demonstrate marked talin1 proteolysis and activation of ER stress following podocyte injury, which are both attenuated with pharmacological inhibition of calpain. In Aim 1, we will define and further characterize the importance of podocyte specific calpain activity in modulating cell matrix regulation. In Aim 2, we will examine the mechanisms of calpain activation leading to ER stress and how it contributes to podocyte dysfunction. By completing these aims, we will have an opportunity to further expand our knowledge of calpain regulation and its downstream effects in podocyte homeostasis.