Role of Calpain in Podocyte Injury

 描述(申请人提供)：慢性肾脏疾病(CKD)通常导致不可逆转的肾功能恶化，进展为终末期肾脏疾病(ESKD)。慢性肾脏病已经成为一个严重的公共卫生问题，从美国疾病控制和预防中心获得的数据显示，到2015年，美国ESKD的新病例数量预计将超过70万名患者。由于足细胞功能障碍继发的肾小球疾病占所有ESKD的90%，详细的分子和遗传学方法来确定足细胞发育和修复的机制可能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过程中是至关重要的，并受钙蛋白酶等蛋白酶的调节。为了进一步确定其重要性，我们还确认了足细胞Calapin活性诱导内质网应激(内质网应激)，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，我们显示了足细胞损伤后显著的talin1蛋白分解和内质网应激激活，这两种作用都被Calain的药理抑制所减弱。在目标1中，我们将定义并进一步表征足细胞特异的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对Calain调控及其在足细胞稳态中的下游影响的了解。

 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.