Role of Calpain in Podocyte Injury

钙蛋白酶在足细胞损伤中的作用

基本信息

批准号：
8889153
负责人：
Shuta Ishibe
金额：
$ 37.46万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8889153
关键词：
Ablation Accounting Actin-Binding Protein Actins Address Apoptosis Applications Grants Area Attenuated Autophagocytosis Biochemical Biology Calpain Cells Chronic Kidney Failure Collagen Type IV Cytoskeleton Data Deterioration Development Dialysis procedure Disease Disease Progression Doxycycline Employee Strikes End stage renal failure Filtration Focal Adhesions Focal Segmental Glomerulosclerosis Foot Process Functional disorder Future Generations Genetic Goals Grant Health Homeostasis Human In Vitro Injury Integrins Kidney Kidney Failure Kidney Transplantation Knock-out Knowledge Laminin Link Mediating Modeling Molecular Genetics Mus Mutation Nephrotic Syndrome PAWR protein Pathogenesis Pathologic Patients Peptide Hydrolases Permeability Phenotype Process Proteins Proteinuria Proteolysis Public Health Recovery Regulation Renal function Renal glomerular disease Research Role Secondary to Severities Stimulus Testing Therapeutic Therapeutic Agents Tissues United States Urine activating transcription factor alpha Actinin biological adaptation to stress calpain inhibitor endoplasmic reticulum stress genetic approach glomerular filtration human PHEMX protein in vivo insight integrin-linked kinase link protein mouse model new therapeutic target podocyte public health relevance repaired research study therapeutic target urinary

项目摘要

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.

描述（由申请人提供）：慢性肾病（CKD）通常会导致肾功能不可逆转地恶化，进而发展为终末期肾病（ESKD），并且从 USRDS 获得的数据表明，CKD 已成为一个严重的公共卫生问题。预计到 2015 年，美国 ESKD 新发病例数将超过 700,000 例。由于继发于足细胞功能障碍的肾小球疾病导致90% 的 ESKD 是通过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，这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至关重要，并且受到调节。为了进一步确定其重要性，我们还发现足细胞钙蛋白酶活性会诱导内质网应激（ER 应激），这是一种保护细胞免受病理刺激的适应性过程。我们的初步数据表明，足细胞损伤后，talin1 蛋白水解和 ER 应激激活，这两种情况均通过钙蛋白酶的药理抑制而减弱。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 ER 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展我们的知识。钙蛋白酶调节及其对足细胞稳态的下游影响。