Senescence and Autophagy as Mediators of Glomerular Injury in Diabetes

衰老和自噬作为糖尿病肾小球损伤的介质

• 批准号: 8226142
• 负责人: Astrid Weins
• 金额: $ 15.66万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8226142
• 关键词: Adhesions; Adhesiveness; Aging; Albuminuria; Apoptosis; Attenuated; Autophagocytosis; Biopsy; Budgets; Cell Aging; Cell Cycle Arrest; Cell Survival; Cells; Chronic Kidney Failure; Clinical; Coculture Techniques; Collection; Complex; Complication; Development; Diabetes Mellitus; Diabetic Nephropathy; Diagnosis; Dialysis procedure; Disease; Disease Progression; Early treatment; Elements; End stage renal failure; Endothelial Cells; Endothelium; Equilibrium; Extracellular Matrix; Focal Adhesions; Foot Process; Homeostasis; Homologous Gene; Human; Hypertrophy; In Vitro; Injury; Kidney; Kidney Failure; Kidney Glomerulus; Left; Link; Maintenance; Mediating; Mediator of activation protein; Medicare; Metabolic stress; Modeling; Molecular; Mus; Nature; Pathologic; Patients; Phenotype; Prevention therapy; Process; Proteinuria; Renal glomerular disease; Reporting; Role; Signal Transduction; Stress; Testing; Tissues; Transplantation; United States; Up-Regulation; Validation; Work; autocrine; base; cell injury; cell type; diabetic; glomerular basement membrane; glomerular filtration; in vivo; inhibition of autophagy; injured; intercellular communication; mesangial cell; mouse model; novel; overexpression; paracrine; paxillin; podocyte; response; senescence; slit diaphragm; therapeutic target

DESCRIPTION (provided by applicant): Diabetic Nephropathy is a highly prevalent and debilitating disease, which is characterized morphologically by degenerative changes of renal podocytes associated with a variable extent of foot process effacement, thickening of glomerular basement membranes, endothelial cell injury, and expansion of the mesangial matrix, all contributing to progressive renal failure. It has become clear in past years that podocytes are injured very early in the course of the disease, and studies on Diabetic Nephropathy have focused primarily on podocyte depletion as mediators of glomerular injury and proteinuria, either by detachment or by apoptosis. However, recent work by our group and others identified features of accelerated senescence in glomeruli of patients with Diabetic Nephropathy. Cellular senescence is an alternative cellular response to prolonged metabolic stress as seen in diabetes, and is characterized by irreversible cell cycle arrest. However, senescent cells remain metabolically active, and recent studies identified the Senescence-Associated Secretory Phenotype (SASP) as a novel means of intercellular communication. Autophagy is closely associated with the senescent phenotype, and is thought to serve as a regulator of both apoptosis and senescence. This project aims to define the role of senescence and autophagy in mediating glomerular injury in Diabetic Nephropathy, and to elucidate the potential role of the SASP in disease progression. To this end, the candidate aims to: 1) Study the role of hic-5 in promoting a senescent phenotype in podocytes in response to sustained diabetic stress through activation of an anchorage-dependent cell survival mechanism in vitro and in vivo, by use of cultured podocytes, mouse models of disease and subsequent validation of results in a collection of human kidney biopsies; 2) Establish the contribution of autophagy to promoting podocyte senescence in diabetic nephropathy in vitro and in vivo by use of cultured podocytes, mouse models of disease and subsequent validation of results in a collection of human kidney biopsies; and 3) Investigate the role of the Senescence Associated Secretory Phenotype in disease progression in the glomerulus by using the podocyte "secretome" as a platform to identify molecular mediators of glomerular injury, followed by validation using co-culture models. Understanding the role of senescence and its associated factors in promoting glomerular injury and intraglomerular cross talk in diabetic nephropathy and potentially other glomerular diseases may help to identify novel and specific therapeutic targets. PUBLIC HEALTH RELEVANCE: This project will help to elucidate mechanisms leading to chronic kidney disease in patients suffering from diabetes mellitus, which represents the leading cause of chronic kidney disease in the United States. About 20% to 30% of patients with diabetes develop diabetic nephropathy, and greater than 50% of all reported patients requiring dialysis or transplantation have diabetes. Consequently, the effects on our Medicare budget are immense: more than 10 billion dollars per year are spent on end stage renal disease patients with a primary diagnosis of diabetes mellitus, and we are currently still lacking specific therapies for prevention and early treatment of this devastating complication.

描述（由申请方提供）：糖尿病肾病是一种高度流行的衰弱性疾病，其形态学特征为与不同程度的足突消失、肾小球基底膜增厚、内皮细胞损伤和系膜基质扩张相关的肾足细胞退行性变化，所有这些均导致进行性肾衰竭。在过去的几年中，足细胞在疾病过程的非常早期就受到损伤已经变得很清楚，并且对糖尿病肾病的研究主要集中在足细胞耗竭上，足细胞耗竭是肾小球损伤和蛋白尿的介导物，其通过脱离或细胞凋亡来实现。然而，我们小组和其他人最近的工作确定了糖尿病肾病患者肾小球加速衰老的特征。细胞衰老是糖尿病患者对长期代谢应激的另一种细胞反应，其特征在于不可逆的细胞周期停滞。然而，衰老细胞仍然保持代谢活性，最近的研究确定了衰老相关的分泌表型（SASP）作为一种新的细胞间通讯手段。自噬与衰老表型密切相关，被认为是细胞凋亡和衰老的调节因子。本项目旨在明确衰老和自噬在糖尿病肾病中介导肾小球损伤的作用，并阐明SASP在疾病进展中的潜在作用。1）通过使用培养的足细胞、小鼠疾病模型和随后在一系列人肾活检中验证结果，研究hic-5在促进足细胞衰老表型中的作用，以响应持续的糖尿病应激，通过体外和体内激活锚定依赖性细胞存活机制; 2）通过使用培养的足细胞、疾病的小鼠模型和随后在一组人肾活检中验证结果，在体外和体内建立自噬对促进糖尿病肾病中足细胞衰老的贡献;和3）通过使用足细胞“分泌组”作为鉴定肾小球损伤的分子介质的平台，随后使用共培养模型验证，研究衰老相关分泌表型在肾小球疾病进展中的作用。了解衰老及其相关因素在糖尿病肾病和其他肾小球疾病中促进肾小球损伤和肾小球内串扰的作用可能有助于确定新的和特异性的治疗靶点。 公共卫生关系：该项目将有助于阐明导致糖尿病患者慢性肾脏疾病的机制，糖尿病是美国慢性肾脏疾病的主要原因。约20%至30%的糖尿病患者发生糖尿病肾病，并且超过50%的需要透析或移植的所有报告患者患有糖尿病。因此，对我们的医疗保险预算的影响是巨大的：每年有超过100亿美元用于主要诊断为糖尿病的终末期肾病患者，而我们目前仍然缺乏预防和早期治疗这种毁灭性并发症的特定疗法。