Senescence and Autophagy as Mediators of Glomerular Injury in Diabetes

描述（由申请人提供）：糖尿病肾病是一种非常普遍且使人衰弱的疾病，其形态学特征是肾足细胞退行性改变，伴有足突不同程度的消退、肾小球基底膜增厚、内皮细胞损伤和系膜基质扩张，所有这些都会导致进行性肾衰竭。在过去的几年里，我们已经清楚地发现足细胞在疾病的早期就受到了损伤，关于糖尿病肾病的研究主要集中在足细胞耗损作为肾小球损伤和蛋白尿的介质，无论是通过脱离还是通过细胞凋亡。然而，我们小组和其他人最近的工作发现了糖尿病肾病患者肾小球加速衰老的特征。细胞衰老是一种替代细胞对长期代谢应激的反应，如在糖尿病中所见，其特征是不可逆的细胞周期停滞。然而，衰老细胞仍然具有代谢活性，最近的研究发现衰老相关分泌表型（Senescence-Associated Secretory Phenotype， SASP）是细胞间通讯的一种新手段。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。为此，该候选人的目标是：1)通过体外和体内培养足细胞、小鼠疾病模型和随后的人类肾脏活检结果验证，通过激活锚定依赖性细胞存活机制，研究hic-5在促进足细胞衰老表型中的作用，以应对持续的糖尿病应激；2)通过培养足细胞、小鼠疾病模型和随后的人类肾活检结果验证，在体外和体内建立自噬对促进糖尿病肾病足细胞衰老的贡献；3)以足细胞“分泌组”为平台，鉴定肾小球损伤的分子介质，研究衰老相关分泌表型在肾小球疾病进展中的作用，然后使用共培养模型进行验证。了解衰老及其相关因素在糖尿病肾病和潜在的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。

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.