Podocyte Microenvironment in Diabetic Nephropathy

当前提案对于PI在糖尿病肾病研究中的学术生涯发展至关重要。PI认为，如果有机会实现其近期职业目标;完善技能，获取知识并促进学习开展本研究所需的新方法，他将准备完成其发展成为具有DN并发症专业知识的独立研究者的长期目标。PI对糖尿病肾病领域做出了重大贡献，现在准备开始向独立职业过渡。 糖尿病是终末期肾病的主要原因，具有明显较高的发病率和死亡率。糖尿病和糖尿病肾病（DN）是一种免疫系统疾病。炎症细胞如单核细胞/巨噬细胞对患病肾脏的浸润支持炎症作为病因因素的作用。在DN中，足细胞生态位（微环境）的改变可能是导致进行性白蛋白尿和进行性肾衰竭的足细胞功能异常的原因。Podocj^e的功能与其复杂的细胞骨架结构密切相关。作为损伤的结果，骨骼肌重排增强，导致足突消失。我们认为巨噬细胞有助于直接足细胞损伤和/或异常足细胞龛，导致DN，并且腺苷A2 A激动剂逆转该过程并减轻损伤。目的1检验肾脏巨噬细胞募集直接导致糖尿病肾损伤的假设。目的2检验巨噬细胞直接介导足细胞损伤和/或产生导致足细胞损伤的异常足细胞龛的假设。目的3：验证A2 A激动剂通过调节巨噬细胞/足细胞相互作用和/或直接通过调节巨噬细胞/足细胞相互作用来改善DN相关肾损伤的假设。 影响足细胞功能

The current proposal is critical for the development of an academic career for the PI in diabetes nephropathy research. The PI feels that if afforded the opportunity to achieve his immediate career goals; to refine the skills, to acquire knowledge and to facilitate learning new methodologies necessary to conduct this research study, he will be prepared to accomplish his long-term goal of developing into independent investigator with expertise in DN complications. The PI has made significant contributions to the field of diabetic kidney disease and is now poised to begin transitioning toward an independent career. Diabetes mellitus is the leading cause of end stage renal disease with markedly higher morbidity and mortality rates. Diabetes and diabetic nephropathy (DN) is a disorder of the immune system. Infiltration of the diseased kidneys by inflammatory cells such as monocytes/macrophages supports the role of inflammation as an etiological factor. In DN, alterations in the podocyte niche (microenvironment) are likely responsible for abnormal podocyte function leading to progressive albuminuria and progressive renal failure. Podocj^e function is intimately linked to its complex cytoskeletal structure. As a result of injury, cjrtoskeletal rearrangement ensues leading to foot process effacement We hj^othesize that macrophages contribute to direct podocyte injury and/or abnormal podocyte niche leading to DN and that adenosine A2A-agonist reverses this process and attenuates injury. Aim 1 tests the hypothesis that kidney macrophage recruitment directly contributes to diabetic renal injury. Aim 2 tests the hypothesis that macrophages directly mediate podocyte injury and/or create an abnormal podocyte niche leading to podocyte injury. Aim 3 tests the hypothesis that A2A-agonists ameliorate renal injury associated with DN by regulating macrophages/podocyte interaction and/or by directly affecting podocyte function.