Podocyte Microenvironment in Diabetic Nephropathy

描述(由申请人提供)： 目前的建议对于PI在糖尿病肾病研究中的学术生涯的发展至关重要。私家侦探认为，如果有机会实现他目前的职业目标；完善进行这项研究所需的技能、获取知识和促进学习新的方法，他将准备完成他的长期目标，即发展成为具有糖尿病肾病并发症专业知识的独立调查员。PI在糖尿病肾病领域做出了重大贡献，现在正准备开始向独立的职业生涯过渡。 糖尿病是终末期肾脏疾病的主要原因，其发病率和死亡率明显较高。糖尿病和糖尿病肾病是一种免疫系统的紊乱。炎症细胞如单核/巨噬细胞对病变肾脏的渗透支持炎症作为致病因素的作用。在糖尿病肾病中，足细胞巢(微环境)的改变可能导致足细胞功能异常，导致进行性蛋白尿和进行性肾功能衰竭。足细胞的功能与其复杂的细胞骨架结构密切相关。由于损伤，细胞骨架重排继而导致足突消失。我们假设巨噬细胞参与了导致糖尿病肾病的直接足细胞损伤和/或异常足细胞生态位，腺苷A2a激动剂逆转了这一过程并减轻了损伤。目的1验证肾巨噬细胞募集直接导致糖尿病肾损害的假说。目的2验证巨噬细胞直接介导足细胞损伤和/或产生异常足细胞生态位导致足细胞损伤的假说。目的3验证A2A型激动剂通过调节巨噬细胞/足细胞相互作用和/或直接影响足细胞功能来减轻糖尿病肾病相关肾损伤的假说。了解糖尿病、巨噬细胞和足细胞之间的相互作用可能有助于更好地阐明糖尿病肾脏疾病的机制，并导致开发新的治疗策略来管理这一疾病过程。

DESCRIPTION (provided by applicant): 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. Podocyte function is intimately linked to its complex cytoskeletal structure. As a result of injury, cytoskeletal rearrangement ensues leading to foot process effacement. We hypothesize 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. An understanding of the interaction between diabetes, macrophages and podocytes may help to better elucidate the mechanisms involved in diabetic renal disease and lead to the development of new therapeutic strategies to manage this disease process.