Podocyte Microenvironment in Diabetic Nephropathy

糖尿病肾病的足细胞微环境

• 批准号: 8139444
• 负责人: Alaa S Awad
• 金额: $ 0.23万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-10 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8139444
• 关键词: Address; Adenosine; Affect; Age; Agonist; Albumins; Albuminuria; Animal Model; Attenuated; Blocking Antibodies; CCL2 gene; Cell Count; Cells; Coculture Techniques; Complex; DNA Sequence Rearrangement; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Dichloromethylene Diphosphonate; Disease; End stage renal failure; Environment; Enzymes; Excretory function; Family; Figs - dietary; Foot Process; Future; G-Protein-Coupled Receptors; Glucose; Goals; Human; Immune System Diseases; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-1 alpha; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Learning; Leukocyte Adhesion Molecules; Leukocyte-Adhesion Receptors; Link; Liposomes; Mediating; Methodology; Morbidity - disease rate; Mus; NPHS2 protein; Nitric Oxide; Play; Principal Investigator; Process; Reactive Oxygen Species; Receptor Activation; Regulation; Reporting; Research; Research Personnel; Role; Small Interfering RNA; Structure; Testing; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Vascular Endothelial Growth Factors; Welts; base; blood pressure regulation; career; chemokine; clinically relevant; cytokine; diabetic; in vivo; mRNA Expression; macrophage; monocyte; mortality; nephrin; novel therapeutic intervention; novel therapeutics; overexpression; podocyte; pressure; programs; protective effect; receptor; research study; skills; type I and type II diabetes; urinary

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.

目前的提案对于糖尿病肾病PI的学术生涯发展至关重要 research. PI认为，如果有机会实现他的直接职业目标，提高技能， 为了获得知识并促进学习进行这项研究所需的新方法， 将准备完成他的长期目标，发展成为独立的调查员， DN并发症。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病因，其发病率和死亡率明显较高 rates.糖尿病和糖尿病肾病（DN）是一种免疫系统疾病。疾病的渗透 炎症细胞如单核细胞/巨噬细胞对肾脏的作用支持炎症作为一种免疫反应， 病因在DN中，足细胞生态位（微环境）的改变可能是导致糖尿病肾病的原因。 足细胞功能异常导致进行性白蛋白尿和进行性肾衰竭。Podocj^e函数 与其复杂的细胞骨架结构密切相关。作为损伤的结果， 我们认为巨噬细胞直接导致足细胞损伤 和/或异常足细胞龛导致DN，腺苷A2 A激动剂逆转这一过程， 减轻损伤。目的1检验肾脏巨噬细胞募集直接有助于 糖尿病肾损伤目的2检验巨噬细胞直接介导足细胞损伤和/或 产生异常的足细胞小生境，导致足细胞损伤。目的3检验A2 A激动剂 通过调节巨噬细胞/足细胞的相互作用和/或通过直接调节巨噬细胞/足细胞的相互作用来改善与DN相关的肾损伤。 影响足细胞功能