Multifunctional role CD36 in progressive renal fibrosis

描述（由申请人提供）： 本申请的目的是进一步确定肾纤维化中的关键途径，特别是在纤维化进展中配体及其受体之间的功能关系。我们的初步数据支持这一假设，清道夫受体CD 36介导的促炎和促纤维化的作用，血小板反应蛋白和氧化脂蛋白在进行性肾纤维化。在对阻塞诱导的慢性损伤的反应中，CD 36介导重要的纤维化反应，因为肾纤维化的严重程度在CD 36缺陷小鼠中显著减弱，并且与NF-κ B活化和氧化应激降低相关，尽管在肾小管中存在较高水平的血小板反应蛋白和硝基酪氨酸（蛋白质氧化的标志物）。第一个目的是阐明慢性肾纤维化动物模型中CD 36与血小板反应蛋白和氧化脂蛋白之间的促纤维化关系：（1）研究血小板反应蛋白-CD 36在TGF-β活化和血管生成中的关系;（2）通过质谱和2-D蛋白质凝胶分析区分氧化剂途径和CD 36调节的氧化蛋白修饰靶点。第二个目的是使用嵌合小鼠策略区分CD 36在纤维发生中的巨噬细胞和肾小管细胞依赖性作用。第三个目的是研究在纤维化过程中肾小管CD 36调节细胞内氧化途径的体外机制。通过提高我们对关键细胞受体及其介导肾纤维化进展的途径的理解，这些研究将有助于确定慢性肾脏病（CKD）的潜在治疗靶点，目的是开发新的治疗方法来停止或减缓CKD的进展，减轻终末期肾病的巨大健康负担。这项研究将为申请人作为肾纤维化领域的独立研究者的学术生涯做好准备。他将获得分子生物学、生物质谱分析、体外模型系统开发方面的进一步培训，并获得肾纤维化领域的专业知识。在Allison Eddy博士的指导下以及与Jay Heinecke和Maria Febbraio博士的合作下提供的丰富环境，以及加入大学专注于肾脏疾病病理生物学的大量富有成效的研究人员社区，将促进向独立的过渡。华盛顿。

DESCRIPTION (provided by applicant): The purpose of this application is to further define key pathways in kidney fibrosis, particularly the functional relationship between ligands and their receptor in the progression of fibrosis. Our preliminary data supports the hypothesis that the scavenger receptor CD36 mediates the proinflammatory and profibrotic effects of thrombospondin and oxidized lipoproteins during progressive renal fibrosis. In response to chronic injury induced by obstruction, CD36 mediates important fibrogenic responses, as the severity of renal fibrosis is significantly attenuated in CD36 deficient mice and is associated with decreased NF-kappa B activation and oxidative stress despite higher levels thrombospondin and nitrotyrosine, a marker of protein oxidation, in the tubulointerstitium. The first aim is to elucidate the profibrotic relationship between CD36 and thrombospondin and oxidized lipoproteins in an animal model of chronic renal fibrosis by: (1) investigating the thrombospondin-CD36 relationship in TGF-beta activation and angiogenesis; and (2) diffentiating oxidant pathways and targets of oxidized protein modification modulated by CD36 through mass spectrometry and 2-D protein gel analysis. The second aim is to differentiate macrophage and renal tubular cell dependent effects of CD36 in fibrogenesis using chimeric mouse strategies. The third aim is to investigate in vitro mechanisms whereby tubular CD36 modulates intracellular oxidation pathways during fibrosis. By improving our understanding of the key cellular receptors and the pathways they mediate in the progression of renal fibrosis, these studies will help to identify potential therapeutic targets for chronic kidney disease (CKD) with the goal of developing novel therapies to halt or slow the progression of CKD and alleviate the tremendous health burden of end-stage renal disease. This research will prepare the applicant for an academic career as an independent investigator in the field of kidney fibrogenesis. He will obtain further training in molecular biology, biological mass spectrometry analysis, develop in vitro model systems and gain expertise in the field of renal fibrosis. The transition to independence will be facilitated by the rich environment provided under the mentorship of Dr. Allison Eddy and collaborations with Drs. Jay Heinecke and Maria Febbraio, and by joining a large community of productive researchers focusing on the pathobiology of renal disease at the University of Washington.