Multifunctional role CD36 in progressive renal fibrosis

描述(由申请人提供)： 这一应用的目的是进一步确定肾脏纤维化的关键途径，特别是配体及其受体在纤维化进展中的功能关系。我们的初步数据支持这一假设，即清道夫受体CD36在进行性肾纤维化过程中介导了凝血酶敏感蛋白和氧化脂蛋白的促炎和促纤维化作用。在对梗阻引起的慢性损伤的反应中，CD36介导了重要的纤维化反应，因为CD36缺陷小鼠的肾脏纤维化严重程度显著减轻，并与尽管肾小管间质中凝血酶反应蛋白和硝基酪氨酸水平升高，但肾小管间质中核因子-kappaB活性和氧化应激降低有关。第一个目的是在慢性肾纤维化动物模型中阐明CD36与血栓反应蛋白和氧化脂蛋白的促纤维化关系：(1)研究血栓反应蛋白-CD36在转化生长因子-β激活和血管生成中的关系；(2)通过质谱学和二维蛋白质凝胶分析来区分CD36调节氧化蛋白修饰的氧化途径和靶点。第二个目的是利用嵌合小鼠策略区分巨噬细胞和肾小管细胞依赖的CD36在纤维化形成中的作用。第三个目的是在体外研究肾小管CD36在纤维化过程中调节细胞内氧化途径的机制。通过加深我们对关键细胞受体及其在肾脏纤维化进展中的调节途径的了解，这些研究将有助于确定慢性肾脏疾病(CKD)的潜在治疗靶点，目标是开发新的治疗方法来阻止或减缓CKD的进展，并减轻终末期肾脏疾病的巨大健康负担。这项研究将为申请人作为肾脏纤维化领域的独立研究员的学术生涯做好准备。他将接受分子生物学、生物质谱分析方面的进一步培训，开发体外模型系统，并获得肾纤维化领域的专业知识。在艾利森·埃迪博士的指导下提供的丰富环境，以及与Jay Heinecke博士和Maria Febbraio博士的合作，以及加入华盛顿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，将促进向独立的过渡。

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.