Multifunctional role CD36 in progressive renal fibrosis

CD36在进行性肾纤维化中的多功能作用

• 批准号: 7446765
• 负责人: DARYL Miyoshi OKAMURA
• 金额: $ 12.93万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7446765
• 关键词: 3-nitrotyrosine; Acute; Advanced Glycosylation End Products; Affect; Amino Acids; Amyloid; Animal Cancer Model; Animal Model; Apoptosis; Apoptotic; Architecture; Atherosclerosis; Attenuated; Award; Biological; Biological Models; Biology; Bone Marrow; CD36 gene; Cell Line; Cells; Chronic; Chronic Kidney Failure; Class; Collaborations; Communities; Data; Development; Disease Progression; Distal; End stage renal failure; Endocytosis; Environment; Epithelial Cells; Etiology; Event; Extracellular Matrix; Family; Fatty Acids; Fibrosis; Foundations; Gel; Goals; Health; In Vitro; Inflammation; Injury; K-Series Research Career Programs; Kidney; Kidney Diseases; Laboratories; Lead; Ligands; Lipoproteins; Macrophage Activation; Malaria; Marrow; Mass Spectrum Analysis; Mediating; Mentors; Mentorship; Modeling; Molecular Biology; Mus; NF-kappa B; Nitrates; Obstruction; Oxidants; Oxidative Stress; Oxidative Stress Pathway; Pathway interactions; Patients; Phospholipids; Play; Post-Translational Protein Processing; Process; Production; Proteins; Proteomics; Purpose; Reactive Oxygen Species; Renal function; Renal tubule structure; Research; Research Personnel; Role; Severities; Signal Pathway; Therapeutic; Time; Tissues; Training; Transforming Growth Factor beta; Transgenic Organisms; Transplantation; Tubular formation; United States; Universities; Ureteral obstruction; Washington; Wild Type Mouse; Work; angiogenesis; atherogenesis; career; cell type; fibrogenesis; improved; in vitro Model; in vivo; macrophage; nitrate; nitration; novel; oxidation; oxidized low density lipoprotein; programs; receptor; receptor function; research study; response; scavenger receptor; therapeutic target; tool

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.

描述（由申请人提供）： 本申请的目的是进一步确定肾纤维化的关键途径，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以下假设：清道夫受体 CD36 在进行性肾纤维化过程中介导血小板反应蛋白和氧化脂蛋白的促炎和促纤维化作用。为了应对梗阻引起的慢性损伤，CD36 介导重要的纤维化反应，因为 CD36 缺陷小鼠的肾纤维化严重程度显着减弱，并且与 NF-κ B 激活和氧化应激减少相关，尽管肾小管间质中血小板反应蛋白和硝基酪氨酸（蛋白质氧化的标志物）水平较高。第一个目的是通过以下方式阐明慢性肾纤维化动物模型中 CD36 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-CD36 在 TGF-β 激活和血管生成中的关系； (2) 通过质谱和二维蛋白凝胶分析区分 CD36 调节的氧化蛋白修饰的氧化途径和靶点。第二个目标是使用嵌合小鼠策略区分 CD36 在纤维发生中的巨噬细胞和肾小管细胞依赖性效应。第三个目标是研究肾小管 CD36 在纤维化过程中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在肾纤维化进展中介导的途径的理解，这些研究将有助于确定慢性肾病（CKD）的潜在治疗靶点，目标是开发新疗法来阻止或减缓 CKD 的进展，并减轻终末期肾病带来的巨大健康负担。这项研究将为申请人作为肾纤维发生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。艾莉森·艾迪博士的指导下提供的丰富环境以及与 Drs. 的合作将促进向独立的过渡。 Jay Heinecke 和 Maria Febbraio，并加入了华盛顿大学一个由专注于肾脏疾病病理学的富有成效的研究人员组成的大型社区。