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Multifunctional role CD36 in progressive renal fibrosis

CD36在进行性肾纤维化中的多功能作用

基本信息

批准号：
7637999
负责人：
DARYL Miyoshi OKAMURA
金额：
$ 12.83万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7637999
关键词：
3-nitrotyrosine Acute Advanced Glycosylation End Products Affect Amino Acids Amyloid Animal Model Apoptosis Apoptotic Architecture Atherosclerosis Attenuated Award Biological Biological Models Biology Bone Marrow CD36 gene Cell Line Cells Chronic Chronic Kidney Failure 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 Reactive Oxygen Species Renal function Renal tubule structure Research Research Personnel Role SR-B proteins 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 nitration novel oxidation oxidized low density lipoprotein programs receptor receptor function research study response scavenger receptor therapeutic target tool

项目摘要

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）：