Uncovering CD36-mediated oxidative and inflammatory pathways in progressive renal

揭示进行性肾病中 CD36 介导的氧化和炎症途径

• 批准号: 7638229
• 负责人: DARYL Miyoshi OKAMURA
• 金额: $ 9.75万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7638229
• 关键词: 3-nitrotyrosine; Advanced Glycosylation End Products; Amino Acids; Amyloid; Animal Model; Apoptotic; Architecture; Arterial Fatty Streak; Atherosclerosis; Attenuated; Award; Binding; Bone Marrow; Bone Marrow Transplantation; CD36 gene; Cells; Chronic; Chronic Kidney Failure; Data; Development; Disease Progression; Distal; End stage renal failure; Epithelial Cells; Etiology; Event; Extracellular Matrix; Fatty Acids; Fibrosis; Funding; Future; Gel; Generations; Goals; Grant; Health; Human; In Vitro; Inflammation; Inflammatory; Injury; Innovative Therapy; Investigation; Kidney; Kidney Diseases; Lead; Ligands; Light; Lipoproteins; Macrophage Activation; Malaria; Marrow; Mass Fragmentography; Mass Spectrum Analysis; Mediating; Modeling; Mus; Nitrates; Obstruction; Oxidants; Oxidative Stress; Oxidative Stress Pathway; Pathologic; Pathway interactions; Patients; Phospholipids; Play; Post-Translational Protein Processing; Production; Proteins; Proteinuria; Proteomics; Renal tubule structure; Research; Research Personnel; Role; SR-B proteins; Severities; Signal Pathway; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Transplantation; Tubular formation; United States; Wild Type Mouse; angiogenesis; atherogenesis; base; career; cell type; cost; design; fibrogenesis; improved; in vitro Model; in vivo; macrophage; oxidation; oxidized low density lipoprotein; programs; public health relevance; receptor; receptor function; scavenger receptor; therapeutic target; uptake

DESCRIPTION (provided by applicant): Chronic kidney disease, regardless of etiology, is characterized by a relentless progression of fibrosis that gradually destroys the normal architecture. Many parallels have been drawn between atherogenesis and the pathogenic mechanisms that cause progressive kidney destruction by fibrosis. 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 studies thus far demonstrate that oxidized lipoproteins, the pathologic component of atherosclerotic lesions, promote fibrogenic pathways in the kidney during chronic injury. CD36 is one of the major scavenger receptors responsible for uptake of oxidized lipoproteins. We recently demonstrated that the severity of fibrosis was significantly attenuated in CD36-deficient mice during chronic injury by obstruction by decreasing oxidative stress and reducing activation of pro-inflammatory pathways. We hypothesize that CD36- expressing macrophages and renal tubular epithelial cells activates cell-specific pro- inflammatory and oxidative pathways through interaction with its ligand oxidized lipoprotein. The studies outlined in this proposal continue the line of investigation in the original K08 and will focus on: (1) defining the major oxidant pathways modulated by CD36 during chronic injury using gas chromatography and mass spectrometry, as well as elucidating the inflammatory pathways activated by CD36; (2) differentiating macrophage-dependent and tubular epithelial cell-dependent effects of CD36 through the generation of chimeric mice with bone marrow transplantation and in vitro models; and (3) extending investigation of the role of CD36 in chronic kidney injury by proteinuria, a model more akin to human renal disease. These studies will improve our understanding of the key cellular receptors and the pathways they mediate in the progression of renal fibrosis. This research will continue to prepare the applicant for an academic career as an independent investigator in the field of kidney fibrogenesis. PUBLIC HEALTH RELEVANCE: The number of patients with chronic kidney disease and end-stage renal disease is increasing at an alarming rate with few therapeutic interventions to halt or reverse fibrosis in human kidneys that are chronically damaged. Our studies on the cellular receptor CD36 and its ligand oxidized lipoprotein will shed new light in the progression of chronic kidney failure with hopes of developing new innovative therapies to alter its natural progression.

描述（由申请人提供）：慢性肾病，无论病因如何，其特征是纤维化不断进展，逐渐破坏正常结构。动脉粥样硬化形成和纤维化引起进行性肾脏破坏的致病机制之间存在许多相似之处。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。迄今为止，我们的研究表明，氧化脂蛋白（动脉粥样硬化病变的病理成分）在慢性损伤期间促进肾脏的纤维化途径。 CD36 是负责摄取氧​​化脂蛋白的主要清道夫受体之一。我们最近证明，通过减少氧化应激和减少促炎途径的激活，CD36 缺陷小鼠在慢性阻塞性损伤期间纤维化的严重程度显着减轻。我们假设表达 CD36 的巨噬细胞和肾小管上皮细胞通过与其配体氧化脂蛋白相互作用来激活细胞特异性促炎和氧化途径。本提案中概述的研究延续了原始 K08 中的研究路线，并将重点关注：（1）使用气相色谱和质谱确定慢性损伤期间 CD36 调节的主要氧化途径，以及阐明 CD36 激活的炎症途径； (2)通过骨髓移植嵌合小鼠和体外模型的产生，区分CD36的巨噬细胞依赖性和肾小管上皮细胞依赖性作用； (3)进一步研究CD36在蛋白尿引起的慢性肾损伤中的作用，这是一种更类似于人类肾脏疾病的模型。这些研究将增进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。这项研究将继续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。公共卫生相关性：患有慢性肾病和终末期肾病的患者数量正在以惊人的速度增加，而几乎没有治疗干预措施可以阻止或逆转长期受损的人类肾脏纤维化。我们对细胞受体 CD36 及其配体氧化脂蛋白的研究将为慢性肾衰竭的进展提供新的线索，并希望开发新的创新疗法来改变其自然进展。