Uncovering CD36-mediated oxidative and inflammatory pathways in progressive renal

描述(由申请人提供)：慢性肾脏疾病，无论病因如何，其特点是纤维化的持续发展，逐渐破坏正常的结构。动脉粥样硬化形成和纤维化导致进行性肾损害的发病机制之间有许多相似之处。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。到目前为止，我们的研究表明，氧化的脂蛋白是动脉粥样硬化病变的病理成分，在慢性损伤过程中促进肾脏的纤维化途径。CD36是氧化型脂蛋白摄取的主要清道夫受体之一。我们最近证明，CD36缺陷小鼠在慢性梗阻损伤过程中，通过减少氧化应激和减少促炎通路的激活，显著减轻了纤维化的严重程度。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的促炎和氧化途径。这项建议中概述的研究延续了最初K08的研究思路，并将重点放在：(1)利用气相色谱和质谱仪确定CD36在慢性肾损伤中调控的主要氧化途径，以及阐明CD36激活的炎症途径；(2)通过建立骨髓移植嵌合小鼠和体外模型，区分CD36对巨噬细胞依赖和肾小管上皮细胞依赖的作用；以及(3)进一步研究CD36在蛋白尿所致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。这些研究将提高我们对关键细胞受体及其在肾纤维化进展中的中介途径的理解。这项研究将继续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准备。公共卫生相关性：慢性肾脏疾病和终末期肾脏疾病患者的数量正在以惊人的速度增加，几乎没有治疗干预措施来阻止或逆转慢性受损的人类肾脏的纤维化。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功能衰竭的进展提供新的线索，希望开发新的创新疗法来改变其自然进展。

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.