Cellular and Molecular Mechanisms of Renal Fibrosis

肾纤维化的细胞和分子机制

• 批准号: 8858400
• 负责人: YANLIN WANG
• 金额: $ 34.04万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-03 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8858400
• 关键词: Affect; American; Biological; Biology; Bone Marrow; CXCR6 gene; Cells; Cellular biology; Chronic Kidney Failure; Clinical; Complex; Deposition; Development; Employee Strikes; Epithelial Cells; Extracellular Matrix; Fibroblasts; Fibrosis; Generations; Genetic; Human; Immune; In Vitro; Incidence; Inflammatory; Injury; Interleukin-13; Kidney; Kidney Diseases; Knowledge; Lead; Lymphocyte; Lymphokines; Mission; Modeling; Molecular; Mononuclear; Myelogenous; PTPRC gene; Pathogenesis; Pathologic; Phenotype; Population; Production; Public Health; Recruitment Activity; Renal function; Research; Role; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Tubular formation; Ureteral obstruction; adiponectin; base; chemokine; cytokine; genetic approach; injured; interstitial; macrophage; monocyte; novel therapeutics; prevent; public health relevance; treatment strategy; uptake

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is a growing public health problem that affects more than 26 million Americans. A key pathologic feature of CKD is renal fibrosis with increased accumulation of extracellular matrix. Renal interstitial fibrosis is characterized by fibroblast activation and excessive production and deposition of extracellular matrix, which leads to the destruction of renal parenchyma and progressive loss of kidney function. The current therapeutic options for this devastating condition are limited and often ineffective. Therefore, a better understanding of the cellular and molecular mechanisms underlying renal fibrosis is essential for developing effective strategies for the treatment of thi progressive kidney disorder. We have studied the factors initiating and controlling renal fibrosis in a model of ureteral obstruction and have discovered a critical and obligate role for immune-inflammatory dysregulation in the initiation of renal fibrosis. Our studies demonstrate that the fibrosis associated with obstructive nephropathy arises from the formation of bone marrow-derived fibroblasts which accumulate in the kidney. The presence and development of these fibroblasts from a CD45+ mononuclear precursor population appear to be driven by and dependent upon induction of the chemokine, CXCL16, in renal tubular epithelial cells and is prevented by genetic deletion of CXCL16. The induction of myeloid fibroblasts is associated with striking induction of IL13, the Th2 lymphokine, which we have shown to be obligate for the induction of myeloid fibroblasts in vitro. In this application, we plan to examine and characterize the immune-inflammatory mechanism arising from renal injury to further understand the cellular and molecular mechanisms of renal fibrosis. Our central hypothesis is that pathologic renal interstitial fibrosis arises from immune-inflammatory dysregulation associated with induction of the chemokine - CXCL16 and the cytokine - adiponectin. We propose that CXCL16 initiates the uptake of a unique myeloid mononuclear cell population obligate to the resultant fibrotic phenotype and adiponectin activates these cells to M2 macrophages and myeloid fibroblasts. To test our hypothesis, we will pursue the following Specific Aims: Specific Aim 1 is to determine the role of CXCL16/CXCR6 in the uptake of bone marrow-derived monocytes into the kidney. Specific Aim 2 is to examine the role of adiponectin signaling in the activation of bone marrow-derived monocytes to M2 macrophages and myeloid fibroblasts. In summary, we plan to utilize biological and genetic approaches to study the role of bone marrow- derived mononuclear cells in the pathogenesis of renal fibrosis. Our plans are directed at understanding the complex biology of these cells and how they are recruited into the kidney, polarized to M2 macrophages, and develop into mature fibroblasts. Results from our studies will provide a new understanding of the molecular and cellular bases of renal fibrosis and could lead to the development of novel therapeutic strategies for the treatment of chronic kidney disease.

描述（由申请人提供）：慢性肾脏疾病（CKD）是一个日益增长的公共卫生问题，影响了超过2600万美国人。 CKD的关键病理特征是肾纤维化，细胞外基质的积累增加。肾脏间质纤维化的特征是成纤维细胞激活，细胞外基质的过度产生和沉积，这导致肾实质的破坏和肾功能的逐渐丧失。这种破坏性状况的当前治疗选择是有限的，而且常常无效。因此，对肾纤维化下的细胞和分子机制的更好理解对于制定有效治疗这种进行性肾脏疾病的有效策略至关重要。 我们已经研究了引发和控制肾纤维化的因素 在输尿管障碍物的模型中，发现了免疫炎症性失调在肾纤维化开始中的关键和义务作用。我们的研究表明，与阻塞性肾病相关的纤维化是由骨髓衍生的成纤维细胞的形成产生的。来自CD45+单核前体种群的这些成纤维细胞的存在和发育似乎是由肾小管上皮细胞中趋化因子CXCL16诱导的驱动和依赖的，并通过CXCL16的遗传缺乏阻止了CXCL16。髓样成纤维细胞的诱导与Th2淋巴细胞IL13的引人注目的诱导有关，我们已证明这对于在体外诱导髓样成纤维细胞诱导很有本质。在此应用程序中，我们计划检查和表征 肾损伤引起的免疫炎性机制进一步了解肾纤维化的细胞和分子机制。我们的中心假设是，病理性肾脏间质纤维化是由与趋化因子-CXCL16和细胞因子 - 脂联素诱导相关的免疫炎性失调引起的。我们建议CXCL16启动对产生的纤维化表型的独特的髓样单核细胞种群的吸收，而脂联素则将这些细胞激活M2巨噬细胞和髓样成纤维细胞。为了检验我们的假设，我们将追求以下特定目的：具体目的1是确定CXCL16/CXCR6在吸收骨髓衍生的单核细胞进入肾脏中的作用。具体目的2是检查脂联素信号传导在骨髓衍生的单核细胞激活M2巨噬细胞和髓样成纤维细胞中的作用。 总而言之，我们计划利用生物学和遗传学方法研究骨髓衍生的单核细胞在肾纤维化发病机理中的作用。我们的计划旨在了解这些细胞的复杂生物学以及如何将它们募集到肾脏，两极化至M2巨噬细胞，并发展为成熟的成纤维细胞。我们的研究结果将为肾纤维化的分子和细胞碱提供新的了解，并可能导致发展新型治疗策略以治疗慢性肾脏疾病。