Cellular and Molecular Mechanisms of Renal Fibrosis

肾纤维化的细胞和分子机制

• 批准号: 8342370
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8342370
• 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; injured; interstitial; macrophage; monocyte; novel therapeutics; prevent; 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. PUBLIC HEALTH RELEVANCE: Our proposed research is highly relevant to public health because understanding the biology of bone marrow-derived cells and their roles in the development of renal fibrosis will provide a new research direction in chronic kidney disease and could lead to the development of novel therapeutic strategies for the treatment of chronic kidney disease. Therefore, the proposed research is relevant to NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human illness.

描述(申请人提供)：慢性肾脏疾病(CKD)是一个日益严重的公共卫生问题，影响着2600多万美国人。慢性肾脏病的一个重要病理特征是肾脏纤维化，细胞外基质积聚增多。肾间质纤维化以成纤维细胞活化、细胞外基质过度产生和沉积为特征，导致肾实质破坏，进行性肾功能丧失。目前对这种毁灭性疾病的治疗选择有限，而且往往无效。因此，更好地了解肾脏纤维化的细胞和分子机制对于制定有效的治疗进行性肾脏疾病的策略是至关重要的。我们已经研究了引发和控制肾纤维化的因素。 在输尿管梗阻的模型中，并发现免疫炎症失调在肾纤维化的启动中起着关键和必要的作用。我们的研究表明，与梗阻性肾病相关的纤维化是由积聚在肾脏中的骨髓源性成纤维细胞形成的。这些来自CD45+单核前体细胞的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的诱导所驱动和依赖的，并通过CXCL16的基因缺失来阻止。髓系成纤维细胞的诱导与Th2淋巴因子IL13的显著诱导有关，我们已经证明IL13是体外诱导髓系成纤维细胞所必需的。在本应用程序中，我们计划检查和表征 探讨肾损伤引起的免疫炎症机制，以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，病理性肾间质纤维化是由与诱导趋化因子CXCL16和细胞因子脂联素相关的免疫-炎症调节失调引起的。我们认为，CXCL16启动了一种独特的髓系单核细胞群的摄取，从而产生了纤维化表型，而脂联素激活了这些细胞向M2巨噬细胞和髓系成纤维细胞转化。为了验证我们的假设，我们将追求以下特定的目标：特定的目标1是确定CXCL16/CXCR6在骨髓来源的单核细胞摄取到肾脏中的作用。具体目的2是研究脂联素信号在骨髓来源的单核细胞激活M2巨噬细胞和髓系成纤维细胞中的作用。综上所述，我们计划利用生物学和遗传学方法来研究骨髓来源的单个核细胞在肾纤维化发病机制中的作用。我们的计划旨在了解这些细胞的复杂生物学，以及它们如何被招募到肾脏，极化成M2巨噬细胞，并发育成成熟的成纤维细胞。我们的研究结果将对肾脏纤维化的分子和细胞基础有新的理解，并可能导致开发新的治疗策略来治疗慢性肾脏疾病。 公共卫生相关性：我们建议的研究与公共卫生高度相关，因为了解骨髓来源细胞的生物学及其在肾脏纤维化发展中的作用将为慢性肾脏疾病提供新的研究方向，并可能导致开发治疗慢性肾脏疾病的新治疗策略。因此，这项拟议的研究与美国国立卫生研究院的使命有关，该使命涉及发展有助于减轻人类疾病负担的基础知识。