Cellular and Molecular Mechanisms of Renal Fibrosis

描述（由申请人提供）：慢性肾脏病（CKD）是一个日益严重的公共卫生问题，影响超过2600万美国人。CKD的一个关键病理特征是肾纤维化和细胞外基质积累增加。肾间质纤维化是以成纤维细胞活化和细胞外基质过度产生和沉积为特征，导致肾实质破坏和肾功能进行性丧失。目前这种毁灭性疾病的治疗选择是有限的，往往无效。因此，更好地了解肾纤维化的细胞和分子机制对于开发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 在输尿管梗阻模型中，发现了免疫炎症失调在肾纤维化起始中的关键和专性作用。我们的研究表明，与梗阻性肾病相关的纤维化是由于骨髓来源的成纤维细胞在肾脏中积累而引起的。这些成纤维细胞从CD 45+单核细胞前体群体的存在和发展似乎是驱动和依赖于诱导的趋化因子，CXCL 16，在肾小管上皮细胞，并阻止CXCL 16的基因缺失。骨髓成纤维细胞的诱导与IL 13的显著诱导相关，IL 13是Th 2淋巴因子，我们已经证明其在体外专性用于骨髓成纤维细胞的诱导。在本申请中，我们计划检查和表征 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趋化因子CXCL 16和细胞因子脂联素诱导相关的免疫炎症失调引起的。我们认为CXCL 16启动了一个独特的骨髓单核细胞群体的摄取，该细胞群体专性于所产生的纤维化表型，脂联素将这些细胞活化为M2巨噬细胞和骨髓成纤维细胞。为了检验我们的假设，我们将追求以下具体目标：具体目标1是确定CXCL 16/CXCR 6在骨髓来源的单核细胞摄取到肾脏中的作用。具体目标2是检查脂联素信号传导在骨髓来源的单核细胞活化为M2巨噬细胞和骨髓成纤维细胞中的作用。 总之，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中，极化为M2巨噬细胞，并发育成成熟的成纤维细胞。我们的研究结果将为肾纤维化的分子和细胞基础提供新的认识，并可能导致慢性肾脏疾病治疗的新治疗策略的开发。

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.