Cellular and Molecular Mechanisms of Renal Fibrosis

项目摘要 慢性肾脏疾病是一个日益严重的公共卫生问题，影响着2600多万美国人。 慢性肾脏疾病的一个重要病理特征是肾纤维化。肾纤维化以成纤维细胞为特征 激活和过度产生和沉积细胞外基质，导致细胞外基质的破坏 肾实质和进行性肾功能丧失到终末期肾病。当前的治疗方法 应对这种毁灭性疾病的选择有限，而且往往无效。因此，更好地理解 肾脏纤维化的细胞和分子机制对于制定有效的治疗策略至关重要 肝纤维化肾病的治疗。 我们研究了启动和控制肾纤维化的因素，发现了一个关键的和 免疫-炎症失调在肾纤维化的发生和发展中的作用。我们的 研究表明，肾脏损伤引起的纤维化与骨的形成有关 积聚在肾脏中的骨髓源性成纤维细胞。这些成纤维细胞的存在和积聚 从CD45单核前体群体和肾脏纤维化的发展是由 依赖于趋化因子CXCL16在肾小管上皮细胞中的诱导，并通过基因阻止 CXCL16或其受体CXCR6的缺失。此外，髓系成纤维细胞的聚集与 Th2细胞因子的显著诱导，激活信号转导和转录激活因子6 (STAT6)刺激肾脏髓系成纤维细胞活化和纤维化形成。激活的STAT6诱导 组蛋白H3K27去甲基酶Jumonji结构域蛋白3(JMJD3)的表达 H3K27去甲基化和髓系成纤维细胞活化。在这份续期申请中，我们计划审查和 研究STAT6-JMJD3信号在髓系成纤维细胞活化中的作用 肾纤维化的细胞和分子机制。我们的中心假设是Th2细胞因子激活 STAT6信号导致JMJD3诱导，组蛋白H3K27去甲基化，髓系成纤维细胞激活，以及 纤维化。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 STAT6信号在骨髓源性成纤维细胞活化中的作用。具体目标2是检查 JMJD3是否介导骨髓源性成纤维细胞的激活。 总而言之，我们计划利用分子、细胞、药理学和遗传学方法来研究 STAT6-JMJD3信号在髓系成纤维细胞活化和肾纤维化发生发展中的作用结果 我们的研究将对肾脏纤维化的细胞和分子机制提供新的理解 并可能导致开发治疗慢性肾脏疾病的新治疗策略。

Project Summary Chronic kidney disease is a growing public health problem that affects more than 26 million Americans. A key pathologic feature of chronic kidney disease is renal fibrosis. Renal 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 to end-stage renal disease. 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 fibrotic kidney disorder. We have studied the factors initiating and controlling renal fibrosis and have discovered a critical and obligate role for immune-inflammatory dysregulation in the initiation and development of renal fibrosis. Our studies have demonstrated that the fibrosis arises from kidney injury is associated with the formation of bone marrow-derived fibroblasts that accumulate in the kidney. The presence and accumulation of these fibroblasts from a CD45+ mononuclear precursor population and the development of renal fibrosis are driven by and dependent upon induction of the chemokine CXCL16 in renal tubular epithelial cells and is prevented by genetic deletion of CXCL16, or its receptor, CXCR6. Furthermore, the accumulation of myeloid fibroblasts is associated with striking induction of Th2 cytokines, which activate signal transducer and activator of transcription 6 (STAT6) to stimulate myeloid fibroblast activation and fibrogenesis in the kidney. Activated STAT6 induces expression of histone H3K27 demethylase, Jumonji domain-containing protein 3 (JMJD3), resulting in histone H3K27 demethylation and myeloid fibroblast activation. In this renewal application, we plan to examine and characterize the role of STAT6-JMJD3 signaling in myeloid fibroblast activation to further understand the cellular and molecular mechanisms of renal fibrosis. Our central hypothesis is that Th2 cytokines activate STAT6 signaling resulting in JMJD3 induction, histone H3K27 demethylation, myeloid fibroblast activation, and fibrogenesis. To test our hypothesis, we will pursue the following Specific Aims: Specific Aim 1 is to determine the role of STAT6 signaling in the activation of bone marrow-derived fibroblasts. Specific Aim 2 is to examine whether JMJD3 mediates bone marrow-derived fibroblast activation. In summary, we plan to utilize molecular, cellular, pharmacological, and genetic approaches to study the role of STAT6-JMJD3 signaling in myeloid fibroblast activation and development of renal fibrosis. Results from our studies will provide a new understanding of the cellular and molecular mechanisms of renal fibrosis and could lead to the development of novel therapeutic strategies for the treatment of chronic kidney disease.