Cellular and Molecular Mechanisms of Renal Fibrosis

肾纤维化的细胞和分子机制

• 批准号: 9926871
• 负责人: YANLIN WANG
• 金额: $ 36.9万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-11 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926871
• 关键词: Affect; American; Bone Marrow; CXCR6 gene; Cell Nucleus; Cellular biology; Chronic Kidney Failure; Complex; Cytoplasm; Deposition; Development; End stage renal failure; Epithelial Cells; Extracellular Matrix; Fibroblasts; Fibrosis; Genetic; Histones; Immune; In Vitro; Inflammatory; Injury to Kidney; JAK3 gene; Janus kinase 3; Kidney; Kidney Diseases; Knock-out; Knowledge; Lead; Lymphocyte; Mediating; Mission; Modeling; Molecular; Mononuclear; Myelogenous; Osteogenesis; PTPRC gene; Pathologic; Pharmacology; Population; Production; Proteins; Public Health; Publishing; Renal function; Research; Role; STAT6 Transcription Factor; Signal Transduction; Testing; Therapeutic; Tubular formation; United States National Institutes of Health; bone; chemokine; chromatin remodeling; cytokine; demethylation; fibrogenesis; genetic approach; human disease; in vivo; kidney fibrosis; monocyte; novel therapeutics; overexpression; prevent; receptor; response to injury; treatment strategy

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.

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关键病理特征是肾纤维化。肾纤维化的特征是成纤维细胞 细胞外基质的激活和过度产生和沉积，这导致细胞外基质的破坏。 肾实质和肾功能逐渐丧失至终末期肾病。当前的治疗性 治疗这种毁灭性疾病的选择有限，而且往往无效。因此，更好地了解 肾纤维化的细胞和分子机制对于制定有效的治疗策略至关重要 纤维化肾病的治疗。 我们已经研究了引发和控制肾纤维化的因素，并发现了一个关键的， 免疫炎症失调在肾纤维化的发生和发展中的专性作用。我们 研究表明，肾损伤引起的纤维化与骨的形成有关 骨髓来源的成纤维细胞，在肾脏中积累。这些成纤维细胞的存在和积累 从CD 45+单核细胞前体群体和肾纤维化的发展是由驱动， 依赖于肾小管上皮细胞中趋化因子CXCL 16的诱导，并通过遗传学途径阻止 CXCL 16或其受体CXCR 6的缺失。此外，骨髓成纤维细胞的积累与 显著诱导Th 2细胞因子，其激活信号转导和转录激活因子6 在一些实施方案中，STAT 6被用于刺激肾中的骨髓成纤维细胞活化和纤维形成。活化的STAT 6诱导 表达组蛋白H3 K27去甲基化酶，含Jumonji结构域的蛋白3（JMJD 3），导致组蛋白H3 K27去甲基化酶， H3 K27去甲基化和髓样成纤维细胞活化。在这次更新申请中，我们计划审查和 表征STAT 6-JMJD 3信号传导在髓样成纤维细胞活化中的作用，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Th 2细胞因子激活 STAT 6信号传导导致JMJD 3诱导、组蛋白H3 K27去甲基化、髓样成纤维细胞活化和 纤维化为了验证我们的假设，我们将追求以下具体目标：具体目标1是确定 STAT 6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 JMJD 3是否介导骨髓来源的成纤维细胞活化。 总之，我们计划利用分子，细胞，药理学和遗传学方法来研究， STAT 6-JMJD 3信号传导在骨髓成纤维细胞活化和肾纤维化发展中的作用。结果 将为肾纤维化的细胞和分子机制提供新的认识 并且可能导致用于治疗慢性肾病的新治疗策略的开发。