Novel mechanisms of kidney inflammation and fibrosis

肾脏炎症和纤维化的新机制

• 批准号: 10563913
• 负责人: YANLIN WANG
• 金额: $ 55.44万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563913
• 关键词: American; CASP1 gene; Cells; ChIP-seq; Chronic; Chronic Kidney Failure; Development; Disease; Experimental Models; Family; Fibrosis; Genetic; Human; IL18 gene; Immune; In Vitro; Inflammasome; Inflammation; Inflammatory; Injury; Injury to Kidney; Kidney; Kidney Diseases; Knock-out; Liquid Chromatography; Macrophage; Macrophage Activation; Mediating; Modeling; Molecular; Myelogenous; Myeloid Cells; Pathway interactions; Peptide Initiation Factors; Pre-Clinical Model; Production; Proteomics; Public Health; Reaction; Regulation; Role; Signal Pathway; Testing; Therapeutic; in vivo; inhibitor; insight; kidney cell; kidney fibrosis; knock-down; marenostrin; nephrogenesis; novel; novel therapeutic intervention; overexpression; pharmacologic; prevent; receptor; renal damage; response; tandem mass spectrometry; treatment strategy

PROJECT SUMMARY Chronic kidney disease (CKD) is a public health problem that afflicts more than 37 million Americans. The current therapeutic options for this progressive disorder are limited; therefore, novel therapeutic strategies are urgently needed. Common features of CKD are kidney inflammation and fibrosis. Inflammation often triggers fibrosis, and fibrosis is the end result of chronic inflammatory reactions. Renal inflammation is characterized by macrophage activation and proinflammatory molecule production. However, the molecular mechanisms underlying macrophage activation are not fully understood. Therefore, the long-term objective of this proposal is to understand the molecular mechanisms of macrophage activation so that effective strategies can be developed for the treatment of CKD. We have identified PU.1 as a critical factor in the regulation of kidney inflammation during the development of CKD. Specifically, we have demonstrated that PU.1 is induced in the kidney in experimental models of CKD and in human kidney with CKD and PU.1 is obligatory for macrophage activation and inflammatory molecule production and development of CKD. Genetic deletion or pharmacological inhibition of PU.1 prevents macrophage activation and inflammatory molecule production in macrophages in vitro, and pharmacological inhibition of PU.1 suppresses macrophage activation, inflammatory molecule production, and fibrosis development in the kidney with obstructive injury. Furthermore, the proinflammatory effect of PU.1 appears to be mediated by the NOD-like receptor family pyrin domain–containing 3 (NLRP3) inflammasome pathway. In this application, we propose to examine and characterize the role of PU.1-NLRP3 pathway in macrophage activation and polarization and proinflammatory and profibrotic molecule production to further understand the molecular mechanisms of inflammation and development of kidney fibrosis. Our central hypothesis is that PU.1 promotes NLRP3 expression and inflammasome activation in macrophages leading to proinflammatory and profibrotic molecule expression and development of kidney fibrosis. To test this hypothesis, we will pursue the following Specific Aims. Specific Aim 1 is to determine the role of PU.1 in macrophage activation and polarization in vitro and in vivo. Specific Aim 2 is to dissect the molecular mechanisms by which PU.1 promotes macrophage activation and polarization. Specific Aim 3 is to explore the therapeutic potential of a selective PU.1 inhibitor for the treatment of CKD. We plan to utilize molecular, genetic, and pharmacological approaches to examine the role of PU.1- NLRP3 pathway in macrophage activation and polarization and development of kidney fibrosis. Results from these studies will provide novel insights into the molecular mechanisms of kidney inflammation and could lead to the development of novel therapeutic strategies for the treatment of CKD.

项目摘要 慢性肾脏疾病（CKD）是一个公共卫生问题，遭受超过3700万美国人的困扰。 这种进行性疾病的当前治疗选择是有限的。因此，新颖的治疗策略 迫切需要。 CKD的常见特征是肾脏注射和纤维化。炎症通常会触发 纤维化和纤维化是慢性炎症反应的最终结果。肾脏炎症的特征是 巨噬细胞激活和促炎分子的产生。但是，分子机制 谷物巨噬细胞的激活尚不完全了解。因此，该提议的长期目标 是了解巨噬细胞激活的分子机制，以便有效的策略可以是 开发用于治疗CKD。 我们已经将PU.1确定为调节肾脏注射的关键因素 CKD的开发。具体而言，我们已经证明了PU.1是在实验中诱导的 CKD和使用CKD和PU.1的人类肾脏模型对于巨噬细胞激活和 CKD的炎症分子产生和发育。遗传缺失或药理学抑制 PU.1防止巨噬细胞的激活和体外巨噬细胞的炎症分子产生，并且 PU.1的药理抑制作用抑制巨噬细胞激活，炎症分子的产生和 阻塞性损伤的肾脏发育。此外，PU.1的促炎作用 似乎是由含有点头的受体家族pyrin结构域介导的3（nlrp3）炎症体 路径。在此应用中，我们建议检查和表征PU.1-NLRP3途径的作用 巨噬细胞激活和极化以及促炎和纤维化分子的产生，以进一步 了解感染和肾纤维化发育的分子机制。我们的中心 假设是PU.1促进了巨噬细胞中的NLRP3表达和炎症体激活 促炎和纤维化分子的表达以及肾纤维化的发育。为了检验这一假设， 我们将追求以下特定目标。具体目的1是确定pu.1在巨噬细胞中的作用 体外和体内激活和极化。特定目的2是剖析分子机制 PU.1促进巨噬细胞的激活和极化。特定目的3是探索的治疗潜力 选择性PU.1抑制剂用于治疗CKD。 我们计划利用分子，遗传和药物方法来检查PU.1-的作用 巨噬细胞激活，极化以及肾纤维化的发展中的NLRP3途径。结果 这些研究将为肾脏注射的分子机制提供新的见解，并可能领导 开发用于治疗CKD的新型治疗策略。