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.

项目总结 慢性肾脏疾病(CKD)是一个公共卫生问题，困扰着3700多万美国人。 目前对这种进行性疾病的治疗选择有限；因此，新的治疗策略 都是迫切需要的。慢性肾脏病的共同特征是肾脏炎症和纤维化。炎症通常会引发 纤维化，而纤维化是慢性炎症反应的最终结果。肾炎的特征是 巨噬细胞的激活和促炎分子的产生。然而，分子机制 巨噬细胞的潜在激活机制尚不完全清楚。因此，这项提议的长期目标是 是为了了解巨噬细胞激活的分子机制，以便有效的策略 专为治疗慢性肾脏病而开发。 我们已经确定PU1是调节肾脏炎症的一个关键因素。 CKD的发展。具体地说，我们已经证明了PU1是在实验性的肾脏中诱导的。 CKD模型及人肾内CKD和PU1对巨噬细胞活化的影响 炎性分子的产生与CKD的发生发展。基因缺失或药物抑制 PU1在体外可抑制巨噬细胞活化和炎症分子的产生 PU1的药理抑制抑制巨噬细胞激活、炎性分子产生和 梗阻性损伤时肾脏纤维化的发展。此外，PU1的促炎作用 似乎是由NLRP3炎症体介导的NOD样受体家族 路径。在这个应用中，我们建议检查和表征PU.1-NLRP3通路在 巨噬细胞的激活和极化以及促炎和促纤维化分子的产生 了解肾纤维化炎症和发展的分子机制。我们的中央 假设PU.1促进巨噬细胞NLRP3表达和炎性小体激活，从而导致 促炎症和促纤维化分子的表达与肾纤维化的发展。为了检验这一假设， 我们将追求以下具体目标。具体目的1是确定PU1在巨噬细胞中的作用 体外和体内的激活和极化。具体目标2是剖析分子机制，通过 PU1促进巨噬细胞活化和极化。具体目标3是探索药物的治疗潜力。 一种治疗慢性肾脏病的选择性PU1抑制剂。 我们计划利用分子、遗传学和药理学方法来研究PU1- NLRP3通路在巨噬细胞活化、极化及肾纤维化发生发展中的作用。结果来自 这些研究将为肾脏炎症的分子机制提供新的见解，并可能导致 开发治疗慢性肾脏病的新的治疗策略。