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Regulation of tubulointerstitial crosstalk by microRNAs in renal fibrosis

肾纤维化中 microRNA 对肾小管间质串扰的调节

基本信息

批准号：
10749334
负责人：
JACQUELINE HO
金额：
$ 31.62万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10749334
关键词：
Adult Aging Cells Chronic Kidney Failure Collagen Data Diabetes Mellitus Disease Effectiveness Etiology Extracellular Matrix Proteins Family Fibrosis Genes Hypertension In Vitro Individual Infusion procedures Injury to Kidney Intervention Kidney Kidney Diseases Kidney Failure Kidney Transplantation Laboratories Mediating Messenger RNA MicroRNAs Modeling Molecular Mus Nephrons Obesity Output Pathologic Pathway interactions Persons Polycystic Kidney Diseases Population Predisposition Prevalence Process Profibrotic signal Regulation Renal dialysis Role Signal Pathway Testing Tubular formation United States Ureteral obstruction Work autosome gain of function inducible gene expression innovation kidney fibrosis member mouse model nephron progenitor new therapeutic target novel therapeutic intervention overexpression pleiotropism pre-clinical renal epithelium repaired response response to injury

项目摘要

(PLEASE KEEP IN WORD, DO NOT PDF) An estimated 37 million people (15% of the population) in the United States have chronic kidney disease. There are currently no specific interventions to decrease the progression of chronic kidney disease, which ultimately leads to renal failure necessitating kidney transplant or dialysis. Regardless of underlying etiology, advancing CKD ultimately results in irreversible nephron loss and renal fibrosis. Fibrosis is part of the normal repair process triggered in response to injury, and dysregulation of this process results in the pathological accumulation of extracellular matrix proteins, primarily collagens. Current therapies have limited effectiveness and at most delay the progression of chronic kidney disease. Understanding the molecular mechanisms that drive the early accumulation of ECM proteins in renal fibrosis will inform novel therapeutic approaches to CKD. Our laboratory was the first to demonstrate that conditional loss of the miR-17~92 cluster (comprised of miR-17, miR-18, miR-19a, miR-19b, miR-20a and miR-92a) in nephron progenitors and their derivatives results in renal hypodysplasia and chronic kidney disease in mice. We now have preliminary data that inducible loss of miR-17~92 in adult renal epithelia results in increased susceptibility to renal fibrosis, and conversely that inducible gain of miR-17~92 in adult renal epithelia is protective against renal fibrosis. Our central hypothesis is that miR-17~92 in renal epithelia functions to limit renal fibrosis. To test this hypothesis, we propose to determine whether the miR-17~92 cluster is sufficient to protect against renal fibrosis in mice.

（请保持文字，不要PDF）据估计，美国有3700万人（占人口的15%）患有慢性肾病。目前没有具体的干预措施来减少慢性肾脏疾病的进展，慢性肾脏疾病最终导致肾衰竭，需要肾移植或透析。无论潜在病因如何，进展的CKD最终导致不可逆的肾单位丢失和肾纤维化。纤维化是响应于损伤而触发的正常修复过程的一部分，并且该过程的失调导致细胞外基质蛋白（主要是胶原蛋白）的病理性积累。目前的治疗方法效果有限，最多延缓慢性肾脏疾病的进展。了解驱动肾纤维化中ECM蛋白早期积累的分子机制将为CKD的新治疗方法提供信息。我们的实验室首次证明了在小鼠肾单位祖细胞及其衍生物中miR-17~92簇（包括miR-17、miR-18、miR-19 a、miR-19 b、miR-20 a和miR-92 a）的条件性缺失导致肾发育不良和慢性肾脏疾病。我们现在有初步的数据表明，成人肾上皮中miR-17~92的可诱导缺失导致肾纤维化的易感性增加，相反，成人肾上皮中miR-17~92的可诱导获得对肾纤维化具有保护作用。我们的中心假设是肾上皮中的miR-17~92具有限制肾纤维化的功能。为了验证这一假设，我们建议确定miR-17~92簇是否足以保护小鼠免受肾纤维化。