Understanding Myofibroblast Progenitor Fate and Function in Renal Fibrosis

了解肾纤维化中肌成纤维细胞祖细胞的命运和功能

• 批准号: 9302747
• 负责人: BENJAMIN D. HUMPHREYS
• 金额: $ 34.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302747
• 关键词: Ablation; Activities of Daily Living; Adult; Aging; Agreement; Alpha Cell; Biological Assay; Blood Vessels; Blood capillaries; Bone Marrow; Caliber; Cell Separation; Cell Transplantation; Cell physiology; Cell surface; Cells; Cellular biology; Chronic Disease; Chronic Kidney Failure; Cicatrix; Clinic; Coculture Techniques; Colony-forming units; Consensus; Data; Disease model; ENG gene; Endothelial Cells; Epithelial Cells; Erinaceidae; Evaluation; Fibroblasts; Fibrosis; Future; Genetic; Health; Histologic; Human; In Vitro; Injury; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Measures; Medical; Mesenchymal; Mesenchymal Stem Cells; Modeling; Morphology; Mus; Muscle Cells; Myofibroblast; Nephrectomy; Organ; PECAM1 gene; PTPRC gene; Parabiosis; Pathway interactions; Patients; Pericytes; Pharmaceutical Preparations; Physiologic pulse; Play; Population; Proliferating; Property; Renal function; Role; Science; Series; Solid; Stem cells; Stromal Cells; Subcutaneous Tissue; Surface; Testing; Therapeutic; Transforming Growth Factors; Translating; Transplantation; Tube; United States; Ureteral obstruction; Vascular Smooth Muscle; angiogenesis; base; capillary; cell type; design; effective therapy; experimental study; fibrogenesis; functional decline; genetic approach; improved; in vivo; interstitial; kidney cell; kidney vascular structure; matrigel; nephrogenesis; novel; novel therapeutics; progenitor; public health relevance; self-renewal; smoothened signaling pathway; targeted treatment; therapeutic target; tool; transcription factor

 DESCRIPTION (provided by applicant): Kidney fibrosis is a critical health problem in the United States because it represents the final common pathway of all chronic kidney diseases yet there is no approved drug to treat it. There is general agreement that myofibroblasts are the cell type responsible for scar formation in fibrotic kidney disease but little consensus about where these cells come from, which is a critical knowledge gap that needs to be brifged in order to discover new therapies to treat chronic kidney disease. We have discovered a new subpopulation of stromal cells, unappreciated in kidney science to date, that represents the major myofibroblast precursor population. These cells expand in fibrosis according to our genetic fate mapping experiments, and ablating these cells ameliorates fibrosis - proving their functional importance. In this proposal we aim to understand the role of these cells in health and chronic disease, to determine whether their ablation improves renal functional parameters in chronic kidney disease models, and to understand their functional capacities. We will use state of the art genetic approaches in vivo and complementary cell isolation, transplantation and in vitro studies to assess their properties ex vivo. Together, the proposed experiments represent a rigorous evaluation of our hypothesis that these cells play a critical role in kidney fibrogenesis and should be targeted therapeutically to halt chronic kidney disease.

 描述（申请人提供）：肾纤维化是美国一个严重的健康问题，因为它代表了所有慢性肾脏疾病的最终共同途径，但目前还没有批准的药物来治疗它。人们普遍认为，肌成纤维细胞是负责纤维化肾脏疾病中瘢痕形成的细胞类型，但对这些细胞的来源几乎没有共识，这是一个关键的知识缺口，需要填补，以发现治疗慢性肾脏疾病的新疗法。我们发现了一种新的基质细胞亚群，迄今为止在肾脏科学中尚未得到重视，它代表了主要的肌成纤维细胞前体细胞群。根据我们的遗传命运作图实验，这些细胞在纤维化中扩增，并且消融这些细胞改善纤维化-证明它们的功能重要性。在这项提案中，我们的目标是了解这些细胞在健康和慢性疾病中的作用，以确定它们的消融是否改善慢性肾脏疾病模型中的肾功能参数，并了解它们的功能能力。我们将使用最先进的体内遗传方法和互补细胞分离、移植和体外研究来评估其体外特性。总之，拟议的实验代表了对我们假设的严格评估，即这些细胞在肾纤维化中起着关键作用，应该在治疗上有针对性地阻止慢性肾脏疾病。