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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：肾脏纤维化是美国的一个严重健康问题，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可以治疗它。人们普遍认为肌成纤维细胞是这种细胞类型。导致纤维化肾病疤痕形成的因素，但对于这些细胞的来源却鲜有共识，这是一个关键的知识差距，为了发现治疗慢性肾病的新疗法，我们发现了一个新的亚群。迄今为止，在肾脏科学中尚未得到重视的基质细胞代表了主要的肌成纤维细胞前体群体，根据我们的基因命运图谱实验，这些细胞会在纤维化过程中扩张，而消除这些细胞可以改善纤维化，从而证明它们的功能重要性。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补充。细胞分离、移植和体外研究来评估它们的离体特性，所提出的实验代表了对我们假设的严格评估，即这些细胞在肾脏纤维形成中发挥着关键作用，并且应该以治疗为目标来阻止慢性肾脏疾病。