Renal myofibroblast: Origin, Activation and Fate

肾肌成纤维细胞：起源、激活和命运

• 批准号: 8117201
• 负责人: YOUHUA LIU
• 金额: $ 31.3万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117201
• 关键词: Abbreviations; Address; Adult; Alteplase; Animals; Binding; Cell Line; Cell membrane; Cells; Chronic; Chronic Kidney Failure; Data; Deterioration; Differentiation Inhibitor; Disease; Effector Cell; End stage renal failure; Epithelial; Epithelial Cells; Epithelium; Experimental Animal Model; Extracellular Domain; Extracellular Matrix; Fibroblasts; Fibrosis; Genetic Transcription; Glycogen Synthase Kinases; Goals; Growth; Health; Human; In Vitro; Inflammation; Injury; Integrins; Kidney; Kidney Diseases; LDL-Receptor Related Protein 1; Lesion; Lipoprotein Receptor; Low Density Lipoprotein Receptor; MAP Kinase Gene; MAPK14 gene; Mediating; Mediator of activation protein; Mesenchymal; Mitogen-Activated Protein Kinases; Molecular; Myofibroblast; NF-kappa B; Nuclear; Outcome; Pathogenesis; Patients; Plasminogen Activator; Play; Population; Process; Production; Proteins; RANTES; Rattus; Regulation; Renal function; Resolution; Role; Signal Pathway; Signal Transduction; Smooth Muscle Actin Staining Method; Source; Streptozocin; T-Lymphocyte; Testing; Transforming Growth Factors; Tubular formation; Tyrosine Phosphorylation; Ureteral obstruction; base; cytokine; design; epithelial to mesenchymal transition; fibrogenesis; helix-loop-helix protein differentiation inhibitor; in vivo; inhibitor/antagonist; insight; integrin-linked kinase; interstitial; receptor; treatment strategy

DESCRIPTION (provided by applicant): Tubulointerstitial fibrosis, a common endpoint outcome of a wide range of chronic kidney diseases (CKD) that progress to end-stage renal failure, is preceded by activation of the a-smooth muscle actin- positive myofibroblasts, the principal effector cells that are responsible for the over-production of extracellular matrix components. This resubmission of a competitive renewal application is a continuation of our long-term efforts to elucidate the origins, activation process and fate of renal myofibroblasts in renal fibrogenesis. Studies in previous project period of this application suggest that myofibroblasts may originate from two major sources: from interstitial fibroblasts via a phenotypic activation and from tubular epithelial cells via epithelial-mesenchymal transition (EMT). In this renewal application, we propose to investigate the molecular mechanism and signal pathways leading to EMT and fibroblast activation. The central hypotheses to be tested are that: 1) transcriptional inhibitors Id1 and Id3 promote tubular epithelial to mesenchymal transition (EMT), via inducing tubular epithelial dedifferentiation and via potentiating renal inflammation; 2) tPA acts as a profibrotic cytokine that promotes the survival and proliferation of interstitial fibroblasts and their myofibroblastic activation. These hypotheses will be addressed by three specific aims at the whole animal, cellular and molecular levels, respectively. Aim 1 is designed to investigate the regulation and function of transcriptional inhibitor Id proteins in mediating tubular EMT and renal inflammation. Aim 2 is to investigate the role of tPA in interstitial myofibroblast activation and to dissect the signaling pathway leading to its action. Aim 3 is to investigate the role of tPA in fibroblast and myofibroblast survival and proliferation. These studies will provide fundamental and important insights into understanding the activation mechanisms of myofibroblasts from both tubular epithelial cells and interstitial fibroblasts. Resolution of these fundamental issues will not only provide mechanistic insights into the pathogenesis of chronic renal fibrosis, but also offers unique opportunities for designing rational strategies for the treatment of this devastating disease. PUBLIC HEALTH RELEVANCE It is estimated that up to 11% of the US adult population has some degree of chronic kidney disease (CKD), and delaying the progression of CKD is still unsolved problem. The studies proposed in this application promises to provide important insights into understanding the origins, activation and fate of renal matrix-producing myofibroblasts in the pathogenesis of CKD. Resolution of these fundamental issues may offer unique opportunities for designing rational strategies for the treatment of human CKD.

描述(由申请人提供)：肾小管间质纤维化是一系列慢性肾脏疾病(CKD)进展为终末期肾功能衰竭的共同终点结局，在此之前，α-平滑肌肌动蛋白阳性的肌纤维母细胞被激活，这是导致细胞外基质成分过度产生的主要效应细胞。这次竞争性续展申请的重新提交是我们长期努力的继续，目的是阐明肾脏成纤维细胞在肾脏纤维化中的起源、激活过程和命运。前期研究表明，肌成纤维细胞可能有两个主要来源：通过表型活化的间质成纤维细胞和通过上皮-间充质转化(EMT)的肾小管上皮细胞。在这一新的应用中，我们建议研究导致EMT和成纤维细胞激活的分子机制和信号通路。需要检验的中心假设是：1)转录抑制物ID1和ID3通过诱导肾小管上皮细胞去分化和增强肾脏炎症，促进肾小管上皮细胞向间充质转化(EMT)；2)tPA作为促纤维化细胞因子，促进间质成纤维细胞的存活和增殖及其肌成纤维细胞的激活。这些假说将通过分别在整个动物、细胞和分子水平上的三个具体目标来解决。目的1研究转录抑制因子ID蛋白在肾小管上皮细胞转化和肾组织炎症中的调节和作用。目的2研究组织型纤溶酶原激活剂(TPA)在间质肌成纤维细胞激活中的作用，并剖析其作用的信号通路。目的3研究组织型纤溶酶原激活剂(TPA)在成纤维细胞和肌成纤维细胞存活和增殖中的作用。这些研究将为理解肾小管上皮细胞和间质成纤维细胞的肌成纤维细胞的激活机制提供基础和重要的见解。这些基本问题的解决不仅将为慢性肾纤维化的发病机制提供机械性的见解，也将为设计合理的治疗这一毁灭性疾病的策略提供独特的机会。公共卫生相关性据估计，高达11%的美国成年人口患有不同程度的慢性肾脏疾病(CKD)，延缓CKD的进展仍然是一个悬而未决的问题。本申请中提出的研究有望为理解CKD发病机制中产生肾脏基质的肌成纤维细胞的起源、激活和命运提供重要的见解。这些根本问题的解决可能为设计合理的治疗人类慢性肾脏病的策略提供独特的机会。