Tenancin-C as a major component of the fibrogenic niche

Tenancin-C 作为纤维形成生态位的主要成分

基本信息

批准号：
10188508
负责人：
Roderick Jason Tan
金额：
$ 39.35万
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：
2003
资助国家：
美国
起止时间：
2003-05-01 至 2024-06-30
项目状态：
已结题

项目摘要

Summary/abstract Tubulointerstitial fibrosis, a common endpoint outcome of a wide range of chronic kidney diseases (CKD), typically initiates at certain focal sites, in which interstitial fibroblasts become activated, proliferate and produce a large amount of extracellular matrix. This competitive renewal application proposes to delineate the role of tenascin C (TNC), a matricellular protein, in orchestrating the formation of fibrogenic microenvironment in kidney fibrosis. Studies in previous project period of this application indicate that TNC is induced rapidly in the early stage of kidney injury and predominantly localizes at the foci rich in fibroblasts. TNC is able to promote renal interstitial fibroblast proliferation in vitro, ex vivo and in vivo. Intriguingly, TNC binds to, recruits and concentrates sonic hedgehog (Shh) and Wnt ligands from surrounding milieu. Based on these observations, the central hypothesis of this application is that TNC organizes a profibrotic microenvironment in which Shh and Wnts are enriched, thereby setting a unique stage facilitating fibroblast activation and proliferation, as well as aggravating tubular injury and inflammation. We will test this hypothesis in three specific aims. Aim 1 is to investigate the role of TNC in establishing fibrogenic microenvironment by recruiting, concentrating and presenting Wnt and Shh ligands. Aim 2 is to investigate the role of injured tubules and activated macrophages in building the fibrogenic niche, and to investigate the role of TNC-rich niche in aggravating tubular injury and inflammation. Aim 3 is to evaluate the therapeutic efficiency of disrupting TNC-enriched microenvironment for treatment of fibrotic CKD. These studies promise to offer novel insights into understanding the role of TNC in organizing a profibrotic microenvironment. The concept that the TNC-rich microenvironment, in which fibrotic factors are recruited and enriched, plays a critical role in renal fibrogenesis represents a new paradigm in our understanding of kidney fibrosis. Undoubtedly, the data generated from this application will have wide implications in comprehending the pathogenesis of tissue fibrosis in general and kidney fibrosis in particular, as well as in designing future therapeutic regimens for treatment.

摘要/摘要肾小管间质纤维化，多种慢性肾脏的常见终点结果疾病（CKD），通常在某些焦点部位开始，其中间质成纤维细胞成为激活，增殖并产生大量细胞外基质。这种竞争性更新申请提议描述替策素蛋白质tenascin C（TNC）的作用肾纤维化中纤维化微环境的形成。上一个项目期间的研究该应用表明，TNC在肾脏损伤的早期迅速诱导和主要位于富含成纤维细胞的焦点。 TNC能够促进肾脏间隙体外，体内和体内成纤维细胞增殖。有趣的是，TNC与新兵和来自周围环境的Sonic Hedgehog（SHH）和Wnt配体。基于这些观察结果，该应用的中心假设是TNC组织了纤维化 SHH和WNT丰富的微环境，从而树立了独特的舞台促进成纤维细胞激活和增殖，并加重管状损伤和炎。我们将以三个具体目标来检验这一假设。目标1是调查 TNC通过招募，集中和呈现Wnt以及 SHH配体。 AIM 2是研究受伤的小管和激活巨噬细胞在建筑物中的作用纤维化生态位，并研究富含TNC的小境在加剧管状损伤和炎。 AIM 3是评估破坏TNC富含的治疗效率微环境治疗纤维化CKD。这些研究承诺将提供新颖的见解了解TNC在组织纤维化微环境中的作用。这个概念富含TNC的微环境（其中募集和丰富纤维化因素）在肾纤维发生代表了我们对肾纤维化的理解。无疑，从本应用程序生成的数据将对理解组织纤维化的发病机理，尤其是肾脏纤维化，以及设计未来治疗治疗方案。