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是多种慢性肾脏病的常见终点结果疾病（CKD），通常始于某些病灶部位，其中间质成纤维细胞变成活化、增殖并产生大量细胞外基质。此次竞争性更新该申请旨在描述肌腱蛋白 C (TNC)（一种基质细胞蛋白）在协调中的作用肾纤维化中纤维化微环境的形成。之前项目期间的研究该应用表明，TNC 在肾损伤早期迅速诱导，并且主要位于富含成纤维细胞的病灶处。 TNC能够促进肾间质体外、离体和体内成纤维细胞增殖。有趣的是，TNC 绑定、招募和浓缩周围环境中的 sonic humighog (Shh) 和 Wnt 配体。基于这些观察，本申请的中心假设是 TNC 组织促纤维化 Shh 和 Wnts 丰富的微环境，从而创造了一个独特的阶段促进成纤维细胞活化和增殖，并加重肾小管损伤和炎。我们将在三个具体目标上检验这一假设。目标 1 是研究 TNC 通过招募、浓缩和呈递 Wnt 和 Wnt 来建立纤维形成微环境嘘配体。目标 2 是研究受损的肾小管和活化的巨噬细胞在构建纤维化生态位，并研究富含 TNC 的生态位在加重肾小管损伤和炎。目标 3 是评估破坏富含 TNC 的治疗效果治疗纤维化 CKD 的微环境。这些研究有望提供新的见解了解 TNC 在组织促纤维化微环境中的作用。这个概念是富含 TNC 的微环境在其中招募和富集纤维化因子，在肾纤维化代表了我们理解肾纤维化的新范例。无疑，从该应用程序生成的数据将对理解一般组织纤维化和特别是肾脏纤维化的发病机制，以及设计未来的治疗方案。