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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.

总结/摘要肾小管间质纤维化，一种广泛的慢性肾脏疾病的常见终点结局慢性肾脏病（CKD）通常在某些病灶部位起始，其中间质成纤维细胞变成活化、增殖并产生大量的细胞外基质。这次竞争性的续约一项应用提出描绘腱生蛋白C（TNC），一种基质细胞蛋白，在协调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在肾损伤的早期阶段被快速诱导，主要定位于富含成纤维细胞的病灶。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，跨国公司与浓缩来自周围环境的音刺猬（Shh）和Wnt配体。基于这些根据观察，本申请的中心假设是TNC组织了一个促纤维化的微环境，其中Shh和Wnts丰富，从而设置一个独特的阶段促进成纤维细胞活化和增殖，以及加重肾小管损伤，炎症我们将在三个具体目标中检验这一假设。目的1是研究 TNC通过募集、浓缩和提呈Wnt及嘘配体。目的二是探讨损伤的肾小管和活化的巨噬细胞在肾小管上皮细胞构建中的作用纤维化的小生境，并探讨富含TNC的小生境在加重肾小管损伤和炎症目的3：评价干扰富含TNC的用于治疗纤维化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。一概念富含TNC的微环境，其中纤维化因子被招募和富集，在纤维化中起着关键作用。肾纤维化代表了我们对肾纤维化理解的新范例。毫无疑问，从这个应用程序产生的数据将有广泛的影响，在理解组织纤维化的发病机制，特别是肾纤维化，以及在设计未来的治疗方案。