Tenancin-C as a major component of the fibrogenic niche

摘要/摘要 肾小管间质纤维化：多种慢性肾脏疾病的共同终点结局 疾病(CKD)，通常起始于某些病灶部位，其中间质成纤维细胞成为 激活、增殖并产生大量的细胞外基质。这是一次竞争性更新 应用程序建议描绘TnC(TNC)，一种基质细胞蛋白，在协调 肾纤维化中致纤维化微环境的形成。在以前的项目期进行的研究 提示TNC在肾损伤的早期即可迅速诱导，并可在肾损伤早期迅速发生。 主要定位于富含成纤维细胞的病灶。TNC能促进肾间质 成纤维细胞在体外、体外和体内的增殖。耐人寻味的是，TNC绑定、招募和 从周围环境中浓缩Sonic Hedgehog(Shh)和Wnt配体。基于这些 观察到，这一应用的中心假设是TNC组织了一种促纤维化 Shh和WNTs丰富的微环境，从而建立了一个独特的舞台 促进成纤维细胞的活化和增殖，以及加重肾小管损伤和 发炎。我们将在三个具体目标上检验这一假设。目标1是调查 TNC通过招募、集中和呈现WNT和WNT来建立纤维化微环境 嘘·莱茨。目的2是研究损伤的小管和激活的巨噬细胞在建筑中的作用。 并探讨富含TNC的生态位在加重肾小管损伤和肾小管损伤中的作用。 发炎。目的3是评价干扰富含TNC的治疗效果。 治疗纤维性CKD的微环境。这些研究有望对以下问题提供新的见解 了解TNC在组织促纤维化微环境中的作用。这个概念就是 在富含TNC的微环境中，纤维化因子被招募和丰富，在 肾纤维化是我们理解肾纤维化的一个新范式。毫无疑问， 此应用程序生成的数据将对理解 一般组织纤维化的发病机制，特别是肾脏纤维化的发病机制，以及设计 未来的治疗方案。

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.