REGULATION OF HEPATIC FIBROGENEISS BY TANGO1

TANGO1 对肝纤维形成的调节

基本信息

批准号：
10319558
负责人：
Jessica L Maiers
金额：
$ 16.22万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-05 至 2022-12-31
项目状态：
已结题

项目摘要

Abstract Liver cirrhosis is the leading cause of end-stage liver disease. A hallmark of cirrhosis is fibrogenesis: secretion and deposition of excess extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs). Prominent among secreted ECM proteins is collagen I. Although the role of collagen I deposition in cirrhosis is well known, therapies aimed at disrupting fibrogenesis are lacking. This is due in part to our poor understanding of procollagen I trafficking through the secretory pathway. Fibrogenic signals such as TGFβ drive expression of the collagen I precursor procollagen I, which is subsequently cotranslationed into the endoplasmic reticulum (ER). Procollagen I fibrils oligomerize within the ER, forming a complex too large (~300nm) to package into canonical ER export vesicles (60-90nm). Thus, additional, unknown cellular machinery is necessary for procollagen I trafficking. If this machinery is disrupted, procollagen fibrils would be retained in the ER and lead to ER stress, activation of the unfolded protein response (UPR), and possibly apoptosis. Recent elegant studies performed in non-liver cells suggested that TANGO1 is critical for the transport of procollagens. Whether TANGO1 facilitates ER export and secretion of collagen I from HSCs, a critical step in fibrogenesis, is unknown. We hypothesize that TANGO1 drives procollagen I export from the ER, requires UPR signaling to mediate this effect, and together TANGO1 and the UPR are critical for fibrogenesis in vivo. This hypothesis is based on preliminary data showing (a) TANGO1 knockdown disrupts procollagen I ER export, leading to UPR signaling and HSC apoptosis, (b) TANGO1 expression is mediated, at least in part, by the UPR-activated transcription factor XBP1, and (c) TANGO1+/- mice are protected from cirrhosis development. The novelty and relevance of studying the role of TANGO1 in procollagen I trafficking and its regulation are two-fold: 1) we can identify new targets to disrupt collagen I secretion in fibrogenesis, and 2) failure to resolve ER stress driven by procollagen I retention may lead to HSC apoptosis. The latter mechanism is favorable for fibrosis resolution. Our long-term goal is to elucidate mechanisms of procollagen I trafficking within HSCs and identify novel therapeutic targets to treat liver cirrhosis. The research proposed here will utilize rigorous in vitro and in vivo approaches to unveil the mechanisms of TANGO1-mediated procollagen I trafficking in HSCs, the regulatory relationship between TANGO1 and the UPR during HSC activation, and finally the role of TANGO1 and the UPR in fibrogenesis and fibrosis regression.

抽象的肝硬化是终末期肝病的主要原因。肝硬化的标志是纤维发生：分泌以及肝星状细胞（HSC）对过多的细胞外基质（ECM）蛋白的沉积。著名的在分泌的ECM蛋白中，有胶原蛋白I。尽管胶原蛋白I沉积在肝硬化中的作用很好已知的旨在破坏纤维化的疗法缺乏。这部分是由于我们对 Procollagen i在秘密途径中贩运。纤维化信号，例如TGFβ驱动器表达胶原蛋白的前体procolagen I，随后将其共转染成内质网（ER）。 procollagen i纤维在急诊室内寡聚，形成一个太大的复合物（〜300nm），无法包装到规范ER出口蔬菜（60-90Nm）。这是另外未知的蜂窝机械 Procollagen I贩运。如果这种机械被破坏，则将procollagen纤维保留在急诊室中并铅为了急诊应力，可以激活展开的蛋白质反应（UPR），并可能激活poptosis。最近的优雅在非肝细胞中进行的研究表明，Tango1对于探针的运输至关重要。 Tango1是否促进了HSC的ER出口和胶原I的分泌，这是纤维化的关键步骤未知。我们假设Tango1驱动procollagen i从急诊室导出，需要UPR 信号传导介导这种效果，并且Tango1和UPR在一起对于体内纤维发生至关重要。该假设基于显示（a）Tango1敲低的初步数据破坏了Procollagen i er 导出，导致UPR信号传导和HSC凋亡，（b）Tango1表达至少部分地介导 UPR激活的转录因子XBP1和（C）Tango1 +/-小鼠免受肝硬化的保护发展。研究Tango1在Procollagen I贩运及其的作用的新颖性和相关性调节是两个方面：1）我们可以确定破坏纤维化中胶原蛋白I的新靶标，而2）未能解决由Procollagen I保留驱动的ER应力可能导致HSC凋亡。后一种机制有利于纤维化分辨率。我们的长期目标是阐明Procolagen I贩运的机制在HSC中，并确定新的治疗靶标以治疗肝硬化。这里提出的研究将利用严格的体外和体内方法来揭示Tango1介导的Procollagen I的机制贩运HSC，HSC激活期间Tango1与UPR之间的调节关系以及最后，Tango1和UPR在纤维发生和纤维化回归中的作用。