CONTROL OF VASCULAR FIBROSIS AND COLLAGEN DEPOSITION BY NOVEL REGULATOR, CRHRC-1

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。对损伤的反应，无论是球囊血管成形术后的再狭窄，还是慢性炎症引起的肺或肾纤维化，都会导致细胞外基质（ECM）成分的积累增加，对组织结构和功能产生有害影响。基于平滑肌α -肌动蛋白的特征性表达，这种反应涉及到被称为肌成纤维细胞的成纤维细胞的激活。作为伤口愈合反应的一部分，这些肌成纤维细胞增殖、迁移并产生大量的ECM，包括I型和III型胶原，以及其他ECM分子。Lindner博士在球囊损伤与正常血管的差异表达序列筛选中发现了一种新的分泌28 kDa的蛋白，称为胶原三螺旋重复含有1 （Cthrc1）。Cthrc1在血管损伤后2周在内侧平滑肌细胞和外膜成纤维细胞中高表达，但在损伤后4周表达下降。Cthrc1在血管平滑肌细胞中的过度表达导致细胞迁移减少和胶原基质沉积减少。这些令人兴奋的结果表明，Cthrc1可能在损伤和慢性炎症的纤维化反应中具有调节作用。拟议的研究将为几个器官系统（最重要的是血管壁）的纤维化反应调节提供重要的新见解。这些研究具有抗纤维化策略的转化潜力

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The response to injury, whether it is restenosis after balloon angioplasty, or pulmonary or renal fibrosis due to chronic inflammation, results in increased accumulation of extracellular matrix (ECM) components with detrimental effects on tissue structure and function. This response involves the activation of fibroblasts termed myofibroblasts based on their characteristic expression of smooth muscle alpha-actin. As part of this wound healing response, these myofibroblasts proliferate, migrate, and produce abundant ECM including collagen type I and type III, as well as other ECM molecules. Dr. Lindner has identified a novel secreted 28 kDa protein called Collagen triple helix repeat containing 1 (Cthrc1) in a screen of differentially expressed sequences in balloon-injured versus normal vessels. Cthrc1 is highly expressed in medial smooth muscle cells and adventitial fibroblasts two weeks after vascular injury but expression declines by 4 weeks post-injury. Over-expression of Cthrc1 in vascular smooth muscle cells results in decreased cell migration and reduced collagen matrix deposition. These exciting results suggest that Cthrc1 may have a regulatory role in the fibrotic response to injury and perhaps chronic inflammation. The proposed studies will provide significant new insights into the regulation of the fibrotic response in several organ systems, most importantly the vessel wall. These studies have translational potential for anti-fibrotic strateg