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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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)成分积累增加，从而对组织结构和功能产生不利影响。这种反应涉及到成纤维细胞的激活，这种细胞被称为肌成纤维细胞，基于其特有的平滑肌α-肌动蛋白表达。作为伤口愈合反应的一部分，这些肌成纤维细胞增殖、迁移并产生丰富的细胞外基质，包括I型和III型胶原以及其他细胞外基质分子。林德纳博士的团队已经在球囊损伤血管和正常血管的差异表达序列筛选中发现了一种新的分泌型28 kDa蛋白质，称为胶原三螺旋重复序列，其中包含1(Ctrc1)。Ctrc1在血管损伤后2周在中膜平滑肌细胞和外膜成纤维细胞中高表达，在损伤后4周表达下降。Ctrc1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，Ctrc1可能在损伤和慢性炎症的纤维化反应中发挥调节作用。拟议的研究将为调节几个器官系统的纤维化反应提供重要的新见解，最重要的是血管壁。这些研究具有抗纤维化策略的翻译潜力。

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's group 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. Overexpression 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 antifibrotic strategies.