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

新型调节剂 CTHRC-1 控制血管纤维化和胶原蛋白沉积

• 批准号: 7959657
• 负责人: VOLKHARD LINDNER
• 金额: $ 18.8万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959657
• 关键词: Balloon Angioplasty; Biology; Blood Vessels; Centers of Research Excellence; Characteristics; Chronic; Collagen; Collagen Type I; Computer Retrieval of Information on Scientific Projects Database; Deposition; Extracellular Matrix; Fibroblasts; Fibrosis; Funding; Grant; Inflammation; Injury; Institution; Kidney; Lung; Medial; Myofibroblast; Proliferating; Proteins; Regulation; Research; Research Personnel; Resources; Role; Smooth Muscle; Smooth Muscle Myocytes; Source; Structure; Tissues; United States National Institutes of Health; Wound Healing; alpha Actin; base; body system; cell motility; injured; insight; novel; overexpression; response; response to injury; restenosis; triple helix

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，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）成分积累增加，对组织结构和功能产生不利影响。 这种反应涉及称为肌成纤维细胞的成纤维细胞的激活，其基于平滑肌α-肌动蛋白的特征表达。 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 ECM，包括 I 型和 III 型胶原蛋白以及其他 ECM 分子。 Lindner 博士的团队通过筛选气球损伤血管与正常血管中的差异表达序列，发现了一种新型分泌型 28 kDa 蛋白质，称为胶原蛋白三螺旋重复序列，其中含有 1 (Cthrc1)。 血管损伤后两周，Cthrc1 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。 血管平滑肌细胞中 Cthrc1 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发挥调节作用。 拟议的研究将为多个器官系统（最重要的是血管壁）纤维化反应的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。