CRGF: Intracellular Mediator During Arterial Remodeling

描述（由申请人提供）：2002年，动脉闭塞占美国死亡人数的30%，成本为2000亿美元。该疾病的主要治疗方法是血管成形术，仅用于晚期病例，失败率为30-50%。最近的研究表明，这种失败是由于重塑，这是一个涉及动脉壁所有层的几何和细胞水平的过程。它的复杂性意味着血管壁层和它们的细胞类型之间的协调。这种交流的确切机制基本上是未知的。申请人寻求验证以下假设：转化生长因子- β (TGF-b)通过细胞内蛋白SmadS作用于内层平滑肌细胞，分泌结缔组织生长因子（CTGF），然后诱导外皮层成纤维细胞的变化。TGF-b刺激过表达smads的平滑肌细胞；将成纤维细胞暴露在有或没有特定CTGF抑制剂的条件培养基中，然后评估典型的重塑变化。然后用纯CTGF刺激成纤维细胞进行比较。我们将研究动物血管成形术模型中CTGF的产生，以及smadS过表达和外源性CTGF对血管重塑的影响。

DESCRIPTION (provided by applicant): In 2002, arterial occlusion accounted for 30% of U.S. deaths and $200 billion in cost. The major therapy for the disease, angioplasty, is used only in advanced cases and has a failure rate of 30-50%. Recent research has shown that this failure is due to remodeling, a process involving all layers of the arterial wall at the geometric and the cellular level. Its complexity implies a coordination among the layers of the vessel wall and their cell types. The precise mechanism of this communication is essentially unexplored. The applicant seeks to test the hypothesis that transforming growth factor-beta (TGF-b) acts on the smooth muscle cells of the medial layer through SmadS, an intracellular protein, to secrete connective tissue growth factor (CTGF), that then induces changes in the fibroblasts of the adventitial layer. SmadS-overexpressing smooth muscle cells will be stimulated with TGF-b; fibroblasts will be exposed to the conditioned media with or without a specific CTGF inhibitor, and will then be assessed for changes typical of remodeling. Fibroblasts will then be stimulated with pure CTGF for comparison. CTGF production in an animal angioplasty model, and the affect of smadS overexpression and exogenous CTGF on remodeling, will be examined.