CRGF: Intracellular Mediator During Arterial Remodeling

2002年，动脉闭塞占美国死亡人数的30%，花费2000亿美元。主要治疗方法 这种疾病，血管成形术，只用于晚期病例，失败率为30- 50%。最近的研究 已经表明，这种失败是由于重塑，这一过程涉及动脉壁的所有层， 几何和细胞水平。其复杂性意味着血管壁各层之间的协调 和细胞类型。这种沟通的确切机制基本上是未探索的。申请人 试图检验转化生长因子-β（TGF-β）作用于平滑肌细胞的假设 通过SmadS（一种细胞内蛋白）分泌结缔组织生长因子 （CTGF），其然后诱导外膜层的成纤维细胞的变化。SmadS-过表达光滑 将肌细胞用TGF-β刺激;将成纤维细胞暴露于条件培养基， 没有特异性CTGF抑制剂，然后评估重塑的典型变化。成纤维 然后用纯CTGF刺激以进行比较。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对重塑的影响。

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-overexpressingsmooth 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.