Inhibition of Aortic Elastolysis by Adenoviral Gene Transfer of the Tissue-Inhibitor of Matrixmetalloproteinase-1 in Fibrillin-1 Deficient Gene Targeted Mice

马凡氏综合征的血管成分以主动脉壁平滑肌细胞中基质金属蛋白酶（MMPs）活性异常升高为特征。这组酶引起主动脉介质的弹性分解，导致血管壁逐渐不稳定。因此，危及生命的主动脉瘤和主动脉夹层可能发生在马凡氏综合征患者的生命早期。纯合子fibrin -1缺陷基因靶向小鼠代表了马凡氏综合征公认的小动物模型。与马凡氏综合征患者相似，该模型表达主动脉壁平滑肌细胞中MMP活性增加，弹性纤维碎片的增加与年龄相关。利用该模型，该项目的目的是通过体外基因转移降低移植主动脉移植物的MMP活性，导致基质金属蛋白酶1 （TIMP-1）的组织抑制剂过表达。在将基因靶向供体动物移植到基因靶向受体动物的肾下主动脉后6周，将通过形态学、组织学和酶谱技术评估移植物是否可以减轻血管介质中的弹性溶解。这一概念的证明可能允许马凡氏综合征的血管成分的因果治疗选择的第一次。

The vascular component of the Marfan syndrome is characterized by an abnormal increase in activity of matrix-metalloproteinases (MMPs) in smooth muscle cells of the aortic wall. This group of enzymes causes elastolysis in the aortic media resulting in a progressive destabilization of the vessel wall. Therefore, life-threatening aortic aneurysms and aortic dissections may develop early in life of patients with Marfan syndrome. The homozygote Fibrillin-1 deficient gene targeted mouse represents an accepted small animal model for the Marfan syndrome. Similar to patients with Marfan syndrome, this model expresses an increased MMP activity in smooth muscle cells of the aortic wall with an age dependent increase in fragmentation of elastic fibers. Using this model, aim of the project is the reduction of MMP activity in transplanted aortic grafts by in vitro gene transfer resulting in overexpression of the tissue inhibitor of matrix-metalloproteinase 1 (TIMP-1). Up to six weeks after infrarenal aortic transplantation of gene targeted donor animals into gene targeted recipient animals, the grafts will be evaluated by morphometrical, histological, and zymographical techniques, whether the elastolysis in the vessel¿s media can be attenuated. Proof of this concept may allow a causal treatment option of the vascular component of the Marfan syndrome for the first time.