Extracellular Mechanisms For Thoracic Aortic Aneurysms

描述（由申请人提供）： 主动脉瘤疾病是美国常见的死亡原因。胸主动脉瘤（TAA）患者尤其具有挑战性，因为手术修复的复杂性和术后发病率高。主动脉瘤代表一种血管重塑过程，其特征在于至少部分由细胞外基质（ECM）降解引起的主动脉中层损失。本项目的总体目标是确定TAA进展的细胞外机制。基质金属蛋白酶（MMP）降解健康和疾病中的ECM。MMPs及其组织抑制剂（TIMPs）由许多细胞类型产生，包括在主动脉中发现的那些。过去的临床研究表明，在切除的主动脉瘤中MMPs和TIMPs之间存在失衡。该项目的中心假设是MMP/TIMP化学计量的改变是TAA进展的早期事件; MMP/TIMP化学计量的靶向调节将直接改变TAA进展; TAA进展的基本细胞机制是成纤维细胞MMP/TIMP表达的区域改变。利用本实验室开发的TAA小鼠模型，该项目将实现以下目标：（1）建立TAA进展与局部MMP/TIMP水平的时空关系;（2）通过靶向MMP-9基因缺失来改变TAA的自然史（MMP功能丧失）或TIMP- 1基因缺失（MMP功能增益）;（3）确定MMP-9基因诱导是TAA进展中的早期事件，并且负责异常MMP/TIMP表达的基本细胞类型是成纤维细胞。该项目的结果将建立对胸动脉瘤形成和进展的机制见解，并为患有这种毁灭性疾病的患者的治疗调节的合理设计提供基础。

DESCRIPTION (provided by applicant): Aneurysmal disease of the aorta is a common cause of death in the United States. Thoracic aortic aneurysm (TAA) patients are particularly challenging because of the complexity of surgical repair and high incidence of postoperative morbidity. Aortic aneurysms represent a vascular remodeling process characterized by loss of the aortic medial layer caused, at least in part, by degradation of the extracellular matrix (ECM). The overall goal of this project is to define the extracellular mechanisms contributing to the progression of TAA. The matrix metalloproteinases (MMPs) degrade the ECM both in health and disease. MMPs and their tissue inhibitors (TIMPs) are produced by many cell types including those found in the aorta. Past clinical studies have suggested an imbalance occurs between MMPs and TIMPs in resected aortic aneurysms. The central hypotheses of this project are that alterations in MMP/TIMP stoichiometry is an early event in TAA progression; that targeted modulation of MMP/TIMP stoichiometry will directly modify TAA progression; and that a fundamental cellular mechanism for TAA progression is regional alterations in fibroblast MMP/TIMP expression. Using a murine model of TAA developed in this laboratory, this project will accomplish the following aims: (1) Establish the temporal-spatial relationship of TAA progression to local MMP/TIMP levels; (2) Modify the natural history of TAA through targeted MMP-9 gene deletion (MMP loss of function) or TIMP- 1 gene deletion (MMP gain of function); (3) Establish that MMP-9 gene induction is an early event in TAA progression and that a fundamental cell type responsible for abnormal MMP/TIMP expression is the fibroblast. The outcomes from this project will establish mechanistic insight into the formation and progression of thoracic aneurysms and provide the basis for rational designs for therapeutic modulation in patients with this devastating disease.