Extracellular Mechanisms For Thoracic Aortic Aneurysms

描述(由申请人提供)： 在美国，主动脉动脉瘤是一种常见的死亡原因。由于胸主动脉瘤(TAA)手术修复的复杂性和术后并发症的高发生率，TAA患者尤其具有挑战性。主动脉瘤是一种血管重塑过程，其特征是至少部分由细胞外基质(ECM)降解引起的主动脉中层丢失。该项目的总体目标是确定促进TAA进展的细胞外机制。基质金属蛋白酶(MMPs)在健康和疾病中都能降解ECM。基质金属蛋白酶及其组织抑制物(TIMP)由多种类型的细胞产生，包括那些在主动脉中发现的细胞。过去的临床研究表明，在切除的主动脉瘤中，MMPs和TIMP之间存在失衡。该项目的中心假设是，基质金属蛋白酶/TIMP化学计量比的改变是TAA进展的早期事件；靶向调节基质金属蛋白酶/TIMP化学计量比将直接改变TAA进展；TAA进展的基本细胞机制是成纤维细胞基质金属蛋白酶/TIMP表达的局部变化。利用本实验室建立的TAA小鼠模型，本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)通过靶向的MMP-9基因缺失(MMP功能丧失)或TIMP-1基因缺失(MMP功能获得)，修改TAA的自然历史；(3)建立MMP9基因诱导是TAA进展过程中的早期事件，并且导致MMP/TIMP异常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主动脉瘤形成和发展的机械洞察力，并为这一毁灭性疾病患者的治疗调整提供合理设计的基础。

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.