Matrix Metalloproteinases in Thoracic Aortic Dissection

描述（由申请人提供）： 我的主要目标是通过一个指导培训计划，将导致独立的翻译和临床研究，重点是治疗胸主动脉夹层发展的研究技能。 基质金属蛋白酶（MMP）降解细胞外基质蛋白，如弹性蛋白和胶原蛋白，并在心血管疾病中发挥关键作用。 越来越多的资料表明，基质金属蛋白酶参与腹主动脉瘤、颅内血管瘤和冠状动脉瘤的发病机制。 更重要的是，动物实验和临床试验都表明，MMPs是预防腹主动脉表达的有希望的靶点。 相比之下，对基质金属蛋白酶在胸主动脉夹层中的作用知之甚少。 基于我们实验室的初步数据，我们的中心假设是MMP-9在夹层后主动脉变性中起重要作用，并代表了治疗干预的潜在靶点。 从拟议的研究中收集的数据将代表开发临床试验的第一步，用于药物预防胸主动脉夹层患者的主动脉扩张和破裂。 本研究的具体目的是：1）确定主动脉壁组织中MMP-9的过度表达是否与主动脉夹层患者胸主动脉变性和动脉瘤形成的进展相一致; 2）探索MMP-9基因内的功能性遗传变异有助于MMP-9过表达的假设，进而导致主动脉夹层患者的胸主动脉变性和动脉瘤形成;和3）调查我们的假设，MMP-9过表达是小鼠主动脉夹层模型中胸主动脉瘤形成和破裂的关键步骤。 在我职业生涯的这个阶段，支持K 08奖的申请将是非常宝贵的，因为它将为未来胸主动脉夹层治疗的独立转化研究奠定坚实的基础。

DESCRIPTION (provided by applicant): My major goal is to develop research skills through a mentored training program that will lead to independent translational and clinical research focusing on the treatment of thoracic aortic dissection. Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins, such as elastin and collagen, and play a key role in cardiovascular disease. Accumulating data demonstrates that MMPs are involved in the pathogenesis of aneurysms of the abdominal aorta, intracranial vessels, and coronary arteries. More importantly, both animal experiments and clinical trials have shown that MMPs are promising targets in the prevention of abdominal aortic expression. In contrast, little is known about the role of MMPs in thoracic aortic dissection. Based on preliminary data from our laboratory, our central hypothesis is that MMP-9 plays an important role in aortic degeneration after dissection and represents a potential target for therapeutic intervention. The data gathered from the proposed study will represent the first step in developing clinical trials for pharmacologic prevention of aortic expansion and rupture in patients with thoracic aortic dissection. The specific aims of this project are: 1) to determine if overexpression of MMP-9 within aortic wall tissue coincides with the progression of thoracic aortic degeneration and aneurysm formation in patients with aortic dissection; 2) to explore the hypothesis that functional genetic variants within the MMP-9 gene contribute to MMP-9 overexpression, which in turn causes thoracic aortic degeneration and aneurysm formation in patients with aortic dissection; and 3) to investigate our hypothesis that MMP-9 overexpression is a key step in thoracic aortic aneurysm formation and rupture in a mouse model of aortic dissection. Support of this application for the K08 award at this stage of my career will be invaluable, as it will allow for the development of a solid foundation for future independent translational research in the treatment of thoracic aortic dissection.