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有指导的培训计划来发展研究技能，该计划将导致专注于胸主动脉夹层治疗的独立翻译和临床研究。基质金属蛋白酶(MMPs)降解细胞外基质蛋白，如弹性蛋白和胶原，在心血管疾病中起关键作用。越来越多的数据表明，MMPs参与了腹主动脉、颅内血管和冠状动脉等动脉瘤的发病过程。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，MMPs在胸主动脉夹层中的作用知之甚少。根据我们实验室的初步数据，我们的中心假设是，基质金属蛋白酶-9在夹层后的主动脉退行性变中起着重要作用，并代表着一个潜在的治疗干预靶点。从拟议的研究中收集的数据将是开发药物预防胸主动脉夹层患者主动脉扩张和破裂的临床试验的第一步。 本项目的具体目的是：1)确定MMP-9在主动脉壁组织中的过度表达是否与主动脉夹层患者胸主动脉退变和动脉瘤的形成过程一致；2)探讨MMP-9基因内的功能性遗传变异导致MMP-9过度表达，进而导致主动脉夹层患者胸主动脉变性和动脉瘤形成的假说；3)在小鼠主动脉夹层模型中，研究我们的假设，即MMP-9的过度表达是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K08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翻译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.