CELLULAR AND MOLEC STUDIES OF ABDOMINAL AORTIC ANEURYSM

为了响应NIA试点研究资助计划的研究目标#4，本申请旨在研究心血管衰老的细胞和分子机制。腹主动脉瘤（AA）是一种致命的疾病，其特征是最大的弹性动脉——主动脉的下部扩张、减弱和突然破裂。AAA是一种老年男性疾病，60岁以上发病率最高。基础和临床研究支持AA是由年龄相关的主动脉壁胺氧化酶（SSAO）结构弱化引起的观点，表明在断奶大鼠中，抑制该酶导致弹性蛋白的形态变化和病理生理学模仿已知的导致人类AAA的衰老变化。为了充分发展这一AAA模型，并获得将开始定义老年人AAA发展机制的初步数据，我们提出了这些试点实验。1)时间过程实验，确定模型主动脉结构和生理变化；我们将这些变化与老化主动脉中发现的变化进行比较，然后进行：2)差异基因显示实验，以确定该模型中伴随早期AAA发展的基因表达的重要变化。这些研究将集中在血管老化的一个重要方面，即主动脉的退行性弹性蛋白变化。通过开发这种动物模型，并关注伴随主动脉老化和AAA发展的遗传变化，我们将能够在未来开展更复杂的机制项目，解决这一重要的衰老血管疾病。

In response to Research Objective #4 of the NIA Pilot Research Grant Program, this application addresses the cellular and molecular mechanisms of cardiovascular aging. Abdominal aortic aneurysm (AA) is a deadly disease characterized by dilatation, weakening, and sudden rupture of the lower portion of the largest elastic artery-the aorta. AAA is a disease of aging men, with peak incidence past the age of 60. Basic and clinical studies support the idea that AA is caused by age-related, structural weakening of the aortic wall's amine oxidase (SSAO) indicate that in weanling rats, inhibition of the enzyme results in morphologic changes in elastin and patho-physiology mimicking known aging changes that lead to AAA in humans. To fully develop this model of AAA, and obtain preliminary data that will begin to define the mechanisms underlying development of AAA in older individuals, we propose these pilot experiments. 1) a time-course experiment that will define aortic structural and physiological changes occurring in the model; we will compare these changes to those found in aging aorta and then do: 2) a differential gene display experiment to define important changes in gene expression that accompany early AAA development in this model. These studies will focus on one important aspect of vascular aging, i.e., degenerative elastin changes in the aorta. By developing this animal model, and focusing on genetic changes that accompany aortic aging and the development of AAA, we will be in a position to pursue a more complex mechanistic future project addressing this important vascular disease of aging.