Mechanisms of abdominal aortic aneurysm formation

描述(由申请人提供)： 这一改进的PPG应用程序旨在提供对腹主动脉瘤(AAA)的启动和传播机制的机械洞察。项目将使用一种AAA模型，在该模型中，血管紧张素II将被注入高脂血症小鼠。这最初是由作为此应用程序中的项目负责人的教员描述的。这种模式现在已经在学术和药学研究项目中被广泛采用。该模型的许多特征再现了人类疾病的特征，包括男性强烈的性别特异性流行，中层细胞外基质的碎裂和炎细胞的存在。对AAA发生过程中细胞序列的研究表明，炎症细胞参与了AAA发育的所有阶段。这一修订计划项目应用的统一假设是，血管紧张素II通过启动腹主动脉中层局部特异性基质降解，导致巨噬细胞募集、内侧夹层和随后的血管重塑，促进动脉瘤的形成。提出了四个项目，机械地定义了这一统一假说中概述的事件顺序。为了促进项目间的研究，提出了4个核心设施。这将一群已经互动多年的教职员工聚集在一起。它们相互作用的协同作用体现在多份联合出版物和赠款上的联合调查员地位上。项目1(Lisa A.Cassis)将研究男性雄激素通过调节血管紧张素1A型受体促进AAA形成的区域特异性。项目2(艾伦·多尔蒂)将确定平滑肌细胞特异性AT1a受体在AAA启动机制中的作用。项目3(Fred C.de Beer)将确定血清淀粉样蛋白A的作用及其与选定的基质金属蛋白酶的相互作用。项目4(南希·R·韦伯)将确定分泌型磷脂酶A2的特定同工酶在AAA演变过程中促进巨噬细胞募集部位炎症的作用。这些项目将得到以下核心部门的支持：a.行政管理。B.人体研究。C.鼠标维护。D.定量病理学。

DESCRIPTION (provided by applicant): This amended PPG application is designed to provide mechanistic insight into the mechanisms involved in the initiation and propagation of abdominal aortic aneurysms (AAAs). Projects will use a model of AAA in which angiotensin II will be infused into hyperlipidemic mice. This was described originally by faculty who are Project Leaders in this application. This model has now been adopted widely in both academic and pharmaceutical research programs. Many characteristics of the model reproduce features of the human disease, including the strong gender specific prevalence in males, fragmentation of medial extracellular matrix and presence of inflammatory cells. Studies on the cellular sequence of events in the development of AAAs demonstrate the involvement of inflammatory cells at all stages of development. The unifying hypothesis of this amended program project application is that angiotensin II promotes aneurysm formation by initiating regional-specific matrix degradation in the media of the abdominal aorta, leading to recruitment of macrophages, medial dissection, and subsequent vascular remodeling. Four projects are proposed that mechanistically define the sequence of events outlined in this unifying hypothesis. To facilitate research among Projects, 4 core facilities are proposed. This brings together a group of faculty who have interacted for several years. The synergy of their interactions is demonstrated by the multiple joint publications and co-investigator status on grants. These projects and cores have been designed to provide mechanistic insight into the development of AAAs in the following areas: Project 1 (Lisa A. Cassis) will study the role of male androgen in promoting regional-specificity of AAA formation through regulation of the angiotensin type 1A receptor. Project 2 (Alan Daugherty) will determine the role of smooth muscle cell specific AT1a receptors in the mechanisms of AAA initiation. Project 3 (Fred C. de Beer) will determine the role of serum amyloid A and its interaction with selected matrix metalloproteinases. Project 4 (Nancy R. Webb) will determine the role of specific isoenzymes of secretory phospholipase A2s in promoting inflammation at the site of macrophage recruitment during the evolving AAA. These projects will be supported by Cores of: A. Administration. B. Human studies. C. Mouse maintenance. D. Quantitative pathology.