Mechanisms of abdominal aortic aneurysm formation

描述（由申请人提供）： 该经修订的PPG应用程序旨在提供对腹主动脉瘤（AAA）引发和传播机制的机械见解。项目将使用AAA模型，其中血管紧张素II将被注入高血压小鼠。这是由本申请中的项目负责人教师最初描述的。该模型现已广泛应用于学术和药学研究项目。该模型的许多特征再现了人类疾病的特征，包括男性中强烈的性别特异性患病率、中膜细胞外基质的碎片化和炎性细胞的存在。对AAAs发展中事件的细胞序列的研究表明，炎症细胞参与了所有发展阶段。该修订项目申请的统一假设是血管紧张素II通过启动腹主动脉中膜的区域特异性基质降解促进动脉瘤形成，导致巨噬细胞募集、中膜夹层和随后的血管重塑。提出了四个项目，机械地定义在这个统一的假设中概述的事件序列。为了方便项目之间的研究，建议4个核心设施。这汇集了一群互动多年的教师。他们之间的相互作用的协同作用体现在多个联合出版物和共同研究者的赠款地位上。这些项目和核心旨在为以下领域的AAAs开发提供机理性见解：项目1（丽莎A。将研究男性雄激素通过调节血管紧张素1A型受体在促进AAA形成的区域特异性中的作用。项目2（Alan Daughthorn）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. Webb）将确定分泌型磷脂酶A2的特异性同工酶在AAA进展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的支持：局B。人类研究。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.