Mechanisms of abdominal aortic aneurysm formation

腹主动脉瘤形成机制

• 批准号: 7077858
• 负责人: Alan Daugherty
• 金额: $ 158.93万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-08 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7077858
• 关键词: abdomen; angiotensin II; aorta aneurysm; cardiovascular disorder epidemiology; disease /disorder model; laboratory mouse; pathologic process

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.

描述（由申请人提供）： 该修订后的PPG应用旨在提供机械洞察力，了解与腹主动脉瘤启动和传播有关的机制（AAAS）。项目将使用AAA模型，其中血管紧张素II将被注入高脂小鼠。这最初是由该申请​​中项目负责人的教师描述的。现在，该模型已在学术和药品研究计划中广泛采用。该模型的许多特征再现了人类疾病的特征，包括男性的强大特异性患病率，内侧细胞外基质的碎片和炎症细胞的存在。关于AAAS发育中事件的细胞序列的研究表明，在发育的各个阶段，炎症细胞的参与。该修订程序项目应用的统一假设是，血管紧张素II通过在腹主动脉介质中启动区域特异性基质降解来促进动脉瘤形成，从而导致巨噬细胞，内侧解剖和随后的血管重塑。提出了四个项目，该项目从机械上定义了此统一假设中概述的事件序列。为了促进项目之间的研究，提出了4个核心设施。这汇集了一群互动了几年的教师。他们的互动的协同作用是由多个联合出版物和赠款的共同投资者地位证明的。这些项目和核心旨在为AAAS在以下领域的发展提供机械洞察：项目1（Lisa A. Cassis）将研究男性雄激素在促进AAA形成区域特异性中的作用，通过调节血管紧张素1A型受体。项目2（Alan Daugherty）将确定平滑肌细胞特异性AT1A受体在AAA启动机理中的作用。项目3（Fred C. de Beer）将确定血清淀粉样蛋白A及其与选定基质金属蛋白酶的相互作用的作用。项目4（Nancy R. Webb）将确定分泌磷脂酶A2的特定同工酶在不断发展的AAA期间巨噬细胞募集部位促进炎症中的作用。这些项目将得到以下核心：A。Administration的支持。 B.人类研究。 C.鼠标维护。 D.定量病理。