Endothelial Mechanotransduction in Thoracic Aneurysm Formation and Progression

项目摘要 该项目基于动脉瘤代表对高壁应变的病理反应的观点， 动脉壁变薄和变弱，而不是像正常代偿期那样变厚和变强， 动脉壁重塑我们假设内皮细胞对干扰的反应的炎症效应 细胞外基质重塑引起的信号改变是这种转换的重要驱动力 从代偿性重塑到病理性重塑拟议的实验将检验这些假设， 阐明炎症与动脉瘤发生或进展之间的联系机制。我们将使用两个 互补模型系统。第一种是马凡氏综合征（MFS）小鼠，其发展为严重的病理性 血管重塑和胸主动脉瘤，由于缺陷，在1。二是持续输液 两种血管收缩剂，诱导代偿性血管重塑或中度病理性 血压升高引起的重塑因此，对这些系统的比较将使我们能够 识别主动脉的生理和病理重塑之间的差异。目标1将测试效果 在一个关键的流量传感基因突变，专门取消机械转导途径， 损害整体功能（内核B和C）。在目标2中，我们将测试整合素突变的影响， 特异性影响基质重塑的炎症方面的相互作用分子（具有核心B和 C）。在目的3中，我们将研究血流在调节血管紧张素II受体1表达中的作用， 确定了动脉瘤形成的介导者（项目1以及核心B和C）。我们也将作出贡献 在机械转导的专业知识，在项目1，2和4的研究。这些实验的结果将提供 了解特定炎症途径如何导致胸主动脉瘤（TAA）， 从而鉴定药理学干预的潜在新靶点。

Project Summary This project is based on the view that aneurysms represent a pathological response to high wall strain in which the artery wall thins and weakens instead of thickening and strengthening as it does in normal compensatory artery wall remodeling. We hypothesize that inflammatory effects of endothelial cell responses to disturbances in blood flow, and from altered signaling due to extracellular matrix remodeling are important drivers of this switch from compensatory to pathological remodeling. The proposed experiments will test these hypotheses and elucidate mechanisms that link inflammation to aneurysm initiation or progression. We will use two complementary model systems. The first is Marfan syndrome (MFS) mice, which develop severe pathological vascular remodeling and thoracic aortic aneurysms due to a defect in fibrillin 1. The second is continuous infusion of two vasoconstrictors, which induce either compensatory vascular remodeling or moderate pathological remodeling in response to elevated blood pressure. Comparison of these systems will therefore allow us to identify differences between physiological and pathological remodeling of the aorta. Aim 1 will test the effects of mutations in a critical flow-sensing gene that specifically abolish mechanotransduction pathways without compromising overall functions (with Cores B and C). In Aim 2, we will test effects of mutations in integrins and interacting molecules that specifically affect the inflammatory aspects of matrix remodeling (with Cores B and C). In Aim 3, we will investigate the role of flow in regulating expression of Angiotensin II receptor 1, a well- established mediator of aneurysm formation (with Project 1 and Cores B and C). We will also contribute expertise in mechanotransduction to studies in Projects 1, 2 and 4. Results from these experiments will provide an understanding of how specific inflammatory pathways contribute to thoracic aortic aneurysms (TAAs) and thereby identify potential new targets for pharmacological intervention.