Endothelial Mechanotransduction in Thoracic Aneurysm Formation and Progression

项目摘要 该项目基于这样的观点，即动脉瘤是对高壁应变的病理反应，在这种情况下 动脉壁变薄变弱，而不是像正常代偿期那样增厚和增强。 动脉壁重塑。我们假设内皮细胞对干扰的炎症反应 在血流中，以及由于细胞外基质重塑而改变的信号是这种转换的重要驱动因素 从代偿性重构到病理性重构。拟议的实验将检验这些假设，并 阐明炎症与动脉瘤的发生或发展有关的机制。我们将使用两个 互补的模型系统。第一种是马凡综合征(MFS)小鼠，它会发展成严重的病理变化 由纤维蛋白缺陷引起的血管重构和胸主动脉瘤1.第二种是持续输液 引起代偿性血管重塑或中度病理改变的两种血管收缩药 血压升高时的重塑。因此，对这些系统的比较将使我们能够 识别主动脉生理性和病理性重塑之间的差异。目标一号将测试其效果 一种关键的流敏感基因的突变，该基因特异性地废除机械转导通路，而不是 整体功能受损(核心B和C)。在目标2中，我们将测试整合素和 相互作用的分子，特别影响基质重塑的炎症方面(与核心B和 c)。在目标3中，我们将研究Flow在调节血管紧张素II受体1表达中的作用。 建立了动脉瘤形成的中介物(项目1和核心B和C)。我们也将做出贡献 在项目1、2和4中的研究中的机械传递方面的专业知识。这些实验的结果将提供 了解特定的炎症途径如何在胸主动脉瘤(TAA)和 从而为药物干预寻找潜在的新靶点。

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.