Catalase: a pivotal regulator of vascular disease

项目总结 腹主动脉瘤的形成是一个复杂的生物和机械过程。 主要特征是导致体内活性氧物种(ROS)失调的生物过程。 动脉壁。这反映在动脉壁的结构变化上，开始时是相对微妙的 细胞外基质的结构和功能最终导致细胞丢失。中国的这些结构性变化 动脉壁表现为血管机械性能的异常，最终导致 动脉瘤的形成。通过使用过表达过氧化氢酶的转基因小鼠模型，我们已经 确定过氧化氢是腹主动脉瘤形成的关键介质。这项提议的中心目标是 更好地确定控制过氧化氢的关键信号通路的功能重要性 以过氧化氢酶的表达为平台开发机制靶向治疗白血病的药物 腹主动脉瘤和更好地了解疾病过程中发生的变异性 在人类身上。在这项建议中，我们有三个主要目标。首先，我们想更好地了解 在更机械性的水平上调节动脉壁中过氧化氢酶的表达，因为它与变化有关 动脉僵硬和腹主动脉瘤形成。第二，我们想把这一知识 从我们的机制研究中获得，并使用一种新的生物力学进行初步治疗研究 我们共同开发的用于预防和治疗腹主动脉瘤的输送系统。最后，我们会 将这些研究推广到人类，并研究过氧化氢酶表达的差异对人类的影响 动脉壁人过氧化氢酶基因启动子区域已知功能多态性的结果 心血管疾病高危人群的生物力学研究。穿过 这些研究，我们希望不仅能更好地了解腹主动脉瘤是如何形成的，而且还能获得 对治疗策略的见解，也许可以更好地了解疾病的可变性 人类。

PROJECT SUMMARY The formation of an abdominal aortic aneurysm is a complex biological and mechanical process that has as a central feature the biological processes that result in a dysregulation of reactive oxygen species (ROS) in the arterial wall. This is reflected in structural changes in the arterial wall that begin as relatively subtle changes in extracellular matrix structure and function and ultimately proceed to cell loss. These structural changes in the arterial wall are manifest as abnormalities in the mechanical properties of the vessel that eventually result in the formation of aneurysms. Through the use of transgenic mouse models that overexpress catalase, we have identified H2O2 as a pivotal mediator of abdominal aneurysm formation. The central goal of this proposal is to better define the functional importance of the critical signaling pathways that govern H2O2 via regulation of catalase expression as a platform for developing mechanism-targeted therapeutics for the treatment of abdominal aortic aneurysms and for a better understanding of the variability in the disease process that occurs in humans. In this proposal, we have three major goals. First, we would like to better understand the regulation of catalase expression in the arterial wall at a much more mechanistic level as it pertains to changes in arterial stiffness and abdominal aortic aneurysm formation. Second, we would like to take the knowledge gained from our mechanistic studies and perform initial therapeutic studies using a novel biomechanical delivery system that we have co-developed to prevent and treat abdominal aortic aneurysms. Finally, we will extend these studies to humans and study the impact of differences in catalase expression that occur as the result of a known functional polymorphism in the promoter region of the human catalase gene on arterial biomechanics in a well characterized human cohort of subjects at risk for cardiovascular disease. Through these studies, we hope to not only better understand how abdominal aortic aneurysms form, but also to gain insights into therapeutic strategies and to perhaps develop a better understanding of disease variability in humans.