Catalase: a pivotal regulator of vascular disease

项目摘要 腹主动脉瘤的形成是一个复杂的生物和机械过程， 核心特征是导致细胞中活性氧（ROS）调节异常的生物过程。 动脉壁这反映在动脉壁的结构变化中，这些结构变化开始为相对细微的变化， 细胞外基质的结构和功能，并最终进行细胞损失。这些结构性的变化 动脉壁的损伤表现为血管机械性能的异常， 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， 确定H2O2作为腹主动脉瘤形成的关键介质。该提案的核心目标是 更好地定义通过调节H2O2的关键信号通路的功能重要性 过氧化氢酶表达作为开发用于治疗糖尿病的机制靶向治疗剂的平台 腹主动脉瘤和更好地了解发生的疾病过程中的变异性 在人类身上。在这项建议中，我们有三个主要目标。首先，我们希望更好地了解 在更机械的水平上调节动脉壁中的过氧化氢酶表达， 动脉硬化和腹主动脉瘤形成。第二，我们要把知识 从我们的机制研究中获得，并使用一种新的生物力学方法进行初步的治疗研究。 我们共同开发的用于预防和治疗腹主动脉瘤的输送系统。最后我们将 将这些研究扩展到人类，并研究过氧化氢酶表达差异的影响， 这是由于动脉粥样硬化斑块上人过氧化氢酶基因启动子区的已知功能多态性所致。 在具有心血管疾病风险的受试者的良好表征的人类队列中的生物力学。通过 通过这些研究，我们希望不仅能更好地了解腹主动脉瘤的形成， 深入了解治疗策略，并可能更好地了解疾病的变异性， 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.