Catalase: a pivotal regulator of vascular disease

过氧化氢酶：血管疾病的关键调节因子

基本信息

批准号：
9271227
负责人：
William Robert Taylor
金额：
$ 33.53万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-13 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9271227
关键词：
Abdomen Abdominal Aortic Aneurysm Aneurysm Aorta Biological Biological Process Biomechanics Blood Vessels Cause of Death Cell Culture Techniques Cells Complex Data Disease Down-Regulation Drug Delivery Systems Enzymes Extracellular Matrix FOXO1A gene Funding Generations Genes Genetic Polymorphism Goals Human Hydrogen Peroxide Inflammation Knowledge Mechanics Mediating Mediator of activation protein Pathology Patients Phenotype Physiological Polymers Process Promoter Regions Property Reactive Oxygen Species Regulation Role Signal Pathway Signal Transduction Single Nucleotide Polymorphism Structure Surrogate Markers System Testing Therapeutic Therapeutic Agents Therapeutic Use Study Time Tissues Transcriptional Regulation Transgenic Mice United States Variant Vascular Diseases Work arterial stiffness base cardiovascular disorder risk catalase cohort insight mechanical properties mouse model novel novel therapeutics overexpression prevent promoter small molecule therapeutics targeted treatment

项目摘要

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.

项目摘要腹主动脉瘤的形成是一种复杂的生物学和机械过程，具有中心特征导致活性氧（ROS）失调的生物过程动脉壁。这反映在动脉壁的结构变化中，而动脉壁的结构变化开始于相对微妙的变化细胞外基质结构和功能，并最终导致细胞损失。这些结构性变化动脉壁在血管的机械性能中表现为异常，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，我们有将H2O2鉴定为腹动脉瘤形成的关键介体。该提议的核心目标是更好地定义了通过调节来控制H2O2的临界信号通路的功能重要性过氧化氢酶的表达是开发针对机制的治疗剂的平台腹主动脉瘤，以更好地了解发生的疾病过程的变异性在人类中。在此提案中，我们有三个主要目标。首先，我们想更好地了解与变化有关在动脉刚度和腹部主动脉瘤形成中。其次，我们想掌握知识从我们的机械研究中获得并使用新型生物力学进行初始治疗研究我们已经共同开发的递送系统可以预防和治疗腹部主动脉瘤。最后，我们会的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人类过氧化氢酶基因启动子区域中已知的功能多态性的结果在具有心血管疾病风险的受试者人类群体中，生物力学。通过这些研究，我们希望不仅能更好地了解腹部主动脉瘤如何形成对治疗策略的见解，并可能对疾病变异性有更好的了解人类。