The Effects of Reactive Oxygen Species on Endothelial Progenitor Cells

描述(由申请人提供)： 本提案描述了一项为期5年的培训计划，旨在发展心血管医学方面的研究学术生涯。首席研究员在该奖项生效时已完成内科医学和心血管医学方面的培训，并打算过渡为一名具有必要科学专长的独立内科科学家。首席赞助商和导师基思·马奇博士是血管重塑和血管生成领域公认的领导者，他将在获奖期间协助首席研究员实现他的科学和职业发展目标。除了他的赞助商外，一个由血管信号、活性氧和祖细胞生物学领域的领先专家组成的咨询委员会将在整个资助期内提供科学指导和职业发展建议。印第安纳大学良好的研究环境，特别是印第安纳血管生物学和医学中心的综合性质，似乎是职业发展成为独立内科科学家的理想选择。本项目将侧重于了解活性氧物种在调节内皮祖细胞功能中的作用。动脉粥样硬化是发病率和死亡率的主要原因。高水平的活性氧簇(ROS)对血管内皮细胞的损伤被称为“氧化应激”，似乎是促进动脉粥样硬化的机制之一。另一方面，低水平的ROS似乎是生理性的，可能介导必要的血管反应。近年来，内皮祖细胞被认为是血管生成和血管再生等血管保护过程中的关键介质。我们的初步数据表明，内皮祖细胞对过氧化氢和同型半胱氨酸产生的ROS很敏感，但目前尚不清楚是什么机制介导了EPC的作用，也不知道ROS如何影响EPC的功能。这些知识是理解ROS在血管系统中的生理和病理生理学作用所必需的。因此，我们将首先在特定的目标1中研究ROS对内皮祖细胞存活、分化和成熟的影响。然后，我们将在目标2中通过检测ROS如何在体外和体内调节内皮祖细胞的功能来补充这一点。最后，我们将在目标3中确定ROS对内皮祖细胞影响的潜在信号转导途径。

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of a research focused academic career in cardiovascular medicine. The principal investigator will have completed his training in internal medicine and cardiovascular medicine at the time of the activation of this award and intends to make the transition into becoming an independent physician scientist with the necessary scientific expertise. The chief sponsor and mentor, Dr. Keith March, is a recognized leader in the field of vascular remodeling and angiogenesis and will assist the principal investigator to accomplish his scientific and career development goals during the award period. In addition to his sponsor, an advisory committee, consisting of leading experts in the areas of vascular signaling, reactive oxygen species and progenitor cell biology, will provide scientific guidance and career development advice throughout the funding period. The excellent research environment at Indiana University and especially the integrative nature of the Indiana Center for Vascular Biology and Medicine appear to be ideal for the career development into an independent physician scientist. This project will focus on understanding the role of reactive oxygen species in modulating the function of endothelial progenitor cells. Atherosclerosis is a major cause of morbidity and mortality. Damage to the vascular endothelium by high levels of reactive oxygen species (ROS) is referred to "oxidative stress" and appears to be one mechanism promoting atherosclerosis. Low levels of ROS on the other hand appear to be physiologic and may mediate necessary vascular responses. Endothelial progenitor cells (EPCs) have recently been identified as key mediators in vasculoprotective processes like angiogenesis and vascular regeneration. Our preliminary data demonstrates that EPCs are sensitive to ROS generated by hydrogen peroxide as well as homocysteine, but it is not known which mechanisms mediate the effects in EPCs or how ROS affect the function of EPCs in detail. This knowledge is required to understand the physiologic and pathophysiologic role of ROS in the vasculature. We will therefore first study the effects of ROS on the survival, differentiation and maturation of EPCs in Specific Aim 1. We will then complement this by examining how ROS can modulate the functions of EPCs in vitro and in vivo in Aim 2. Finally, we will identify potential signal transduction pathways mediating the ROS effects on endothelial progenitor cells in Aim 3.