The Effects of Reactive Oxygen Species on Endothelial Progenitor Cells

描述（由申请人提供）： 该提案描述了一个为期5年的培训计划，以发展心血管医学研究为重点的学术生涯。主要研究者将在激活该奖项时完成内科和心血管医学的培训，并打算过渡成为具有必要科学专业知识的独立医生科学家。主要发起人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，将协助主要研究者在获奖期间完成其科学和职业发展目标。除了他的赞助商，一个咨询委员会，由血管信号，活性氧和祖细胞生物学领域的领先专家组成，将在整个资助期间提供科学指导和职业发展建议。在印第安纳州大学，特别是印第安纳州中心血管生物学和医学的综合性优良的研究环境似乎是理想的职业发展成为一个独立的医生科学家。本计画将著重于了解活性氧在内皮祖细胞功能调控中的角色。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（ROS）对血管内皮的损伤被称为“氧化应激”，似乎是促进动脉粥样硬化的一种机制。另一方面，低水平的ROS似乎是生理性的，并且可能介导必要的血管反应。内皮祖细胞（Endothelial progenitor cells，EPCs）是近年来发现的在血管新生和血管再生等血管保护过程中起重要作用的细胞因子。我们的初步数据表明，EPCs对过氧化氢和同型半胱氨酸产生的ROS敏感，但尚不清楚哪些机制介导EPCs的作用，以及ROS如何详细影响EPCs的功能。这些知识是了解ROS在血管系统中的生理和病理生理作用所必需的。因此，我们将首先研究ROS对Specific Aim 1中EPCs的存活、分化和成熟的影响。然后，我们将通过研究ROS如何在体外和体内调节EPCs的功能来补充这一点。最后，我们将确定潜在的信号转导途径介导的活性氧对内皮祖细胞的影响在目标3。

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.