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.