The primary objective of this proposal is the development of the principal investigator into an independent clinician scientist in the field of cardiovascular disease. The applicant is a pediatric critical care physician who actively participates in basic science research albeit with limited time away from clinical duties (35%). If funded, this award will allow 75% time for research training and pursuit of specific scientific aims. Under the sponsorship of a well-recognized adenosine pharmacologist, the proposal includes a curriculum of graduate level courses, regularly scheduled scientific seminars, attendance at national meetings, training in scientific techniques, and further involvement in the mentoring of graduate students. Within the fully supportive setting of a university-based school of medicine, a multidisciplinary advisory committee of established scientists and clinician scientists will guide the career development of the principal investigator. The proposed research will examine the relative roles of adenosine A2A and A2B receptors in myocardial tolerance to ischemia-reperfusion. Adenosine is a """"""""retaliatory metabolite"""""""" released during imbalances of metabolic supply and demand that exerts cardioprotective responses through activation of at least four different receptor subtypes. Clarifying the contribution(s) of each adenosine receptor subtype in response to ischemia-reperfusion remains an essential step in developing potential pharmacologic therapies for the clinical management of heart disease. While A2A receptors are primarily responsible for regulation of coronary flow, their contribution to protection from ischemia-reperfusion is just beginning to be appreciated. Less is known about whether A2B receptor activation is protective during ischemia-reperfusion in part due to the unavailability of selective and potent A2B antagonists. Harnessing the specificity of gene-knockout models and combining it with a traditional receptor-ligand approach, it is now possible to distinctly isolate the protective contribution of each of these receptor subtypes during ischemia-reperfusion using two lines of mice with targeted deletion of either A2A or A2B receptors.
The specific aims are: 1) Characterize the effects of ischemia-reperfusion in isolated hearts from adenosine A2A and A2B receptor knockout mice, 2) Develop an in vivo model of regional myocardial ischemia-reperfusion in adenosine A2A and A2B receptor knockout mice, and 3) Examine the subcellular signaling mechanisms involved in protection from ischemia-reperfusion in adenosine A2A and A2B receptor knockout mice.
