Mechanisms of Cardiac Protection with A1 Overexpression

点击翻译按钮获取中文摘要

The principal investigator of this K02 application is a Pediatric Cardiologist with 50% time for research on an NHLBI R01 and an AHA Established Investigator Grant. The applicant has successfully established a productive research laboratory but the lack of research time is hindering further career development. The long-term career goals of the applicant are to continue to expand his research program, to maintain a clinical presence in pediatric cardiology and to continue to train scientists. The immediate career objective with the K02 award is to devote 75% time to the laboratory and to obtain multiple R01 funding. If the K02 award is funded, the applicant will devote 75% time to the lab by eliminating several time consuming clinical activities. The plans for career development include: a) learning new techniques from collaborators including gene transfer technology and cDNA microarray analysis, b) taking courses at Cold Spring Harbor to learn new research techniques, and c) attending local seminars (see appendix) and national meetings. The environment for faculty development is outstanding at the University of Virginia with multiple research centers including the Cardiovascular Research Center and the Child Health Research Center, both of which have core labs and multiple investigators for active collaboration. The research plan for this proposal includes both funded research from the applicant's R01 and EIG examining myocardial protection from hypoxia and ischemia in a transgenic model overexpressing A1 adenosine receptors as well as new directions with new techniques learned from collaborators. A cardiac specific A1 receptor transgene was introduced into the mouse genome producing approximately 100-fold overexpression of functional A1 receptors in the heart. Initial work has demonstrated beneficial functional and metabolic effects of A1 overexpression during global ischemia-reperfusion and hypoxia. New directions in the lab include examining inhibition of apoptosis as a mechanism of protection and implementation of an in vivo model to study myocardial ischemia in the intact animal. cDNA microarray analysis will also be used to assess changes in gene expression associated with myocardial protection. The long-term goal of gene therapy will also be addressed with new work on viral gene transfer vectors. This award will enhance the career development of the principal investigator and will support a research program designed to answer new questions in clinically relevant cardiovascular science.