Mechanisms of Cardiac Protection with A1 Overexpression

这项K02申请的主要研究员是一位儿科心脏病专家，他有50%的时间研究NHLBI R01，并获得了AHA设立的研究员补助金。申请者成功地建立了一个富有成效的研究实验室，但缺乏研究时间阻碍了进一步的职业发展。申请者的长期职业目标是继续扩大他的研究计划，保持儿科心脏病学的临床存在，并继续培训科学家。K02奖的直接职业目标是将75%的时间投入实验室，并获得多笔R01资金。如果K02奖获得资助，申请者将把75%的时间投入实验室，省去几项耗时的临床活动。职业发展计划包括：a)向合作者学习新技术，包括基因转移技术和cdna微阵列分析；b)在冷泉港参加课程，学习新的研究技术；c)参加当地研讨会(见附录)和全国会议。弗吉尼亚大学拥有多个研究中心，包括心血管研究中心和儿童健康研究中心，这两个中心都有核心实验室和多名研究人员进行积极合作，为教师发展提供了出色的环境。这项提案的研究计划既包括申请人的R01和EIG资助的研究，检查过度表达A1腺苷受体的转基因模型对心肌缺氧和缺血的保护作用，也包括从合作者那里学到的新技术的新方向。心脏特异性A1受体转基因被引入到小鼠基因组中，在心脏中产生大约100倍的功能A1受体的过度表达。初步研究表明，在全脑缺血-再灌流和缺氧过程中，A1的过度表达对机体的功能和代谢有好处。该实验室的新方向包括检查作为保护机制的细胞凋亡的抑制，以及实施体内模型来研究完整动物的心肌缺血。基因芯片分析也将被用来评估与心肌保护相关的基因表达的变化。基因治疗的长期目标也将通过病毒基因转移载体的新工作来解决。该奖项将促进首席研究员的职业发展，并将支持旨在回答临床相关心血管科学新问题的研究计划。

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.