Pathways of fetal programming of coronary dysfunction

描述（由申请人提供）：本提案详细介绍了一个为期5年的培训计划，以发展在基础科学领域进行独立研究所需的技能。主要研究者，一个委员会认证的儿科医生完成第三年的奖学金培训新生儿，目前正在申请奖学金培训的选修年奠定尽可能坚实的基础，在学术医学事业的成功。这个培训项目的中心是研究产前皮质类固醇暴露后绵羊冠状动脉生理学的改变。总体假设是地塞米松诱导的冠状动脉环氧化酶（考克斯）依赖性前列腺素和活性氧（ROS）产生的下调是胎儿编程的一个重要方面，导致冠状动脉张力升高。冠状动脉反应性的这种改变可以为观察到的不良宫内环境、低出生体重和随后的冠状动脉疾病之间的相关性提供机制解释。Jeffrey Segar博士将指导Pi的训练，Fred Lamb博士将担任共同赞助人。他们在绵羊心血管生理学方面是公认的研究者，他们在冠状动脉功能障碍研究方面的共同兴趣促进了一个智力刺激的合作环境，已经推动其他人进入成功的研究生涯。Roghair博士的初步数据表明，类固醇诱导的COX介导的血管反应性的改变与基础ROS产生的减少有关，这导致了以下特定目标的发展：1）确定野牡丹素在冠状动脉功能障碍的胎儿编程中的作用; 2）测试妊娠早期地塞米松暴露改变花生四烯酸诱导的活性氧产生的假设;和3）确定所观察到的导管冠状动脉反应性的改变是否在生理学相关的阻力冠状小动脉中可见。

DESCRIPTION (provided by applicant): This proposal details a 5 year training program to develop the skills necessary to pursue independent research in basic science. The principal investigator, a board-certified Pediatrician completing the third year of fellowship training in Neonatology, is currently applying for an elective year of fellowship training to lay as strong a foundation as possible for a successful career in academic medicine. This training program centers upon studies of altered ovine coronary artery physiology following antenatal corticosteroid exposure. The global hypothesis is that dexamethasone-induced downregulation of coronary artery cyclooxygenase (COX)-depenendent prostaglandin and reactive oxygen species (ROS) production is an important aspect of fetal programming, resulting in heightened coronary artery tone. Such alterations in coronary artery reactivity could provide a mechanistic explaination for the observed associations between an adverse intrauterine environment, low birth weight and subsequent coronary artery disease. Dr. Jeffrey Segar will mentor the Pi's training with Dr. Fred Lamb acting as co-sponsor. They are well established investigators in ovine cardiovascular physiology, and their mutual interest in the study of coronary artery dysfunction 'fosters an intellectually stimulating collaborative environment that has already propelled others into successful research careers. Dr. Roghair's preliminary data demonstrating steroid-induced alterations in COX-mediated vascular reactivty in association with deceased basal ROS production has led to the evolution of the following specific aims: 1) define the role of prostaglandins in the fetal programming of coronary artery dysfunction; 2) test the hypothesis that early gestation dexamethasone exposure alters arachidonic acid-induced reactive oxygen species production; and 3) determine whether the observed alterations in conduit coronary artery reactivity are seen in physiologically-relevant resistance coronary arterioles.