Pathways of fetal programming of coronary dysfunction

描述(由申请人提供)：这份建议书详细说明了一项为期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。首席研究员是一名获得董事会认证的儿科医生，完成了新生儿科学第三年的奖学金培训，目前正在申请一年的选择性奖学金培训，以尽可能为在学术医学领域的成功职业生涯奠定坚实的基础。这项培训计划的中心是研究产前接触皮质类固醇后绵羊冠状动脉生理学的变化。全球假说是，地塞米松诱导的冠状动脉环氧合酶(COX)依赖性前列腺素和活性氧(ROS)的产生下调是胎儿程序化的一个重要方面，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联系提供一个机制上的解释。杰弗里·西格博士将指导PI的培训，弗雷德·兰姆博士是共同发起人。他们是绵羊心血管生理学方面的知名研究人员，他们对冠状动脉功能障碍研究的共同兴趣培养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。Rogair博士的初步数据表明，类固醇诱导的COX介导的血管反应性改变与死亡的基础ROS产生相关，导致了以下特定目标的演变：1)确定前列腺素在胎儿冠状动脉功能障碍的编程中的作用；2)检验怀孕早期接触地塞米松改变花生四烯酸诱导的活性氧产生的假说；以及3)确定所观察到的管状冠状动脉反应性改变是否出现在生理相关的阻力冠状动脉小动脉中。

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.