Pathways of fetal programming of coronary dysfunction

冠状动脉功能障碍的胎儿编程途径

• 批准号: 7099218
• 负责人: ROBERT D ROGHAIR
• 金额: $ 12.58万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-10 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099218
• 关键词: arachidonate; arterioles; cardiovascular disorder risk; coronary artery; coronary disorder; dexamethasone; early experience; enzyme activity; free radical oxygen; gene expression; gestational age; high performance liquid chromatography; polymerase chain reaction; prostaglandin E; prostaglandin endoperoxide synthase; sheep; vascular resistance; vasodilation

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.

描述（由申请人提供）：该提案详细介绍了一项为期5年的培训计划，以开发从事基础科学领域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，完成了新生儿学研究金培训的第三年，目前正在申请选修年度的奖学金培训，以尽可能为成功的学术医学职业生涯提供尽可能强大的基础。该训练计划集中在产前皮质类固醇暴露后对卵巢冠状动脉生理改变的研究。全球假设是，地塞米松诱导的冠状动脉环氧合酶（COX） - 替代前列腺素和活性氧（ROS）产生的下调是胎儿编程的重要方面，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宫内不良环境，低出生体重和随后的冠状动脉疾病之间的关联提供机械解释。杰弗里·塞加（Jeffrey Segar）博士将与弗雷德·兰姆（Fred Lamb）博士担任共同赞助者的培训有关PI的培训。他们是卵巢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的研究的共同兴趣“促进了一种智力刺激的协作环境，该环境已经推动了其他人进入成功的研究职业。 Roghair博士的初步数据表明，与已故的基底ROS产生相关的Cox介导的血管重新反应的改变导致了以下具体目的的演变：1）定义前列腺素在冠状动脉动脉功能障碍的胎儿程序中的作用； 2）检验以下假设：早期妊娠地塞米松暴露会改变蛛网膜酸诱导的活性氧的产生； 3）确定在生理上与抗性冠状动脉冠状动脉群体中观察到的导管冠状动脉反应的改变。