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: 7676184
• 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/7676184
• 关键词: Adrenal Cortex Hormones; Agonist; Arachidonic Acids; Basic Science; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Development; Dexamethasone; Dinoprostone; Disease; Down-Regulation; Endothelial Cells; Endothelium; Environment; Evaluation; Evolution; Exposure to; Fellowship; Fostering; Foundations; Functional disorder; Glucocorticoids; Hydrogen Peroxide; Hypertension; Inflammation; Life; Low Birth Weight Infant; Mediating; Medicine; Mentors; Metabolism; Microcirculatory Bed; Modeling; Morbidity - disease rate; Muscle Tonus; Neonatology; Pathogenesis; Pathway interactions; Perinatal Exposure; Physiology; Play; Pregnancy; Principal Investigator; Production; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Reactive Oxygen Species; Regulation; Research; Research Personnel; Resistance; Risk Factors; Role; Signal Transduction; Smooth Muscle; Splanchnic Circulation; Steroids; Stroke; Testing; Training; Training Programs; Vasodilator Agents; Vasomotor; Western World; arteriole; career; fetal; fetal programming; ilium; interest; metabolomics; mortality; offspring; pediatrician; postnatal; programs; response; skills; vasoconstriction

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，旨在培养从事基础科学独立研究所需的技能。主要研究者是一名经过委员会认证的儿科医生，完成了新生儿学第三年的进修培训，目前正在申请选修一年的进修培训，为学术医学领域的成功职业生涯奠定尽可能坚实的基础。该培训计划的重点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。普遍的假设是，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）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变化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关联提供机制解释。 Jeffrey Segar 博士将指导 Pi 的培训，Fred Lamb 博士将担任联合发起人。他们是绵羊心血管生理学领域的知名研究人员，他们对冠状动脉功能障碍研究的共同兴趣“营造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 介导的血管反应性变化与基础 ROS 产生的减少有关，这导致了以下具体目标的演变：1）确定前列腺素在冠状动脉功能障碍的胎儿编程中的作用； 2) 检验妊娠早期地塞米松暴露会改变花生四烯酸诱导的活性氧产生的假设； 3) 确定观察到的导管冠状动脉反应性变化是否出现在生理相关阻力冠状动脉中。