Oxygen-Mediated Regulation of PDE5 in the Developing Pulmonary Vasculature

描述(由申请人提供)： 这份提案描述了一项为期五年的培训计划，旨在发展新生儿学的学术生涯。首席研究员已经完成了新生儿科学的结构化奖学金培训，现在，她将通过基础科学和翻译资源的独特整合来扩展她的科学技能。这个项目将促进我们对氧气介导的细胞信号的理解，将其应用于肺血管生物学和危重新生儿的临床护理。罗宾·H·斯坦霍恩将指导首席研究员的科学发展。斯坦霍恩博士是新生儿肺血管生物学领域公认的领导者。她是新生儿科主任，培养了许多临床研究员、博士后研究员和研究生。为了加强培训，该计划将招募儿科学教授保罗·舒梅克的专业知识。舒马克博士是全国知名的细胞内氧气感应机制专家。此外，一个由备受尊敬的医学科学家组成的咨询委员会将提供科学和职业建议。新生儿持续性肺动脉高压(PPHN)是一种威胁新生儿生命的临床综合征，其特征是肺血管从宫内到宫外的转换失败。尽管100%氧气和吸入一氧化氮(INO)是PPHN婴儿的标准治疗方法，但越来越多的证据表明，暴露在高氧环境中可能会对细胞水平产生持久的影响。我们的长期研究目标是更好地了解PPHN的发病机制，并开发新的治疗方法来改善PPHN婴儿的预后。一个潜在的干预目标是肺中的主要磷酸二酯酶亚型，磷酸二酯酶5(PDE5)。我们的中心假设是，PDE5是新生儿肺血管张力的关键介质，其表达和活性受到PPHN发病机制和PPHN治疗(如氧气)的影响。了解氧介导的PDE5的调节将在理解PPHN的发病机制中发挥关键作用，并将影响临床治疗，因为PDE5可能被证明是一个重要的治疗靶点。该项目的主要目标是描述氧气及其下游靶点对健康围产期肺血管和PPHN中PDE5基因表达和活性的影响。本文介绍的研究的成功完成将为靶向抗氧化剂和PDE5抑制剂的临床试验提供基础科学基础，以防止氧对肺血管系统的损害，从而影响公众健康。这些药物不仅有可能改善患有PPHN的婴儿的预后，而且对所有人都是如此 需要高氧通风的婴儿和儿童，无论其病因如何 潜在的疾病。 (摘要结束)

DESCRIPTION (provided by applicant): This proposal describes a five year training program for the development of an academic career in Neonatology. The principal investigator has completed structured fellowship training in Neonatology and now, will expand upon her scientific skills through a unique integration of basic science and translational resources. This program will promote our understanding of oxygen-mediated cellular signaling, as applied to pulmonary vascular biology and the clinical care of critically ill neonates. Robin H. Steinhorn will mentor the principal investigator's scientific development. Dr. Steinhorn is a recognized leader in the field of neonatal pulmonary vascular biology. She is the Division Head of Neonatology and has trained numerous clinical fellows, postdoctoral fellows, and graduate students. To enhance the training, the program will enlist the expertise of Paul Schumacker, Professor of Pediatrics. Dr. Schumacker is a nationally known expert in mechanisms of oxygen-sensing within the cell. In addition, an advisory committee of highly regarded medical scientists will provide scientific and career advice. Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening clinical syndrome of newborn infants, characterized by failed transition of the pulmonary vasculature from intrauterine to extrauterine life. Although ventilation with 100% oxygen and inhaled nitric oxide (iNO) is standard therapy for infants with PPHN, there is growing evidence that exposure to hyperoxia may have lasting effects on a cellular level. Our long-term research goal is to better understand the pathogenesis of PPHN and to develop novel therapies to improve the outcomes of infants with PPHN. One potential target for intervention is the major phosphodiesterase isoform in the lung, phosphodiesterase 5 (PDE5). Our central hypothesis is that PDE5 is a critical mediator of neonatal pulmonary vascular tone, and that its expression and activity are impacted by PPHN pathogenesis as well as PPHN therapies, such as oxygen. Understanding oxygenmediated regulation of PDE5 will play a critical role in understanding PPHN pathogenesis and will impact clinical management, as PDE5 may prove to be an important therapeutic target. The major goal of this project is to delineate the effects of oxygen and its downstream targets on PDE5 gene expression and activity, both in the healthy perinatal pulmonary vasculature and in PPHN. The successful completion of the studies presented here will impact public health by providing a basic science foundation for clinical trials of both targeted antioxidants and PDE5 inhibitors to prevent oxygen-mediated damage to the pulmonary vasculature. These drugs have the potential to not only improve outcomes for infants with PPHN, but for all infants and children who require ventilation with high levels of oxygen, regardless of the etiology of their underlying disease. (End of Abstract)