Oxygen-Mediated Regulation of PDE5 in the Developing Pulmonary Vasculature

肺血管系统发育中 PDE5 的氧气介导调节

• 批准号: 7185978
• 负责人: KATHRYN N FARROW
• 金额: $ 13.09万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7185978
• 关键词: Advisory Committees; Affect; Animals; Antioxidants; Basic Science; Biological Assay; Biology; Blood Platelets; Blood Vessels; Caring; Cells; Chemicals; Child; Chronic lung disease; Clinical; Clinical Management; Clinical Trials; Condition; Critical Illness; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Delivery Rooms; Development; Disease; Environmental air flow; Etiology; Exposure to; Fellowship; Fluorescence Resonance Energy Transfer; Fluorescent Probes; Foundations; Future; Gene Expression; Goals; Head; Human; Hyperoxia; Infant; Intervention; Life; Literature; Long-Term Effects; Lung; Mediating; Mediator of activation protein; Medical; Mentors; Messenger RNA; Modality; Modeling; Neonatal; Neonatology; Newborn Infant; Oxidants; Oxidative Stress; Oxygen; Pathogenesis; Pediatrics; Perinatal; Persistent Fetal Circulation Syndrome; Pharmaceutical Preparations; Phospho-Specific Antibodies; Phosphorylation; Phosphorylation Site; Play; Polymerase Chain Reaction; Postdoctoral Fellow; Premature Infant; Principal Investigator; Production; Program Development; Protein Isoforms; Public Health; Pulmonary Hypertension; Pulmonary artery structure; Reactive Oxygen Species; Regulation; Regulatory Pathway; Relaxation; Research; Research Personnel; Resources; Resuscitation; Robin bird; Role; Scientist; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Standards of Weights and Measures; Stomach; Stress; Structure; Students; Syndrome; Testing; Therapeutic; Time; Training; Training Programs; Ventilator; Western Blotting; abstracting; base; career; design; expectation; fetal; guanylate; immunocytochemistry; improved; infant outcome; inhaled nitric oxide; inhibitor/antagonist; insight; neonatal pulmonary hypertension; neonate; novel; phosphodiesterase V; phosphoric diester hydrolase; prevent; professor; programs; protein expression; response; skills; therapeutic target; vascular bed

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)

描述（由申请人提供）： 该提案描述了新生儿学学术职业发展的五年培训计划。首席研究员已经完成了新生儿学的结构化进修培训，现在将通过基础科学和转化资源的独特整合来扩展她的科学技能。该计划将促进我们对氧介导的细胞信号传导的理解，并将其应用于肺血管生物学和危重新生儿的临床护理。 Robin H. Steinhorn 将指导首席研究员的科学发展。 Steinhorn 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，培养了众多临床研究员、博士后研究员和研究生。为了加强培训，该计划将聘请儿科教授保罗·舒马克 (Paul Schumacker) 的专业知识。舒马克博士是全国知名的细胞内氧传感机制专家。此外，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）是一种危及新生儿生命的临床综合征，其特征是肺血管系统从宫内向宫外的过渡失败。尽管 100% 氧气和吸入一氧化氮 (iNO) 通气是 PPHN 婴儿的标准治疗方法，但越来越多的证据表明，暴露于高氧可能会对细胞水平产生持久影响。我们的长期研究目标是更好地了解 PPHN 的发病机制，并开发新的疗法来改善 PPHN 婴儿的预后。干预的一个潜在目标是肺部的主要磷酸二酯酶同工型磷酸二酯酶 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 发病机制以及 PPHN 治疗（例如氧气）的影响。了解 PDE5 的氧介导调节将在了解 PPHN 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标对健康围产期肺血管系统和 PPHN 中 PDE5 基因表达和活性的影响。这里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，以防止氧介导的肺血管损伤，从而影响公共健康。这些药物不仅有可能改善 PPHN 婴儿的预后，而且有可能改善所有患者的预后 需要高浓度氧气通气的婴儿和儿童，无论其病因如何 原发疾病。 （摘要完）