Systemic Mediators and Biomarkers of Injury in Preterm Infants with Intermittent Hypoxemia

摘要 该提案描述了一个指导培训和研究计划，将促进埃利的发展 Abu Jawdeh，医学博士，哲学博士、新生儿呼吸控制的独立临床和翻译研究者 和间歇性低氧血症（IH）。Abu Jawdeh博士将补充他目前作为生物学家的背景 和临床科学家获得基础科学方法和生物标志物科学的新知识。的目标 学习基本的科学技术和方法是阿布·贾德博士实现飞跃的必要条件。 了解IH的损伤机制，并在未来开发治疗方法。他将实现这些目标 通过结构化的指导，严格的实验室实践经验，正式的课堂作业和技能培训。 一个在临床、转化和基础科学方面有着良好记录的导师团队将监督博士。 Abu Jawdeh的发展和进步研究独立。 尽管在新生儿重症监护方面取得了重大进展，但早产儿仍继续遭受严重的 发病率和神经发育障碍。早产儿的社会成本约为260亿美元 极早产儿的护理费用是晚期早产儿的20倍。主要 早产的后果是呼吸暂停和肺部疾病，导致反复发生IH;阵发性下降 血氧饱和度这些IH发作每天发生多达数百起事件，具有累积效应 新生儿的结果。虽然将IH与损伤联系起来的证据越来越多，但IH相关的程度 IH与损伤的关系以及IH对损伤的病理生理机制尚不清楚。这些知识 对IH的机制理解的差距为改善临床结局造成了关键障碍。我们的目标 这项建议是为了更好地了解IH损伤的机制和生物标志物，以便发现和滴定 未来的治疗。通过早产儿的前瞻性临床队列和体外细胞培养 在实验中，我们将首先测试IH增加全身循环配体（生物介质）的假设， 利用少突胶质细胞祖细胞（OPC）体外细胞培养系统损伤脑细胞。识别生物- IH引起的细胞死亡和损伤的介质和途径将有助于开发治疗方法， 体外然后，我们将研究IH相关脑损伤的有前途的生物标志物Neurolyent-L（NfL）， 早期神经学结果的预测因子。识别损伤的生物标志物将允许对新生儿的 结果和监测IH治疗的有效性和滴定在未来。我们有试验数据支持 我们的目标和假设。这将是第一次这样的研究和机制进行调查， 早产儿IH。

ABSTRACT This proposal describes a mentored training and research plan that will facilitate the development of Elie Abu Jawdeh, M.D., Ph.D., to an independent clinical and translational investigator in neonatal respiratory control and intermittent hypoxemia (IH). Dr. Abu Jawdeh will complement his current background as a neonatologist and a clinical scientist to attain new knowledge in basic science methods and biomarker science. The goal of learning basic science techniques and methods is imperative for Dr. Abu Jawdeh to make the leap into understanding mechanisms of injury from IH and develop treatments in the future. He will achieve these goals through structured mentorship, rigorous hands-on laboratory experiences, formal classwork, and skills training. A team of mentors with an established track record in clinical, translational, and basic sciences will oversee Dr. Abu Jawdeh’s development and progress to research independence. Despite significant progress in neonatal intensive care, preterm infants continue to suffer from significant morbidities and neurodevelopmental impairment. The societal cost of prematurity is approximately 26 billion dollars with the cost of care for an extremely preterm infant being 20 times that of a late preterm infant. Major consequences of prematurity are apnea and lung disease that lead to repeated occurrences of IH; episodic drops in blood oxygen saturation. These IH episodes, occurring up to hundreds of events/day, have a cumulative effect on neonatal outcomes. While the evidence linking IH to impairments is mounting, the degree of IH associated with injury and pathophysiological mechanisms for IH’s contribution to injury remain unclear. This knowledge gap in the mechanistic understanding of IH creates a critical barrier to improving clinical outcomes. Our goal for this proposal is to better understand mechanisms and biomarkers of injury from IH in order to discover and titrate treatments in the future. Through both a prospective clinical cohort of preterm infants and in vitro cell culture experiments, we will first test the hypothesis that IH increases systemic circulating ligands (bio-mediators) that injure brain cells using in vitro cell culture system of oligodendrocyte progenitor cells (OPC). Identifying bio- mediators and pathways of cell death and injury from IH will help develop treatments that we will also explore in vitro. Then, we will investigate a promising biomarker Neurofilament-L (NfL) for IH-related brain injury and predictor of early neurological outcome. Identifying biomarkers of injury will allow prognostication of neonatal outcomes and monitoring of IH treatment effectiveness and titration in the future. We have pilot data to support both our Aims and hypotheses. This will be the first time such studies and mechanisms are investigated in preterm infants with IH.