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

间歇性低氧血症早产儿损伤的全身介质和生物标志物

• 批准号: 10664182
• 负责人: Elie G Abu Jawdeh
• 金额: $ 16.1万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-12 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664182
• 关键词: Adult; Animal Model; Apnea; Axon; Basic Science; Biological Markers; Blood; Blood - brain barrier anatomy; Brain Injuries; Caffeine; Cell Culture System; Cell Culture Techniques; Cell Death; Cells; Central Nervous System; Cessation of life; Clinical; Clinical Investigator; Clinical Sciences; Complement; Data; Development; Development Plans; Disease; Doctor of Medicine; Doctor of Philosophy; Drops; Early identification; Enzyme-Linked Immunosorbent Assay; Event; Exclusion; Frequencies; Future; Generations; Goals; Health Care Costs; Hypoxemia; Impairment; In Vitro; Incubated; Infant; Inflammation; Inflammatory; Injury; Intervention; Knowledge; Lead; Learning; Ligands; Link; Lung diseases; Measures; Mediator; Mentors; Mentorship; Methods; Monitor; Morbidity - disease rate; Neonatal; Neonatal Intensive Care; Neonatal Intensive Care Units; Nervous System Trauma; Neurodevelopmental Impairment; Neurofilament-L; Neurological outcome; Neurological status; Newborn Infant; Nurses; Oligodendroglia; Outcome; Oxygen; Pathway interactions; Patients; Pattern; Plasma; Premature Birth; Premature Infant; Process; Protein Fragment; Proteomics; Published Comment; Quality of life; Research; Risk; Role; Science; Scientist; Severities; Statistical Models; Structure; Supplementation; TLR2 gene; Techniques; Testing; Time; Titrations; Training; Translational Research; Treatment Effectiveness; Urine; Ventilator; Work; biomarker identification; blood-brain barrier crossing; blood-brain barrier function; brain cell; care costs; care outcomes; cell injury; clinical biomarkers; cohort; comparison control; early detection biomarkers; efficacious treatment; experimental study; extreme prematurity; improved; indexing; inhibitor; laboratory experience; neonatal morbidity; neonatal outcome; neurobehavior; oligodendrocyte progenitor; outcome prediction; premature; prognostication; prospective; pulmonary function; receptor; respiratory; skills training; societal costs; stem cells; synergism; systemic inflammatory response; therapy development; tool; translational scientist; treatment strategy; white matter injury

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.

抽象的 该提案描述了一项指导培训和研究计划，将促进 Elie 的发展 Abu Jawdeh，医学博士、哲学博士，新生儿呼吸控制领域的独立临床和转化研究者 和间歇性低氧血症（IH）。 Abu Jawdeh 博士将补充他目前作为新生儿科医生的背景 和临床科学家，以获得基础科学方法和生物标志物科学的新知识。目标是 学习基础科学技术和方法对于 Abu Jawdeh 博士的飞跃至关重要 了解 IH 造成的损伤机制并开发未来的治疗方法。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、转化和基础科学领域拥有丰富经验的导师团队将监督 Dr. Abu Jawdeh 在研究独立方面的发展和进步。 尽管新生儿重症监护取得了重大进展，但早产儿仍然面临着严重的问题 发病率和神经发育障碍。早产的社会成本约为260亿 美元，极度早产儿的护理费用是晚期早产儿的 20 倍。主要的 早产的后果是呼吸暂停和肺部疾病，导致反复发生 IH；偶发性下降 在血氧饱和度中。这些 IH 事件每天发生多达数百起事件，具有累积效应 关于新生儿结局。尽管越来越多的证据将 IH 与损伤联系起来，但 IH 的相关程度 IH 对损伤的影响以及 IH 对损伤的病理生理机制仍不清楚。这些知识 对 IH 机制理解的差距为改善临床结果造成了关键障碍。我们的目标是 该提案是为了更好地了解 IH 损伤的机制和生物标志物，以便发现和滴定 未来的治疗。通过早产儿前瞻性临床队列和体外细胞培养 实验中，我们将首先检验 IH 增加全身循环配体（生物介质）的假设， 使用少突胶质细胞祖细胞（OPC）的体外细胞培养系统损伤脑细胞。识别生物 IH 导致的细胞死亡和损伤的介质和途径将有助于开发治疗方法，我们也将在 体外。然后，我们将研究一种有前途的生物标志物 Neurofilament-L (NfL)，用于 IH 相关脑损伤和 早期神经系统结果的预测因子。识别损伤的生物标志物将有助于预测新生儿 未来 IH 治疗效果和滴定的结果和监测。我们有试点数据支持 我们的目标和假设。这将是首次对此类研究和机制进行调查 患有 IH 的早产儿。

项目成果

Severe Intraventricular Hemorrhage is Associated with Lung Injury in Preterm Infants on Mechanical Ventilation.

严重脑室内出血与机械通气早产儿的肺损伤有关。

• DOI: 10.26502/jppch.74050168
• 发表时间: 2023
• 期刊: Journal of pediatrics, perinatology and child health
• 作者: Piatek,Monika;Jawdeh,ElieGAbu;Giannone,Peter;Miller,Brandon;Schadler,Aric;Hanna,Mina
• 通讯作者: Hanna,Mina

The Impact of Intermittent Hypoxemia on Type 1 Retinopathy of Prematurity in Preterm Infants.

间歇性低氧血症对早产儿 1 型视网膜病变的影响。

• DOI: 10.1101/2023.09.25.23295922
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Haratbar,SamanehRabienia;Chen,Li;Cheng,Qiang;Singh,Dara;Fathi,Faraneh;Mohtasebi,Mehrana;Liu,Xuhui;Patwardhan,Abhijit;Bhandary,Prasad;Bada,HenriettaS;Yu,Guoqiang;AbuJawdeh,ElieG
• 通讯作者: AbuJawdeh,ElieG