Contribution of Pediatric OSA in Memory and Learning

摘要 这是一项全面的指导式研究培训建议，旨在支持 独立的医生兼科学家。申请者是麻醉学和儿科学助理教授， 贝勒医学院(BCM)，并得到卓越的设施、临床和基础设施的支持 研究和指导。麻醉学部门保证75%的保护研究时间， 表明机构优先事项和充足的资源，以促进申请者的研究和成功。这 提案包括在过去两年中获得的强劲的初步数据，这些数据部分由 申请者的两个竞争性研究奖项：克莱顿奖，以及来自TCH麻醉师的资金- 头儿。基于多学科和跨领域的研究，申请者确定了六个高度 支持性的和成熟的科学家导师。该提案还概述了一项教育计划，其中包括 课业、钳工和学术活动，以完成训练并促进独立。儿科 阻塞性睡眠呼吸暂停(OSA)的发生率约为7%，有几种不良后遗症，包括 神经认知功能障碍，涉及行为、情绪抑制、学习和记忆，未知 可逆势。这项建议旨在用全面和全面的 翻译研究方法建立一种新的儿童阻塞性睡眠呼吸暂停的临床前模型 人类的表型。使用人类多导睡眠图和幼年小鼠血氧饱和度数据的组合，我们 量化儿童阻塞性睡眠呼吸暂停综合征和年龄匹配的新生小鼠的神经认知变化。这项提议将 OSA诱导生后海马区时间依赖性可逆性改变的假说检验 神经生物学，导致学习能力下降。提出了两个目标来检验这一假设：目标 1将确定间歇性低氧(IH)对早期学习和记忆的暂时影响 发育中的大脑。Aim 2将通过长时程突触确定IH对海马区的影响 在海马片中增强以询问突触功能，b)识别齿状回中的细胞类型 量化变化，以及c)研究救援表型的突触和细胞成分。这个 这些数据的意义包括：1)根据曝光时间为手术决策提供信息；2)阐明 OSA诱导的海马区损伤的突触和细胞数据，以及3)OSA诱导的海马损伤的可行性和决定因素 神经认知可逆性。完成这项为期5年的指导奖后，申请者可以将 阻塞性睡眠呼吸暂停综合征分子机制的围手术期麻醉实践 海马区受损。它为独立的内科医生-科学家致力于 改善了阻塞性睡眠呼吸暂停综合征儿童的健康目标。

ABSTRACT This is a comprehensive mentored research training proposal aimed to support the development of an independent physician-scientist. The applicant is an Assistant Professor of Anesthesiology & Pediatrics at Baylor College of Medicine (BCM), and is supported by the outstanding facilities, clinical and fundamental research, and mentorship. The Anesthesiology Department guarantees a 75% protected research time, indicating institutional priority and ample resources to facilitate the applicant's research and success. This proposal includes strong preliminary data obtained in the past two years, that have been partially funded by the applicant's two competitive research awards: The Clayton Award, and funds from the TCH Anesthesiologist-in- Chief. Based on the multidisciplinary and intersectional research, the applicant has identified six highly supportive and established scientist mentors. This proposal also outlines an educational plan that includes coursework, benchwork, and scholarly activities to complete his training and facilitate independence. Pediatric Obstructive Sleep Apnea (OSA), with an incidence of ~7%, has several untoward sequelae, including neurocognitive dysfunction involving behavior, emotional inhibition, and learning and memory, with unknown reversibility potentials. This proposal aims to characterize neurocognitive changes using a comprehensive and translational study approach to develop a novel pre-clinical model of pediatric OSA that faithfully recapitulates the human phenotype. Using a combination of human polysomnographic and young murine oximetry data we quantify the neurocognitive changes in pediatric OSA, and in age-matched neonatal mice. This proposal will test the hypothesis that OSA induces time-dependent reversible changes in postnatal hippocampal neurobiology, leading to decreased learning capacity. Two aims are proposed to test this hypothesis: Aim 1 will determine the temporal effects of intermittent hypoxia (IH) on learning and memory in the early developing brain. Aim 2 will determine the effects of IH on the hippocampus through a) long term synaptic potentiation in hippocampal slices to interrogate synaptic function, b) identify cell types in the dentate gyrus to quantify changes, and c) study the synaptic and cellular components of the rescue phenotype. The significance of these data include: 1) inform surgical decision making based on exposure timing, 2) elucidate synaptic and cellular data underlying OSA-induced hippocampal injury, and 3) feasibility and determinants of neurocognitive reversibility. Completion of this 5-year mentored award allows the applicant to combine perioperative anesthesia practice with an exploration of the molecular mechanisms of OSA-induced hippocampal damage. It paves the road for an independent physician-scientist committed to informing improved health targets in children with OSA.