Contribution of Pediatric OSA in Memory and Learning

摘要 这是一个全面的指导研究培训建议，旨在支持发展一个 独立的物理学家和科学家申请人是麻醉学和儿科学助理教授， 贝勒医学院（Baylor College of Medicine），并得到优秀设施的支持，临床和基础 研究和指导麻醉科保证75%的研究时间受到保护， 显示院校的优先次序和充足的资源，以促进申请人的研究和成功。这 提案包括过去两年获得的强有力的初步数据，这些数据部分由 申请人的两个有竞争力的研究奖：克莱顿奖，以及TCH麻醉师的资金。 头儿基于多学科和交叉研究，申请人已经确定了六个高度 支持和建立科学家导师。该提案还概述了一项教育计划，其中包括 课程作业、钳工作业和学术活动，以完成培训并促进独立性。儿科 阻塞性睡眠呼吸暂停（OSA）的发病率约为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 可逆电位该提案旨在使用一个全面的， 一种转化研究方法，旨在开发一种新的儿科OSA临床前模型， 人类的表型结合人类多导睡眠图和年轻小鼠血氧测定数据， 量化儿童OSA和年龄匹配的新生小鼠的神经认知变化。这项建议会 检验OSA诱导出生后海马神经元时间依赖性可逆变化的假设。 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： 1将确定间歇性缺氧（IH）对早期学习和记忆的时间效应。 大脑发育目的2：探讨IH对海马的影响，包括：a）长时程突触， 增强海马切片以询问突触功能，B）鉴定齿状回中的细胞类型， 量化变化，和c）研究拯救表型的突触和细胞组分。的 这些数据重要性包括：1）基于暴露时间通知外科决策，2）阐明 OSA诱导海马损伤的突触和细胞数据，以及3） 神经认知可逆性完成这5年的指导奖允许申请人结合联合收割机 围手术期麻醉实践与OSA诱导的分子机制的探索 海马损伤它为一个独立的医学科学家铺平了道路， 改善OSA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.