Contribution of Pediatric OSA in Memory and Learning

儿科 OSA 对记忆和学习的贡献

• 批准号: 10348559
• 负责人: Arvind Chandrakantan
• 金额: $ 14.97万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10348559
• 关键词: Acute; Address; Age; Anatomy; Anesthesia procedures; Anesthesiology; Award; Behavior; Behavioral Model; Brain; Chemosensitization; Child; Childhood; Chronic; Clinical; Clinical Research; Cognitive; Coupled; Data; Decision Making; Development; Disease; Disease Progression; Electrophysiology (science); Emotional; Exhibits; Exposure to; Functional disorder; Funding; Funding Applicant; Health; Hippocampus (Brain); Human; Hypoxia; Immunohistochemistry; Impaired cognition; Incidence; Individual; Infant; Injury; Intervention; Knowledge; Learning; Long-Term Potentiation; Measurable; Medicine; Memory; Mentored Research Scientist Development Award; Mentors; Mentorship; Modeling; Molecular; Mus; Neurobiology; Neurocognitive; Neurologic; Neurologic Dysfunctions; Neurons; Obstructive Sleep Apnea; Onset of illness; Operative Surgical Procedures; Outcome; Oxygen saturation measurement; Pediatrics; Perioperative; Perioperative complication; Phenotype; Physicians; Physiological; Polysomnography; Positioning Attribute; Postoperative Hemorrhage; Pre-Clinical Model; Research; Research Training; Resources; Risk; School-Age Population; Scientist; Site; Slice; Stains; Surgeon; Synapses; Synaptic plasticity; Testing; Therapeutic; Time; Training; base; behavioral phenotyping; brain cell; cell type; clinically relevant; college; critical period; dentate gyrus; experience; fundamental research; improved; life-long learning; memory encoding; mouse model; multidisciplinary; negative affect; neonatal mice; neonate; neurobehavior; neurogenesis; normoxia; novel; postnatal; professor; respiratory; response; restoration; skills; standard care; success; synaptic function; translational study

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.

抽象的 这是一项全面的指导性研究培训提案，旨在支持 独立医师科学家。申请人是麻醉学和儿科助理教授 贝勒医学院 (BCM)，拥有一流的设施、临床和基础设施支持 研究和指导。麻醉科保证75%的受保护研究时间， 表明机构的优先权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，这些数据的部分资金来自 申请人的两项竞争性研究奖项：克莱顿奖和 TCH 麻醉师资助 首席。基于多学科交叉研究，申请人确定了六项高度 支持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 课程作业、实验作业和学术活动，以完成他的培训并促进独立。儿科 阻塞性睡眠呼吸暂停 (OSA) 的发生率约为 7%，会产生多种不良后遗症，包括 神经认知功能障碍，涉及行为、情绪抑制、学习记忆等，原因不明 可逆性潜力。该提案旨在使用全面和全面的方法来描述神经认知变化的特征 转化研究方法开发一种新的儿科 OSA 临床前模型，忠实地概括 人类表型。结合人类多导睡眠图和年轻小鼠血氧测定数据，我们 量化儿童 OSA 和年龄匹配的新生小鼠的神经认知变化。该提案将 检验 OSA 引起出生后海马的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： 目标 1 将确定间歇性缺氧（IH）对早期学习和记忆的时间影响 正在发育的大脑。目标 2 将通过 a) 长期突触确定 IH 对海马体的影响 海马切片中的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，c) 研究救援表型的突触和细胞成分。这 这些数据的重要性包括：1）根据暴露时间为手术决策提供信息，2）阐明 OSA 引起的海马损伤的突触和细胞数据，以及 3) 的可行性和决定因素 神经认知的可逆性。完成这个为期 5 年的指导奖项使申请人能够结合 围术期麻醉实践及OSA诱发分子机制的探索 海马体损伤。它为致力于提供信息的独立医师科学家铺平了道路 改善患有 OSA 的儿童的健康目标。