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研究培训计划，旨在支持 独立的医师科学家。申请人是麻醉与儿科的助理教授 贝勒医学院（BCM），并得到了杰出的临床和基本设施的支持 研究和指导。麻醉科保证了75％的保护时间， 指出机构优先级和充足的资源，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大初步数据，这些数据已由 申请人的两个竞争性研究奖：克莱顿奖和TCH麻醉师的资金 首席。基于多学科和交叉研究，申请人确定了六个高度 支持和成熟的科学家导师。该提案还概述了一个教育计划，其中包括 课程工作，基准和学术活动，以完成他的培训并促进独立性。小儿 阻塞性睡眠呼吸暂停（OSA）的发生率约为7％，有几个不愉快的后遗症，包括 神经认知功能障碍涉及行为，情绪抑制以及学习和记忆，未知 可逆性潜力。该建议旨在使用全面和 转化研究方法是开发一种新颖的小儿OSA临床前模型，该模型忠实地概括了 人类表型。结合人类多个学术和年轻的鼠血氧仪数据的组合我们 量化小儿OSA和年龄匹配的新生小鼠的神经认知变化。该提议将 检验以下假设，即OSA诱导产后海马的时间依赖性可逆变化 神经生物学，导致学习能力降低。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 发展大脑。 AIM 2将通过A）长期突触确定IH对海马的影响 海马切片的增强以询问突触功能，b）识别齿状回的细胞类型 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诱导的海马损伤的突触和细胞数据，3）可行性和决定因素 神经认知的可逆性。完成这项5年指导奖的完成允许申请人合并 围手术期麻醉实践，并探索OSA诱导的分子机制 海马伤害。它为一名独立医师科学家铺平了道路，致力于通知 改善了OSA儿童的健康目标。