Neuronal injury after pediatric cardiac arrest, hypothermia, and rewarming

小儿心脏骤停、体温过低和复温后的神经元损伤

• 批准号: 8768053
• 负责人: Jennifer Kim Lee
• 金额: $ 19.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768053
• 关键词: Address; Adjuvant; Adverse effects; Advisory Committees; Anatomy; Anesthesiology; Apoptosis; Apoptotic; Asphyxia; Award; Basic Science; Biochemical; Birth trauma; Blood Vessels; Brain; Brain Injuries; Brain region; Cardiac; Caring; Caspase; Cell Death; Cell Death Signaling Process; Cerebrospinal Fluid; Cerebrovascular Physiology; Cessation of life; Child; Childhood; Clinical; Clinical Investigator Award; Clinical Research; Complement Activation; Critical Care; Data; Development; Development Plans; Endoplasmic Reticulum; Ensure; Environment; Equipment; Experimental Models; Family suidae; Funding; Generations; Guidelines; Heart Arrest; Homeostasis; Hypoxia; Hypoxic Brain Damage; Incidence; Infant; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Ischemia; Knowledge; Laboratories; Laboratory Research; Learning; Medicine; Mentors; Mentorship; Modeling; Monitor; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; Necrosis; Neonatal; Neurocognitive; Neurologic; Neurological outcome; Neuronal Injury; Neurons; Neurosciences; Oligodendroglia; Oxidative Stress; Pathway interactions; Patient Care; Physiological; Proteins; Randomized; Reactive Oxygen Species; Receptor Activation; Recording of previous events; Recovery; Research; Research Project Grants; Resuscitation; Rewarming; Risk; Role; Scientist; Seizures; Signaling Molecule; Techniques; Therapeutic; Therapeutic Effect; Therapeutic Uses; Thick; Time; Training; Training Programs; Translating; United States National Institutes of Health; Universities; Vulnerable Populations; Work; base; career development; caspase-3; cerebrovascular; clinically relevant; cytokine; disability; endoplasmic reticulum stress; experience; improved; inflammatory marker; inhibitor/antagonist; innovation; mortality; multidisciplinary; natural hypothermia; neonatal hypoxic-ischemic brain injury; neonatal resuscitation; neonate; neuron loss; neuroprotection; neurosurgery; pediatrician; prevent; programs; public health relevance; putamen; research and development; research study; response; skills; success; white matter

DESCRIPTION (provided by applicant): This K08 proposal describes a 5-year training program for Dr. Jennifer Lee. In this program, Dr. Lee will acquire laboratory and research skills that are essential for her success in academic medicine to enable her to obtain independent NIH funding in pediatric neuroprotection research. Candidate and Career Development Plan: Dr. Jennifer Lee, a pediatric anesthesiologist and pediatrician with formal training in pediatric critial care medicine, has studied cerebrovascular autoregulation in experimental neonatal models under the mentorship of Dr. Raymond Koehler since 2006. More recently, she extended her work to evaluate autoregulation in a model of pediatric hypoxic-asphyxic (HA) cardiac arrest, therapeutic hypothermia, and rewarming. She has translated her laboratory work to patient care by leading several clinical studies involving autoregulation monitoring and neurologic outcomes in neonates with hypoxic-ischemic encephalopathy (HIE), children resuscitated from cardiac arrest, and children undergoing neurosurgery. Thus far, her laboratory research has focused primarily on physiologic experiments of vascular reactivity. However, she has not had the opportunity to take formal coursework or study the biochemical, cellular, and mechanistic effects of therapeutic hypothermia and rewarming after HA brain injury. To continue her development as a clinician-scientist, Dr. Lee intends to study neuronal and oligodendrocyte cell death pathways, the unfolded protein response (UPR) that occurs with endoplasmic reticulum stress, oxidative stress, inflammation, and cortical injury after delayed hypothermia and different rates of rewarming in a clinically relevant model of HA cardiac arrest. This work will enable her to obtain more advanced technical skills that will make her more competitive in basic science research. Her coursework is timed to parallel her laboratory skill development and to address each Aim in her proposal. With the proposed career development and research plans, Dr. Lee will learn the skills necessary to become a successful clinician-scientist with independent NIH funding. Environment: The Johns Hopkins University (JHU) Department of Anesthesiology and Critical Care Medicine is well equipped to support Dr. Lee's research and career development with the K08 award. The Department is currently supporting her with 75% protected, non-clinical time for research. With the K08 award, she will continue to have this protected time. Her co-mentors, Dr. Raymond Koehler and Dr. Lee Martin, are world- renowned experts in cerebrovascular physiology, neuroprotection after hypoxic-ischemic injury, cell death mechanisms, and cellular neuroscience; they have long histories of NIH funding and successful mentoring of clinician-scientists. Dr. Lee also has an experienced, multidisciplinary advisory committee of experts in neuronal cell death mechanisms, hypoxic brain injuries, therapeutic hypothermia/rewarming, and pediatric resuscitation medicine to guide and support her research and career development. All equipment necessary to carry out the proposed experiments is accessible within her department. She will have the full support of her mentors, laboratory manager, and technicians to learn and perform the laboratory techniques outlined in the research plan. JHU has provided Dr. Lee with an environment that will ensure her success in the K08 program. Research Project: Despite the use of therapeutic hypothermia, neurologic morbidity remains high in neonatal HIE and after pediatric cardiac arrest. Experimental models of HA cardiac arrest have shown that therapeutic hypothermia decreases neuronal death from necrosis. However, preliminary laboratory data and clinical studies suggest that rewarming from hypothermia may shift neuronal and oligodendrocyte cell death from necrotic to apoptotic pathways and increase oxidative stress and inflammation, thus raising the risk of secondary brain injury. Moreover, preliminary data indicate that activation of the UPR from endoplasmic reticulum stress after a hypoxic insult may promote apoptosis in the white matter yet be neuroprotective in other regions of the brain. Aim 1 will determine whether rewarming and different rates of rewarming increase cortical neuroapoptosis, oligodendrocyte apoptosis, oxidative stress, inflammatory markers, seizures, and cortical injury after HA injury. Aim 2 will determine if caspase-3 inhibition prevents neuronal and oligodendrocyte cell death during rewarming, thus providing an adjuvant neuroprotective therapy. Aim 3 will determine if UPR activation from rewarming after HA injury induces white matter apoptosis but is neuroprotective in other anatomic regions; and whether modulation of the UPR response influences neuroprotection. Findings from this project will have important implications for pediatric and neonatal resuscitation guidelines. They will also provide a basis for further investigations of adjunct therapies to reduce the adverse effects of rewarming after pediatric cardiac arrest and HIE.

描述（由申请人提供）：本 K08 提案描述了 Jennifer Lee 博士的 5 年培训计划。在这个项目中，李博士将获得实验室和研究技能，这对于她在学术医学领域取得成功至关重要，使她能够在儿科神经保护研究方面获得独立的 NIH 资助。候选人和职业发展计划：Jennifer Lee 博士是一名儿科麻醉师和儿科医生，接受过儿科重症监护医学方面的正规培训，自 2006 年以来，在 Raymond Koehler 博士的指导下研究了实验性新生儿模型中的脑血管自动调节。最近，她扩展了自己的研究领域致力于评估儿童缺氧窒息（HA）心脏骤停、治疗性低温和复温模型中的自动调节。她通过领导多项涉及缺氧缺血性脑病 (HIE) 新生儿、心脏骤停复苏儿童和接受神经外科手术的儿童的自动调节监测和神经系统结果的临床研究，将实验室工作转化为患者护理。到目前为止，她的实验室研究主要集中在血管反应性的生理实验上。然而，她没有机会参加正式课程或研究 HA 脑损伤后低温治疗和复温的生化、细胞和机械效应。为了继续她作为一名临床医生科学家的发展，李博士打算研究神经元和少突胶质细胞死亡途径、未折叠蛋白反应（UPR），该反应是在延迟低温和不同的治疗后内质网应激、氧化应激、炎症和皮质损伤中发生的。临床相关的 HA 心脏骤停模型中的复温率。这项工作将使她获得更先进的技术技能，使她在基础科学研究中更具竞争力。她的课程作业时间安排与她的实验室技能发展并行，并解决她提案中的每个目标。通过拟议的职业发展和研究计划，李博士将学习成为一名成功的临床医生科学家所需的技能，并获得独立的 NIH 资助。环境：约翰·霍普金斯大学 (JHU) 麻醉学和重症监护医学系具备充分的条件来支持 Lee 博士的研究和职业发展，并授予 K08 奖。该部门目前为她提供 75% 受保护的非临床时间用于研究。有了K08奖，她将继续拥有这段受保护的时光。她的共同导师Raymond Koehler博士和Lee Martin博士是脑血管生理学、缺氧缺血性损伤后神经保护、细胞死亡机制和细胞神经科学领域的世界知名专家；他们拥有 NIH 资助和成功指导临床医生科学家的悠久历史。李博士还拥有一个经验丰富的多学科咨询委员会，由神经元细胞死亡机制、缺氧性脑损伤、治疗性低温/复温和儿科复苏医学领域的专家组成，以指导和支持她的研究和职业发展。进行拟议实验所需的所有设备都可以在她的部门内使用。她将得到导师、实验室经理和技术人员的全力支持，学习和执行研究计划中概述的实验室技术。 JHU 为李博士提供了一个确保她在 K08 项目中取得成功的环境。研究项目：尽管使用了低温治疗，但新生儿 HIE 和小儿心脏骤停后的神经系统发病率仍然很高。 HA 心脏骤停的实验模型表明，治疗性低温可减少神经元坏死死亡。然而，初步实验室数据和临床研究表明，低温复温可能会将神经元和少突胶质细胞死亡从坏死途径转变为凋亡途径，并增加氧化应激和炎症，从而增加继发性脑损伤的风险。此外，初步数据表明，缺氧损伤后内质网应激激活 UPR 可能会促进白质细胞凋亡，但对大脑其他区域具有神经保护作用。目标 1 将确定复温和不同复温速率是否会增加 HA 损伤后皮质神经细胞凋亡、少突胶质细胞凋亡、氧化应激、炎症标志物、癫痫发作和皮质损伤。目标 2 将确定 caspase-3 抑制是否可以防止复温期间神经元和少突胶质细胞死亡，从而提供辅助神经保护治疗。目标 3 将确定 HA 损伤后复温引起的 UPR 激活是否会诱导白质细胞凋亡，但对其他解剖区域具有神经保护作用； UPR 反应的调节是否影响神经保护。该项目的研究结果将对儿科和新生儿复苏指南产生重要影响。它们还将为进一步研究辅助疗法提供基础，以减少小儿心脏骤停和 HIE 后复温的不利影响。