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: 8850919
• 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/8850919
• 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; Health; 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; 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）：这份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，这对她在学术医学上的成功至关重要，使她能够获得独立的NIH资助，进行儿科神经保护研究。候选人和职业发展规划：Jennifer Lee博士，儿科麻醉师和儿科医生，接受过儿科重症医学的正规培训，自2006年以来在Raymond Koehler博士的指导下研究实验性新生儿模型的脑血管自动调节。最近，她扩展了她的工作，以评估儿童缺氧-窒息（HA）心脏骤停，治疗性低温和复温模型中的自我调节。她将自己的实验室工作转化为患者护理，领导了几项临床研究，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我调节监测和神经系统预后。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的课程，也没有机会研究HA脑损伤后治疗性低温和复温的生化、细胞和机制影响。为了继续她作为临床科学家的发展，Dr. Lee打算在HA心脏骤停的临床相关模型中研究神经元和少突胶质细胞死亡途径，延迟性低温和不同复温率后发生的内质网应激、氧化应激、炎症和皮质损伤的未折叠蛋白反应（UPR）。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方面更具竞争力。她的课程安排与她的实验室技能发展相匹配，并在她的提案中解决每个目标。通过提出的职业发展和研究计划，李博士将学习必要的技能，成为一名成功的临床科学家，拥有独立的NIH资助。环境：约翰霍普金斯大学（JHU）麻醉学和重症医学系装备良好，以K08奖支持李博士的研究和职业发展。该部门目前为她提供75%的非临床研究保护时间。有了K08奖，她将继续拥有这种受保护的时间。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；他们长期为NIH提供资金，并成功地指导了临床科学家。她还拥有一个由神经细胞死亡机制、缺氧脑损伤、治疗性低温/复温和儿科复苏医学专家组成的经验丰富的多学科咨询委员会，以指导和支持她的研究和职业发展。在她的部门内可以获得进行拟议实验所需的所有设备。她将得到她的导师、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：尽管使用了治疗性低温，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，初步的实验室数据和临床研究表明，低温后的再升温可能使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引起的UPR激活可能促进白质细胞凋亡，但对大脑其他区域具有神经保护作用。目的1将确定复温和不同复温率是否会增加血凝素损伤后皮质神经凋亡、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。目的2将确定caspase-3抑制是否能在升温过程中防止神经元和少突胶质细胞死亡，从而提供一种辅助神经保护治疗。目的3将确定血凝素损伤后再加热的UPR激活是否诱导白质凋亡，但在其他解剖区域具有神经保护作用；以及UPR反应的调节是否影响神经保护。这个项目的发现将对儿科和新生儿复苏指南有重要意义。这也将为进一步研究辅助疗法以减少小儿心脏骤停和HIE后复温的不良反应提供基础。