Metabolic Dysfunction and Neuroprotection after Pediatric Head Injury

小儿头部受伤后的代谢功能障碍和神经保护

• 批准号: 8624716
• 负责人: Susanna Scafidi
• 金额: $ 19.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624716
• 关键词: Acute Brain Injuries; Address; Aerobic; Animal Model; Apoptosis; Astrocytes; Basic Science; Biochemical; Biochemical Reaction; Bioenergetics; Brain; Brain Injuries; Brain region; Bypass; Cause of Death; Cell Death; Cells; Cerebral hemisphere; Cerebrum; Cessation of life; Child; Childhood; Childhood Injury; Citric Acid Cycle; Clinical; Cognitive; Collaborations; Contralateral; Control Animal; Craniocerebral Trauma; Critical Care; Data; Depressed mood; Development; Diffusion Magnetic Resonance Imaging; Doctor of Medicine; Doctor of Philosophy; Dose; Drug vehicle; Early treatment; Energy Metabolism; Environment; Enzyme Inhibition; Enzymes; Experimental Designs; Exposure to; Faculty; Failure; Foundations; Functional disorder; Glucose; Glycolysis; Goals; Head; Hippocampus (Brain); Histopathology; Hydroxybutyrates; Immunohistochemistry; Impairment; Interdisciplinary Study; Investigation; Ketones; Label; Laboratories; Lesion; Levocarnitine Acetyl; Life; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maryland; Measurement; Mediating; Mentors; Mentorship; Metabolic; Methods; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Motor; NMR Spectroscopy; Neurologic; Neurological outcome; Neurons; Oxidative Phosphorylation; Oxidative Stress; Pharmaceutical Preparations; Postdoctoral Fellow; Principal Investigator; Production; Program Development; Publishing; Pyruvate; Pyruvate Carboxylase; Pyruvate Dehydrogenase Complex; Pyruvate Metabolism Pathway; Rattus; Reaction; Recording of previous events; Recovery; Research; Research Personnel; Respiration; Scientist; Spectrum Analysis; Techniques; Testing; Time; Training; Training Programs; Translating; Trauma; Traumatic Brain Injury; United States; Universities; Walking; behavior test; brain cell; career; controlled cortical impact; design; disability; enzyme activity; experience; gamma-Aminobutyric Acid; graduate student; immunoreactivity; improved; in vivo; injured; medical schools; mitochondrial dysfunction; morris water maze; mortality; neurobehavioral; neurochemistry; neuronal survival; neuropathology; neuroprotection; neurotransmitter biosynthesis; novel; object recognition; pediatric traumatic brain injury; public health relevance; pyruvate dehydrogenase; sham surgery; skills

DESCRIPTION (provided by applicant): This K08 proposal describes a 5-year training program for the development of an academic career in pediatric traumatic brain injury research. The overall objective for the Principal Investigator (PI), Susanna Scafidi, M.D., is to fully develop the scientific skill-set necessary to become an independent investigator focusing on new metabolic approaches to treating traumatic brain injury in children. The training program is designed to enable the PI to apply biochemical, cellular and molecular investigations to delineate mechanisms of metabolic dysfunction associated with pediatric traumatic brain injury. Gary Fiskum, Ph.D. the primary mentor; is an expert in mitochondrial bioenergetics, oxidative stress, and apoptosis following acute brain injury and has trained numerous junior faculty, postdoctoral fellows and graduate students. Alan Faden is a clinician-scientist with vast track record of studying brain trauma; Mary McKenna, Ph.D. is an internationally recognized expert in brain energy metabolism and brain development, and has a strong history of successful mentorship. In addition, advisory oversight committee of distinguished researchers will provide career guidance and scientific support. The University of Maryland School of Medicine offers a superb environment for basic science research as well as multidisciplinary collaborations. The training program consists of combination of specific didactic coursework, practical experimental techniques, experimental design and data interpretation. The research plan of this proposal is designed to elucidate specific alterations in aerobic brain energy metabolism after brain injury in developing brain and evaluate possible neuroprotective strategies. Traumatic brain injury (TBI) is the leading cause of pediatric morbidity and mortality, yet, there is no specific treatment and a significant number of head-injured children suffer from life-long disabilities. TBI is characterized by inhibition of cerebral aerobic energy metabolism, but the underlying mechanisms for cerebral energy failure are not well understood. Our findings suggest that energy failure post TBI is due to specific mitochondrial enzymes impairment, which precludes pyruvate, generated via glycolysis, from being utilized in the mitochondria for energy production. In addition to glucose, the developing brain can utilize alternative substrates, i.e. 2-hydroxybutyrate (BHB) and acetyl-L-carnitine (ALCAR), that bypass the inhibition of pyruvate metabolism. We hypothesize that (1) inhibition of cerebral aerobic energy metabolism after TBI is due to dysfunction of pyruvate dehydrogenase, astrocytic pyruvate carboxylase and (2) that exposure to pharmacologic levels of BHB and ALCAR will maintain cerebral oxidative energy metabolism and inhibit cell death. These hypotheses will be tested using a controlled cortical impact model of traumatic brain injury in immature 21-22 day old rats. Methods of approach to the Specific Aims needed to test these hypotheses include the use of animal models, behavioral tests, quantitative histopathology, immunohistochemistry, enzyme activity measurements, ex vivo NMR spectroscopy, state of the art in vivo Magnetic resonance imaging (MRI) and Magnetic resonance spectroscopy (MRS) and other methods in collaboration with the mentors will provide the PI with a broad experience in laboratory techniques that will greatly promote the candidate's career as a clinician/investigator in the field of pediatric critical care. PUBLIC HEALTH RELEVANCE: TBI is a leading cause of death and long-term disability in children in United States. The proposed studies aim to determine the cell specific metabolic changes occur after brain trauma in developing brain. The studies will also assess whether the natural capability of developing brain to use alternative substrates for energy may provide neuroprotection if these substrates are administered in pharmacologic doses shortly after TBI.

描述（由申请人提供）：本K 08提案描述了一个为期5年的培训计划，用于发展儿科创伤性脑损伤研究的学术生涯。主要研究者（PI）Susanna Scafidi，M.D.的总体目标，是充分发展必要的科学技能，成为一个独立的研究者，专注于新的代谢方法来治疗儿童创伤性脑损伤。该培训计划旨在使PI能够应用生化，细胞和分子研究来描述与小儿创伤性脑损伤相关的代谢功能障碍机制。加里·菲斯库姆博士第一导师;是线粒体生物能量学、氧化应激和急性脑损伤后细胞凋亡方面的专家，并培训了许多初级教师、博士后研究员和研究生。艾伦·法登是一位临床科学家，在研究脑创伤方面有着丰富的记录;玛丽·麦肯纳博士。是国际公认的大脑能量代谢和大脑发育方面的专家，并拥有成功的指导历史。此外，由杰出研究人员组成的咨询监督委员会将提供职业指导和科学支持。马里兰州大学医学院为基础科学研究和多学科合作提供了极好的环境。该培训计划包括具体的教学课程，实用的实验技术，实验设计和数据解释相结合。本研究计划旨在阐明发育中脑损伤后有氧脑能量代谢的特定变化，并评估可能的神经保护策略。创伤性脑损伤（TBI）是儿科发病率和死亡率的主要原因，然而，没有特定的治疗方法，大量头部受伤的儿童终身残疾。TBI的特点是脑有氧代谢的抑制，但脑能量衰竭的潜在机制还不清楚。我们的研究结果表明，TBI后的能量衰竭是由于特定的线粒体酶损伤，这排除了丙酮酸，通过糖酵解产生，从被利用在线粒体中的能量生产。除了葡萄糖，发育中的大脑可以利用替代底物，即2-羟基丁酸（BHB）和乙酰-L-肉毒碱（ALCAR），绕过丙酮酸代谢的抑制。我们假设：（1）TBI后大脑有氧能量代谢的抑制是由于丙酮酸脱氢酶、星形胶质细胞丙酮酸羧化酶功能障碍所致;（2）暴露于药理学水平的BHB和ALCAR将维持大脑氧化能量代谢并抑制细胞死亡。将使用未成熟的21-22日龄大鼠中创伤性脑损伤的受控皮质撞击模型来测试这些假设。测试这些假设所需的特定目标的方法包括使用动物模型、行为测试、定量组织病理学、免疫组织化学、酶活性测量、离体NMR光谱学，体内磁共振成像（MRI）和磁共振波谱（MRS）的最新技术水平以及与导师合作的其他方法将为PI提供实验室技术方面的广泛经验，这将极大地促进候选人作为临床医生的职业生涯。儿科重症监护领域的调查员。 公共卫生相关性：TBI是美国儿童死亡和长期残疾的主要原因。这些研究旨在确定发育中的脑损伤后发生的细胞特异性代谢变化。这些研究还将评估发育中的大脑使用替代底物作为能量的自然能力是否可以提供神经保护，如果这些底物在TBI后不久以药理学剂量施用的话。