Mitochondrial Dysfunction in Pediatric Head Injury

小儿头部损伤中的线粒体功能障碍

• 批准号: 6800065
• 负责人: COURTNEY L ROBERTSON
• 金额: $ 16.85万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6800065
• 关键词: Bax gene /protein; apoptosis; brain circulation; brain injury; calcium metabolism; cytochrome c; disease /disorder model; enzyme activity; free radical oxygen; immunocytochemistry; juvenile animal; laboratory rat; lactic acidosis; membrane permeability; membrane potentials; mitochondrial disease /disorder; oxidative stress; pediatrics; pyruvate dehydrogenase

DESCRIPTION (provided by applicant): Following traumatic brain injury (TBI), the immature rat brain experiences many secondary insults that lead to delayed cell death. Although considerable evidence indicates that mitochondria are primary mediators of ischemic and excitotoxic neural cell death and survival, relatively little is known regarding mitochondrial involvement in adult TBI, and nothing has been reported for models of pediatric TBI. Limited studies of the immature rat brain have demonstrated vulnerability to many known mediators of mitochondrial injury, including elevated intracellular calcium and oxidative stress. Mitochondrial alterations can also trigger the cascade of caspase activities that mediate apoptosis, a process of programmed cell death that appears particularly important in TBI. The working hypothesis for the proposed study is that the response of brain mitochondria to metabolic acidosis, elevated calcium, oxidative stress, and pro-apoptotic proteins plays an integral role in the neurochemical, histologic, and neurologic outcome following pediatric TBI. We will test the following mechanistic hypotheses using a clinically relevant model of pediatric TBI: 1) Mitochondrial injury early after TBI increases the sensitivity of mitochondria to cellular factors that promote apoptotic or necrotic cell death cascades. 2) Cerebral lactic acidosis after TBI promotes cytochrome c release, mediated by mitochondrial swelling due to activation of the membrane permeability transition. 3) Oxidative stress following TBI contributes to mitochondrial dysfunction, cell death and neurologic injury. This study will help define the molecular mechanisms by which mitochondria are injured after TBI in immature animals. This may identify novel targets for neuroprotection following TBI in infants and children. This proposal is intended to provide for the research experience and career development of the applicant, specifically involving the mechanisms of, and therapeutic strategies for, the treatment of acute brain injury. The Departments of Anesthesiology and Pediatrics, and the Brain Injury and Neuroprotection Research Group at the University of Maryland will provide a rich environment for the study of experimental brain injury, and have a strong commitment to fostering meaningful and contemporary research in this field.

描述（由申请人提供）：在创伤性脑损伤（TBI）之后，未成熟的大鼠脑经历了许多次要损伤，导致细胞死亡延迟。尽管有大量证据表明线粒体是缺血性和兴奋性神经细胞死亡和生存的主要介体，但对于成人TBI的线粒体参与而言，相对较少，而小儿TBI模型没有任何报道。对未成熟大鼠脑的有限研究表明，对许多已知的线粒体损伤介质（包括细胞内钙和氧化应激）的脆弱性。线粒体的改变还可以触发介导凋亡的级联反应，这是一种在TBI中尤为重要的程序性细胞死亡过程。拟议研究的工作假设是，脑线粒体对代谢性酸中毒，钙，氧化应激升高和促凋亡蛋白的反应在儿科TBI后神经化学，组织学和神经系统结局中起着不可或缺的作用。我们将使用小儿TBI的临床相关模型检验以下机械假设：1）TBI后早期的线粒体损伤提高了线粒体对促进凋亡或坏死性细胞死亡级联反应的细胞因子的敏感性。 2）TBI后脑乳酸性酸中毒促进细胞色素C释放，这是由于膜通透性过渡的激活而导致线粒体肿胀介导的。 3）TBI后的氧化应激有助于线粒体功能障碍，细胞死亡和神经系统损伤。这项研究将有助于定义未成熟动物TBI后线粒体受伤的分子机制。这可以确定婴儿和儿童TBI后神经保护的新靶标。该建议旨在为申请人的研究经验和职业发展提供，特别是涉及急性脑损伤治疗的机制和治疗策略。麻醉和儿科的系，马里兰大学的脑损伤和神经保护研究小组将为实验性脑损伤提供丰富的环境，并有坚定的承诺，致力于在该领域培养有意义的现代研究。