Mitochondrial Dysfunction in Pediatric Head Injury

小儿头部损伤中的线粒体功能障碍

• 批准号: 6544206
• 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/6544206
• 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）后，未成熟的大鼠大脑经历许多导致延迟细胞死亡的二次损伤。虽然相当多的证据表明，线粒体是缺血性和兴奋性神经细胞死亡和存活的主要介质，相对较少的是已知的线粒体参与成人TBI，没有任何报道的儿科TBI模型。对未成熟大鼠大脑的有限研究已经证明了对许多已知的线粒体损伤介质的脆弱性，包括细胞内钙离子升高和氧化应激。线粒体的改变也可以触发介导凋亡的半胱天冬酶活性的级联反应，这是一种在TBI中显得特别重要的程序性细胞死亡过程。这项研究的工作假设是，脑线粒体对代谢性酸中毒、钙离子升高、氧化应激和促凋亡蛋白的反应在儿童TBI后的神经化学、组织学和神经学结果中起着不可或缺的作用。我们将使用儿科TBI的临床相关模型来测试以下机制假设：1）TBI后早期的线粒体损伤增加了线粒体对促进凋亡或坏死细胞死亡级联的细胞因子的敏感性。2)脑外伤后的乳酸酸中毒促进细胞色素c的释放，介导的线粒体肿胀由于激活膜通透性转换。3)TBI后的氧化应激导致线粒体功能障碍、细胞死亡和神经损伤。这项研究将有助于确定线粒体在未成熟动物TBI后受损的分子机制。这可能会发现新的目标，为脑外伤后的婴儿和儿童的神经保护。该提案旨在提供申请人的研究经验和职业发展，特别是涉及急性脑损伤治疗的机制和治疗策略。麻醉学和儿科学系以及马里兰州大学的脑损伤和神经保护研究小组将为实验性脑损伤的研究提供丰富的环境，并致力于促进该领域有意义的当代研究。