Mitochondrial Dysfunction in Pediatric Head Injury

描述（由申请人提供）：创伤性脑损伤（TBI）后，未成熟的大鼠大脑经历许多继发性损伤，导致细胞死亡延迟。尽管大量证据表明线粒体是缺血性和兴奋性毒性神经细胞死亡和存活的主要介质，但线粒体参与成人TBI的研究相对较少，儿童TBI模型也没有报道。对未成熟大鼠脑的有限研究已经证明了许多已知的线粒体损伤介质的脆弱性，包括细胞内钙升高和氧化应激。线粒体改变也可以触发介导凋亡的caspase活性级联反应，这是一种程序性细胞死亡过程，在TBI中显得尤为重要。该研究的工作假设是，脑线粒体对代谢性酸中毒、钙升高、氧化应激和促凋亡蛋白的反应在儿童创伤性脑损伤后的神经化学、组织学和神经系统预后中起着不可或缺的作用。我们将使用临床相关的儿童TBI模型验证以下机制假设：1)TBI后早期线粒体损伤增加线粒体对细胞因子的敏感性，促进细胞凋亡或坏死细胞死亡级联反应。2)脑外伤后脑乳酸性酸中毒促进细胞色素c释放，这是由细胞膜通透性转变激活引起的线粒体肿胀所介导的。3)脑外伤后氧化应激导致线粒体功能障碍、细胞死亡和神经损伤。本研究将有助于确定未成熟动物脑外伤后线粒体损伤的分子机制。这可能为婴儿和儿童创伤性脑损伤后的神经保护确定新的靶点。本提案旨在为申请人提供研究经验和职业发展，特别是涉及急性脑损伤的治疗机制和治疗策略。马里兰大学的麻醉科和儿科以及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，并致力于促进这一领域有意义的当代研究。

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.