Mitochondrial Dysfunction in Pediatric Head Injury

描述(申请人提供)：创伤性脑损伤(TBI)后，未成熟的大鼠的大脑经历了许多二次伤害，导致延迟性细胞死亡。虽然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，但关于线粒体参与成人脑损伤的研究相对较少，而且还没有关于儿童脑损伤模型的报道。对未成熟大鼠脑的有限研究表明，线粒体损伤的许多已知介质易受影响，包括细胞内钙升高和氧化应激。线粒体的改变也可以触发caspase活性的级联，从而介导细胞凋亡，这是一个细胞程序性死亡的过程，在脑损伤中显得尤为重要。这项研究的工作假设是，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脑外伤后的神经化学、组织学和神经学结果中起着不可或缺的作用。我们将使用临床相关的儿童脑损伤模型来检验以下机制假说：1)脑损伤后早期线粒体损伤增加了线粒体对促进细胞凋亡或坏死性细胞死亡级联反应的细胞因子的敏感性。2)脑挫裂伤后脑乳酸酸中毒可促进细胞色素c的释放，其机制可能与激活膜通透性转换引起的线粒体肿胀有关。3)脑创伤后氧化应激导致线粒体功能障碍、细胞死亡和神经损伤。本研究将有助于明确幼年动物脑创伤后线粒体损伤的分子机制。这可能确定婴儿和儿童脑外伤后神经保护的新靶点。这项建议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的治疗机制和治疗策略。马里兰大学麻醉学和儿科学系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，并致力于促进该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.