Mitochondria as a target for protection against hypoxic-ischemic brain injury

线粒体作为预防缺氧缺血性脑损伤的靶标

• 批准号: 8111590
• 负责人: Vadim S Ten
• 金额: $ 20.03万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111590
• 关键词: Acceleration; Aconitate Hydratase; Adult; Animals; Antioxidants; Asphyxia; Attenuated; Bioenergetics; Biological; Birth; Brain; Brain Injuries; Cerebral Ischemia-Hypoxia; Cerebrum; Child; Clinical; Complex; Complication; Coupled; Data; Development; Disabled Persons; Disease; Electron Transport; Event; Exhibits; Failure; Generations; Glutathione Disulfide; Hyperoxia; Hypoxemia; Hypoxia; Infant; Injury; Ischemic Brain Injury; Ischemic-Hypoxic Encephalopathy; Life; Link; Measures; Metabolic; Mitochondria; Mitochondrial Matrix; Mus; NADH dehydrogenase (ubiquinone); Neonatal; Neurologic; Neuronal Injury; Oxidative Stress; Permeability; Process; Production; Reactive Oxygen Species; Recovery; Reperfusion Therapy; Research; Respiration; Respiratory Burst; Respiratory Chain; Role; Source; Stroke; Succinates; Testing; Therapeutic; Tissues; Translations; attenuation; base; cell injury; clinical practice; clinically relevant; design; disability; handicapping condition; improved; in vivo; inhibitor/antagonist; innovation; mitochondrial dysfunction; mitochondrial membrane; mouse model; neonatal hypoxic-ischemic brain injury; neuroprotection; novel; novel therapeutics; oxidative damage; prevent; restoration

DESCRIPTION (provided by applicant): It is estimated that 1.2 million infants die annually from birth asphyxia and its complication, hypoxic- ischemic (HI) brain injury. In U.S. neonatal HI-brain injury remains one of the major causes for a life-long neurological disability in children. This indicates an urgent need to develop therapeutic strategies based on a better understanding the mechanisms of HI injury in the developing brain. Mitochondrial dysfunction is the most fundamental biological event leading to neuronal injury in this disease. Although, mitochondrial complex-I (C-I) is severely inhibited by a HI insult, upon re-oxygenation/reperfusion the energy-generating function of C-I rapidly recovers. This reperfusion-driven re-activation of C-I is tightly linked to the generation of reactive oxygen species (ROS). We hypothesize that the inhibition of mitochondrial C-I recovery upon reperfusion represents a therapeutic strategy against an oxidative burst during early reperfusion. We show that compared to controls, mice exposed to C-I inhibitor, pyridaben exhibited significant attenuation of cerebral injury, despite a sluggish recovery of the C-I linked mitochondrial respiration. Mitochondria isolated from these pyridaben-exposed HI-mice demonstrated a limited acceleration in ROS production during reperfusion. This suggests that during reperfusion post-HI restoration of electron transport flow in the C-I contributes not only to cellular recovery, but also to cellular injury. Specific aims are designed to determine; Aim 1, whether an inhibition of the C-I recovery during reperfusion attenuates oxidative damage to mitochondrial matrix and as a result, increases mitochondrial tolerance to Ca++ induced opening of permeability transition pore (PTP). and Aim 2, whether hypoxemia during reperfusion slow down reactivation of mitochondrial C-I and whether this protects brain against reperfusion-driven oxidative stress Thus, the project is designed to establish both, mechanistic rationale and a clinical translation for an innovative therapeutic concept of a gradual metabolic recovery of the C-I directed against reperfusion-driven oxidative stress. PUBLIC HEALTH RELEVANCE: This proposal is focused to develop a novel therapeutic concept for protection of the ischemic brain against reperfusion-driven oxidative stress. Potential implication of this research is very broad, because an ischemic brain injury (stroke, hypoxic-ischemic encephalopathy) is a leading cause for neurological handicap in adults and children.

描述（由申请人提供）：据估计，每年有120万婴儿死于出生窒息及其并发症，缺氧缺血性（HI）脑损伤。在美国，新生儿HI-脑损伤仍然是儿童终身神经残疾的主要原因之一。这表明迫切需要开发治疗策略的基础上更好地了解HI损伤的机制，在发育中的大脑。线粒体功能障碍是导致神经元损伤的最基本的生物学事件。尽管线粒体复合物-I（C-I）被HI损伤严重抑制，但在再氧合/再灌注后，C-I的能量产生功能迅速恢复。这种再灌注驱动的C-I再激活与活性氧（ROS）的产生密切相关。我们推测，再灌注后线粒体C-I恢复的抑制代表了在早期再灌注期间对抗氧化爆发的治疗策略。我们发现，与对照组相比，暴露于C-I抑制剂的小鼠，哒螨灵表现出显着的脑损伤的衰减，尽管缓慢恢复的C-I连接的线粒体呼吸。从这些哒螨灵暴露的HI小鼠中分离的线粒体证明了再灌注期间ROS产生的有限加速。这表明，在再灌注后HI恢复的电子传递流在C-I不仅有助于细胞的恢复，但也对细胞损伤。具体目的是为了确定：目的1，是否在再灌注期间抑制C-I恢复减弱线粒体基质的氧化损伤，并因此增加线粒体对Ca++诱导的通透性转换孔（PTP）开放的耐受性。和目标2，再灌注期间的低氧血症是否减缓线粒体C-I的再活化，以及这是否保护脑免受再灌注驱动的氧化应激。因此，该项目被设计为建立针对再灌注驱动的氧化应激的C-I的逐渐代谢恢复的创新治疗概念的机械原理和临床转化。 公共卫生关系：该建议的重点是开发一种新的治疗概念，用于保护缺血性脑免受再灌注驱动的氧化应激。这项研究的潜在意义是非常广泛的，因为缺血性脑损伤（中风，缺氧缺血性脑病）是成人和儿童神经障碍的主要原因。