Acute Brain Injury, Mechanisms and Consequences

急性脑损伤、机制和后果

• 批准号: 8122824
• 负责人: JOHN W OLNEY
• 金额: $ 24.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122824
• 关键词: Acute Brain Injuries; Address; Adult; Alcoholic Intoxication; Apoptosis; Apoptotic; Attention; Behavioral; Birth; Brain; Brain Hypoxia-Ischemia; Brain Mass; Cavia; Cell Death; Cells; Childhood; Craniocerebral Trauma; Development; Discipline of obstetrics; Ethanol; Exposure to; Fetal Alcohol Syndrome; Functional disorder; Funding; GABA Receptor; Glutamate Receptor; Grant; Human; Hyperactive behavior; Incidence; Infant; Ischemia; Learning Disorders; Major Depressive Disorder; Medicine; Molecular; Mus; N-Methylaspartate; Nerve Degeneration; Neurons; Pattern; Perinatal Brain Injury; Pharmaceutical Preparations; Pharmacological Treatment; Population; Property; Psychotic Disorders; Rattus; Role; Staging; Syndrome; Third Pregnancy Trimester; Time; Work; alcohol exposure; caspase-3; drug of abuse; neurobehavioral; neuropsychiatry; neurotoxic; prevent; receptor; synaptogenesis

This is an application for competing renewal of an RO1 grant which was funded for 3 years (11/1/98 - 10/31/01) to support studies aimed at clarfying the role(s) of excitotoxic and/or apoptotic cell death mechanisms in developmental (perinatal) brain injury associated with head trauma and hypoxia/ischemia. In addition to addressing these aims during the grant period, the PI has made the unanticipated discovery that during the synaptogenesis period of development transient ethanol intoxication triggers a massive wave of apoptotic neurodegeneration, deleting millions of neurons from many different regions of the developing rat, mouse or guinea pig brain. Our findings document that ethanol triggers apoptosis by a dual mechanism - blockade of NMDA glutamate receptors and excessive activation of GABAA receptors. We propose that our findings can help explain the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). Significance of this discovery is broadened by accompanying evidence that ethanol's neurotoxic properties are shared by numerous other agents that either block NMDA glutamate receptors or activate GABA^ receptors, and many of these agents are drugs of abuse and/or are used regularly in obstetric and pediatric medicine. An important feature of our findings is that within the synaptogenesis period (first 2 weeks after birth for rats and mice, but third trimester and first several years after birth for humans) different neuronal populations have different temporal patterns for responding to the apoptosis-inducing effects of these drugs. Thus, depending on the timing of exposure, different combinations of neuronal groups will be deleted, which signifies that this is a neurodevelopmental mechanism that can contribute to a wide spectrum of neuropsychiatric disturbances. Consistent with this interpretation is evidence that victims of FAS manifest not only childhood hyperactivity/attention deficit and learning disorders, but have a high incidence of adult onset psychiatric disturbances, including major depressive disorder and psychosis. The aims of this competing renewal proposal are threefold, the first being to continue exploring the role of excitotoxic and apoptotic mechanisms in ischemic neurodegeneration, and the second and third being to more fully characterize molecular, neuropathological and neurobehavioral aspects of the apoptotic neurodegenerative syndrome we have found can be induced in the developing mouse brain by transient exposure to ethanol during synaptogenesis.

这是竞争RO1赠款竞争的申请，该赠款已有3年（11/1/98-- 10/31/01）支持旨在阐明兴奋性和/或凋亡细胞死亡机制的作用的研究 与头部外伤和缺氧/缺血有关的发育（围产期）脑损伤。此外 在赠款期间，PI在赠款期间解决了这些目标，这是一个意外的发现 发育的突触发生瞬态乙醇中毒期会引发大量凋亡波 神经变性，从许多不同区域的大鼠，小鼠或 豚鼠大脑。我们的发现证明乙醇通过双重机制触发凋亡 - 阻塞 NMDA谷氨酸受体和GABAA受体的过度激活。我们建议我们的发现可以 帮助解释与人类胎儿相关的脑部质量减少和终身神经行为障碍 酒精综合征（FAS）。这一发现的重要性通过伴随的证据表明乙醇的意义扩大了 神经毒性特性由许多其他阻断NMDA谷氨酸受体或 激活GABA^受体，其中许多药物是滥用药物和/或定期用于产科和/或 小儿医学。我们发现的一个重要特征是在突触发生期内（头2周 大鼠和小鼠出生后，但第三个孕期和人类出生后的头几年）不同的神经元 种群具有不同的时间模式，以应对这些药物的凋亡诱导作用。 因此，根据暴露的时间，将删除神经元组的不同组合，这将被删除 表示这是一种神经发育机制，可以有助于广泛的神经精神病学 干扰。与这种解释一致的证据表明，FAS的受害者不仅表现出童年 多动症/注意力不足和学习障碍，但成人发作的发病率很高 干扰，包括重大抑郁症和精神病。该竞争更新提案的目的 是三倍，第一个是继续探索缺血性兴奋性和凋亡机制的作用 神经变性，第二和第三是分子，神经病理学和 我们发现的凋亡神经退行性综合征的神经行为方面可以在 突触发生过程中通过短暂暴露于乙醇来发展小鼠脑。