MECHANISMS OF NEUROPROTECTION IN LIMBIC SYSTEM

边缘系统的神经保护机制

• 批准号: 6849727
• 负责人: ALEXEI D KONDRATYEV
• 金额: $ 17.11万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-15 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6849727
• 关键词: RNase protection assay; brain mapping; electroconvulsive therapy; fibroblast growth factor; gene expression; generalized seizures; glutamate receptor; growth factor receptors; histochemistry /cytochemistry; laboratory rat; limbic system; microelectrodes; molecular genetics; nerve growth factors; neural degeneration; neural plasticity; neuropharmacologic agent; neuropharmacology; neurophysiology; neuroprotectants; neutralizing antibody; nonhuman therapy evaluation; phosphorylation; receptor coupling; receptor expression; western blottings

DESCRIPTION (adapted from applicant's abstract): The research and career development plans proposed in this application will expand the applicant s expertise into neuropharmacology and integrative neuroscience as applied to studies of neuroplasticity and neuroprotection in animal models of neuropsychiatric disorders. The studies proposed will take advantage of the recent observation that exposure to brief, highly controlled seizures induced by low-intensity eLeciroconvulsive shock (ECS), confer a marked resistance to neuronal cell death induced by diverse insults This effect is accompanied by a marked induction of expression of specific neurotrophic factors in lhnbic system regions. The working hypothesis for the proposed studies is that enhanced receptor-mediated actions of the neurotrophic factors are a crucial component of the neuroprotective influence of ECS exposure. In particular, the extent to which receptors for two major neurotrophic factors, basic fibroblast growth factor (bFGF) and nerve growth factor (NGF), become activated and/or upregulated following repeated ECS treatment will be evaluated in specific brain areas of rats. The Specific Aims will test whether I) repeated ECS results in activation and/or enhanced biosynthesis of receptors for bFGF and NGF in limbic system regions; 2) the neuroprotective action of repeated ECS is dependent upon activation of receptors for bFGF and/or NGF; 3) differential changes in expression of glutamate receptors will accompany the changes in bFGF and/or 4GF expression following repeated ECS; and 4) differential changes in expression of glutamate receptors are dependent upon activation of receptors for bFGF and/or NGF following repeated ECS. The experiments designed to pursue these Specific Aims will provide an ideal opportunity for the applicant to gain both theoretical and practical expertise in the combined use of pharmacological, physiological and neurohistological approaches to the study of animal models. The applicant's strong background in molecular approaches in vitro will be brought to bear on an analysis of changes occurring in vivo in the intact animal. The career development plan will facilitate a substantial shift in the applicant's research capabilities and focus, so that it will become possible for the applicant to build an independent research program devoted to elucidating molecular mechanisms that determine vulnerability to neuronal cell death in the brain of the intact animal. The ability to evaluate the multifactorial impact of therapeutic interventions in intact animal models will prepare the applicant to pursue research on animal models of neuropsychiatric disorders and place his molecular skills in the context of neurohistopathogy, pharmacology, anatomy and physiology. Structured mentored activities and short courses will guide the development of expertise in these areas necessary for the proposed studies and for the long-term career advancement of the applicant as a versatile neuroscientist.

描述（改编自申请人的摘要）：研究和职业生涯 本申请书所建议的发展计划， 神经药理学和综合神经科学的专业知识， 神经可塑性和神经保护的动物模型研究 神经精神障碍拟议的研究将利用 最近的观察表明，暴露于短暂的，高度控制的癫痫发作诱导 低强度电惊厥性休克（ECS），赋予对 不同损伤诱导的神经元细胞死亡这种效应伴随着神经元细胞死亡。 特异性神经营养因子在脑内表达的显著诱导 系统区域。拟议研究的工作假设是， 增强受体介导的神经营养因子的作用是至关重要的， ECS暴露的神经保护作用的组成部分。特别是 两种主要神经营养因子，碱性成纤维细胞 生长因子（bFGF）和神经生长因子（NGF），变得活化和/或 在重复ECS治疗后的上调将在特定的 老鼠的大脑区域具体目标将测试I）是否重复ECS 导致bFGF受体的激活和/或增强的生物合成， 神经生长因子在边缘系统区域; 2）重复ECS的神经保护作用是 依赖于bFGF和/或NGF受体的激活; 3）差异 谷氨酸受体表达的变化将伴随bFGF的变化， 和/或4GF表达的差异变化;和 谷氨酸受体的表达依赖于受体的激活 bFGF和/或NGF在重复ECS后的变化。这些实验旨在 这些具体目标将为申请人提供一个理想的机会， 在理论和实践的专业知识相结合的使用， 药理学、生理学和神经组织学方法来研究 动物模型申请人在分子方法方面的强大背景， 将在体外对体内发生的变化进行分析， 完整的动物。职业发展计划将促进 改变申请人的研究能力和重点，使其 使申请人有可能建立一个独立的研究计划 致力于阐明分子机制，决定脆弱性， 完整动物脑中的神经元细胞死亡。评估能力 在完整动物模型中治疗干预的多因素影响 将准备申请人进行动物模型的研究， 神经精神疾病，并将他的分子技能放在 神经组织病理学、药理学、解剖学和生理学。结构化指导 活动和短期课程将指导这些领域的专门知识的发展， 建议的研究和长期职业所需的领域 申请人作为一个多才多艺的神经科学家的进步。

项目成果

Phosphorylation of histone H2A.X as an early marker of neuronal endangerment following seizures in the adult rat brain.

• DOI: 10.1523/jneurosci.0092-11.2011
• 发表时间: 2011-05-25
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Crowe SL;Tsukerman S;Gale K;Jorgensen TJ;Kondratyev AD
• 通讯作者: Kondratyev AD