MECHANISMS OF NEUROPROTECTION IN LIMBIC SYSTEM

边缘系统的神经保护机制

• 批准号: 6499221
• 负责人: ALEXEI D KONDRATYEV
• 金额: $ 16.11万
• 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 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6499221
• 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 本申请中提出的发展计划将扩大申请人的范围 神经药理学和综合神经科学的专业知识应用于 动物模型的神经可塑性和神经保护研究 神经精神疾病。拟议的研究将利用 最近的观察表明，短暂的、高度控制的癫痫发作会诱发 通过低强度电子惊厥休克（ECS），赋予显着的抵抗力 由不同的损伤引起的神经元细胞死亡这种效应伴随着 显着诱导 lhnbic 中特定神经营养因子的表达 系统区域。拟议研究的工作假设是 增强神经营养因子的受体介导作用是至关重要的 ECS 暴露的神经保护影响的组成部分。特别是， 两种主要神经营养因子（碱性成纤维细胞）的受体程度 生长因子（bFGF）和神经生长因子（NGF）被激活和/或 重复 ECS 治疗后上调将在具体评估 大鼠的大脑区域。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 边缘系统区域的 NGF； 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）微分 谷氨酸受体表达的变化将伴随bFGF的变化 和/或重复 ECS 后的 4GF 表达； 4）差异变化 谷氨酸受体的表达取决于受体的激活 重复 ECS 后用于 bFGF 和/或 NGF。实验旨在追求 这些具体目标将为申请人提供理想的机会 结合使用理论和实践专业知识 药理学、生理学和神经组织学方法的研究 动物模型。申请人在分子方法方面具有深厚的背景 体外将用于分析体内发生的变化 完整的动物。职业发展计划将促进实质性 申请人的研究能力和重点发生转变，以便 申请人有可能建立独立的研究计划 致力于阐明决定脆弱性的分子机制 完整动物大脑中的神经元细胞死亡。评估能力 完整动物模型中治疗干预的多因素影响 将为申请人进行动物模型研究做好准备 神经精神疾病并将他的分子技能置于 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业知识的发展 拟议研究和长期职业生涯所需的领域 申请人作为多才多艺的神经科学家的进步。