MECHANISMS OF NEUROPROTECTION IN LIMBIC SYSTEM

简介(摘自申请者摘要)：研究和职业 本申请书中提出的发展计划将扩大申请人S 神经药理学和综合神经科学方面的专业知识，适用于 神经可塑性和神经保护作用的动物模型研究 神经精神障碍。建议的研究将利用 最近的观察表明，暴露在短暂的、高度可控的癫痫发作中会导致 通过低强度的电休克(ECS)，对 由不同的侮辱引起的神经细胞死亡这种效应伴随着 特异性神经营养因子在骨髓细胞中的显著诱导表达 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暴露的神经保护影响的组成部分。尤其是， 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治疗后的上调将在特定情况下进行评估 大鼠的大脑区域。具体目标将测试i)是否重复ECS 结果激活和/或增强bFGF和/或受体的生物合成 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 依赖碱性成纤维细胞生长因子和/或神经生长因子受体的激活；3)差异 谷氨酸受体表达的变化将伴随着bFGFs的变化 和/或4GF在反复ECS后的表达；以及4)在 谷氨酸受体的表达依赖于受体的激活 对于反复ECS后的bFGF和/或NGF。旨在继续进行的实验 这些具体目标将为申请者提供一个理想的机会来获得 理论和实践两方面的专业知识结合使用 药理学、生理学和神经组织学方法研究 动物模型。申请者在分子方法方面有很强的背景 体外实验将对体内发生的变化进行分析 完好无损的动物。职业发展计划将促进 转移申请者的研究能力和重点，使其 使申请者有可能建立独立的研究计划 致力于阐明决定易感性的分子机制 完整动物脑内神经细胞死亡。评估能力 治疗干预对完整动物模型的多因素影响 将为申请者进行动物模型研究做好准备 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方面的专门知识的发展 拟议学习和长期职业生涯所需的领域 将申请人提升为多才多艺的神经学家。

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.