NERVE GROWTH FACTOR RECEPTOR-MEDIATED TRANSPORT IN CNS

中枢神经系统中神经生长因子受体介导的转运

• 批准号: 3410269
• 负责人: JOHN B SCHWEITZER
• 金额: $ 11.41万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3410269
• 关键词: Alzheimer's disease; acetylcholine; biological transport; cell type; disease /disorder model; electroencephalography; experimental brain lesion; growth factor receptors; immunocytochemistry; immunotoxicity; laboratory mouse; laboratory rat; locus coeruleus; mesencephalon; model design /development; monoclonal antibody; nervous system disorder; neuritic plaques; neurofibrillary tangles; neuronal transport; neurons; neurotoxins; neurotrophic factors; prosencephalon; suprachiasmatic nucleus

A monoclonal antibody which recognizes the rat NGF receptor (MAB 192) has been shown following intraventricular injection to be internalized and transported specifically and bilaterally to most of the neurons of the cholinergic basal forebrain (CBF). The functional properties of the CBF are not well understood, partly because it is a diffuse system which has not, until now, been amenable to specific experimental manipulation, but it is implicated in learning, memory, and the regulation of sleep patterns. the CBF is one of the major sites of neuronal degeneration, and loss of cholinergic markers is one of the most consistent and severe neurochemical deficits in Alzheimer's disease (AD). The major goal of this proposal is to create an animal model of forebrain cholinergic deficit by the intraventricular delivery to the CBF of MAB 192 linked to a ribosome inactivating protein, saporin; this immunotoxin (IT) offers potentially superior specificity when compared with classical lesioning techniques. This toxin has been synthesized and delivered intraventricularly and in preliminary experiments shows clear evidence of major toxicity to NGF receptor-bearing cholinergic neurons; adjacent (and distant) non-NGF receptor-bearing, cholinergic neurons are unaffected. The animal model will be evaluated by morphological, biochemical, and behavioral techniques. The following is proposed toward the goal of using an IT to create a rat model of forebrain cholinergic deficit: 1) Preparing the IT's in sufficient quantities to use in vivo and establishing the dose and mode of intraventricular injection which will optimize the production of a forebrain cholinergic deficit, as judged by morphological and biochemical criteria. This will include studies designed to show whether actual neuron death, as opposed to loss of cholinergic phenotype, is produced by the IT; 2) Examining other brain regions [both non-cholinergic but NGF receptor (+) areas, cholinergic regions which are NGF receptor (-), and an unrelated system, that of the n. locus ceruleus] using similar methods to assess the specificity of the damage produced by the IT; 3) Evaluating behavioral deficits in learning, memory, and sleep patterns in rats with a well- characterized, IT-induced forebrain cholinergic deficit. This animal model will ultimately allow the investigation of the function of the CBF by examining the deficits (morphological, biochemical, behavioral) created by deletion of the system; the potential contribution of cholinergic deficits to the observed derangements in AD can also be assessed.

识别大鼠 NGF 受体 (MAB 192) 的单克隆抗体具有 已显示脑室内注射后被内化并 特异性地双向转运至大部分神经元 胆碱能基底前脑（CBF）。 CBF的功能特性 还没有被很好地理解，部分原因是它是一个分散的系统 到目前为止，尚不适合特定的实验操作，但它 与学习、记忆和睡眠模式的调节有关。 CBF是神经元变性和丧失的主要部位之一 胆碱能标记物是最一致和最严重的神经化学物质之一 阿尔茨海默病（AD）的缺陷。 该提案的主要目标是 创建前脑胆碱能缺陷的动物模型 脑室内将与核糖体相连的 MAB 192 递送至 CBF 失活蛋白、皂草素；这种免疫毒素（IT）可能提供 与经典损伤技术相比具有更高的特异性。 该毒素已在心室内合成并递送 初步实验显示出对 NGF 有重大毒性的明确证据 携带受体的胆碱能神经元；邻近（和远处）非 NGF 携带受体的胆碱能神经元不受影响。 动物模型 将通过形态学、生化和行为技术进行评估。 为实现利用IT创造老鼠的目标，提出以下建议 前脑胆碱能缺陷模型：1）准备IT 足够的体内使用量并确定剂量和模式 脑室内注射，这将优化 通过形态学和生化判断，前脑胆碱能缺陷 标准。 这将包括旨在证明实际神经元是否存在的研究 与胆碱能表型丧失相反，死亡是由 IT 造成的； 2) 检查其他脑区[均为非胆碱能但NGF受体(+) NGF 受体 (-) 区域、胆碱能区域以及一个不相关的区域 系统，n的系统。蓝斑]使用类似的方法来评估 IT 造成的损害的特殊性； 3）评估行为 健康状况良好的老鼠在学习、记忆和睡眠模式方面存在缺陷 其特征是 IT 引起的前脑胆碱能缺陷。 这个动物模型 最终将允许通过以下方式调查 CBF 的功能 检查由以下因素造成的缺陷（形态学、生化、行为） 删除系统；胆碱能缺陷的潜在贡献 还可以评估 AD 中观察到的紊乱。