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: 3410271
• 负责人: JOHN B SCHWEITZER
• 金额: $ 5.67万
• 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 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3410271
• 关键词: Alzheimer's disease; autoradiography; hippocampus; histochemistry /cytochemistry; immunoconjugates; laboratory mouse; laboratory rat; monoclonal antibody; neurochemistry; neuronal transport; neurons; neuropil; neurotrophic factors; nicotinic receptors; prosencephalon; radiotracer; receptor mediated endocytosis; toxin; tritium

This study will explore the surprising observation that, when injected into the lateral ventricle of the rat, both nerve growth factor (NGF) and a monoclonal antibody directed against the NGF receptor, IgG 192, are transported bilaterally to numerous neurons with topographic and morphologic characteristics of the cholinergic basal forebrain (CBF) system. The data indicated that the observed phenomenon is receptor-mediated, and it presumably represents intra-axonal retrograde transport. The present proposal has 3 major specific aims: 1) Thorough characterization of this phenomenon using radiolabeled NGF and IgG 192 in autoradiographic experiments and native IgG 192 in standard immunohistochemical experiments. Data will be obtained regarding the time course and relative efficiency of the accumulation of NGF and IgG 192 in neurons, in terminal fields and potentially at the portal of entry into neuropil. Choline acetyltransferase (CAT) immunohistochemistry will be used to confirm the putative cholinergic nature of the labeled neurons and to map the population of CBF neurons involved in the transport process; 2) other peptides and immunoglobulins will be radiolabeled and their ability to undergo similar transport will be assessed; 3) an already synthesized specific hybrid toxin, IgG 192 coupled to the A subunit of ricin toxin, will be injected into the rat lateral ventricle and its ability to produce a cholinergic deficit will be evaluated by morphologic and biochemical means. The CBF is one of the primary sites of neuronal degeneration in Alzheimer's disease (AD), and NGF has been shown to greatly decrease the cell death observed in CBF neurons following axotomy. If funded, this proposal will explore the extent to which NGF or other ligands that recognize the NGF receptor can be injected into cerebrospinal fluid (CSF) and reach the CBF in a specific manner. This will have important implications with regard to: 1) the potential administration of NGF or other drugs to a population of neurons of critical importance in AD by the relatively simple means of injections into the CSF; 2) the possible exposure of CBF neurons to pathologic agents that gain access to CSF, and; 3) the creation of an animal model of forebrain cholinergic deficit using a specific toxin that offers potentially superior specificity when compared to more classical lesioning techniques.

这项研究将探索令人惊讶的观察结果，即当 注射入大鼠侧脑室，均有神经生长 NGF 因子和针对 NGF 的单克隆抗体 受体 IgG 192 被双边转运到许多神经元 具有地形和形态特征 胆碱能基底前脑（CBF）系统。 数据表明 观察到的现象是受体介导的，并且可能 代表轴突内逆行运输。 现在的 该提案有 3 个主要具体目标：1) 全面表征 第 192 章 放射自显影实验和标准中的天然 IgG 192 免疫组织化学实验。 将获得数据 关于时间进程和相对效率 NGF 和 IgG 192 在神经元末端区域积聚 并可能位于神经毡的入口处。 胆碱 乙酰转移酶（CAT）免疫组织化学将用于 确认标记神经元的假定胆碱能性质，并且 绘制参与运输的 CBF 神经元群图 过程; 2) 其他肽和免疫球蛋白将是 放射性标记及其进行类似运输的能力将 评估； 3) 已经合成的特定混合毒素，IgG 192 与蓖麻毒素的 A 亚基偶联，将被注射到 大鼠侧脑室及其产生胆碱能的能力 缺陷将通过形态学和生化手段进行评估。 CBF是神经元变性的主要部位之一 阿尔茨海默氏病 (AD) 和 NGF 已被证明对 减少 CBF 神经元中观察到的细胞死亡 轴切术。 如果获得资助，该提案将探讨在多大程度上 NGF或识别NGF受体的其他配体可以是 注射到脑脊液（CSF）中并在一定时间内到达CBF 具体方式。 这将产生重要影响 关于：1) NGF 或其他药物的潜在施用 对 AD 中至关重要的神经元群体 脑脊液注射方法相对简单； 2）可能的 CBF 神经元暴露于病理因子，从而获得 脑脊液，和； 3）前脑动物模型的建立 使用特定毒素的胆碱能缺陷可能提供 与更经典的损伤相比具有更高的特异性 技术。