NEUROTROPHIC FACTOR AND NEUROTRANSMITTER REPLACEMENT

神经营养因子和神经递质替代

• 批准号: 6548542
• 负责人: FRED H GAGE
• 金额: $ 18.38万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6548542
• 关键词: Alzheimer's disease; Lentivirus; acetylcholine; aging; amyloid proteins; animal old age; behavior test; choline acetyltransferase; cognition disorders; disease /disorder model; gene delivery system; gene therapy; genetically modified animals; laboratory mouse; laboratory rat; nerve growth factors; neural degeneration; neurogenesis; neuroprotectants; neurotransmitter metabolism; nonhuman therapy evaluation; transfection /expression vector

In Project 1 we aim to therapeutically deliver trophic factors or neurotransmitter enzymes to protect against age-related dysfunctions found in aged rats or transgenic mouse models of Alzheimer's disease. The degeneration of cholinergic neurons is one of the most consistent findings in AD. We propose to use viral vectors to investigate therapeutic approaches of direct gene delivery to animal models of AD primarily focused on lentiviral vectors. Three complementary strategies will be developed to reverse the morphological and behavior deficits associated with aging in normal aged rats and a transgenic mouse model of AD. The first strategy is to restore function using ChAT to replace or supplement depleted acetylcholine in aged rats. The second strategy places the emphasis on neuroprotection using the NGF gene and product to protect ChAT neurons from age related death, and enhance the function of the remaining neurons. A progression within these two strategies from constitutive to regulatable expression will be made as we improve our lentiviral vectors. The third strategy focuses on the interplay between amyloid precursor protein (APP), and the cholinergic system. Lentiviral factors delivering either NGF or ChAT will be injected into the hippocampus of transgenic animals over expressing APP to elucidate whether the cholinergic system regulates amyloid processing, alters plaque formation, or may improve behavioral performance. Functional and anatomical effects of direct gene delivery of choline acetyltransferase (ChAT) and nerve growth factor (NGF) to the aged brain have not been evaluated. Using lentiviral vectors, we can deliver these molecules to discrete populations of cells within the central nervous system (CNS), measuring the effects of direct (ChAT), or indirect (NGF) cholinergic enhancement on cognition, neuronal and synaptic changes, and amyloid processing.

在项目 1 中，我们的目标是治疗性地传递营养因子或神经递质酶，以防止老年大鼠或阿尔茨海默病转基因小鼠模型中发现的与年龄相关的功能障碍。胆碱能神经元的退化是 AD 中最一致的发现之一。我们建议使用病毒载体来研究将基因直接递送至 AD 动物模型的治疗方法，主要关注慢病毒载体。将开发三种互补策略来逆转正常老年大鼠和 AD 转基因小鼠模型中与衰老相关的形态和行为缺陷。第一个策略是使用 ChAT 来替代或补充老年大鼠耗尽的乙酰胆碱来恢复功能。第二种策略强调神经保护，使用 NGF 基因和产物来保护 ChAT 神经元免受年龄相关性死亡，并增强剩余神经元的功能。随着我们改进慢病毒载体，这两种策略将取得从组成型表达到可调节表达的进展。第三种策略侧重于淀粉样前体蛋白（APP）和胆碱能系统之间的相互作用。传递 NGF 或 ChAT 的慢病毒因子将被注射到过度表达 APP 的转基因动物的海马中，以阐明胆碱能系统是否调节淀粉样蛋白加工、改变斑块形成或可能改善行为表现。胆碱乙酰转移酶 (ChAT) 和神经生长因子 (NGF) 直接基因传递至老年大脑的功能和解剖学影响尚未得到评估。使用慢病毒载体，我们可以将这些分子递送至中枢神经系统 (CNS) 内的离散细胞群，测量直接 (ChAT) 或间接 (NGF) 胆碱能增强对认知、神经元和突触变化以及淀粉样蛋白加工的影响。