PSYCHOPHARMACOLOGICAL EFFECTS OF EXOGENOUS CHOLINE

此应用程序请求继续支持对两个家庭的研究 脑膜中的化学物质-磷脂(例如， 卵磷脂)和淀粉样前体蛋白(APP)-可能 参与引起阿尔茨海默病(AD)。在中国进行的研究 我们实验室自该项目上次竞争评审以来(1992年6月) 已经表明，在其他方面，类APP的生产，就像我们 先前显示，其转化为非淀粉样变性(即推测 无毒)可溶性形式--可由脑神经递质控制 (去甲肾上腺素通过β受体起作用)和第二信使(环状 大脑和单个细胞中的胞苷水平可能会限制 PC直接前体CDP-胆碱的生产；作为一种 结果-CDP-胆碱可用作治疗中风和 记忆受损；当一些细胞被要求增加 它们产生新膜的速度(例如，轴突生长 在暴露于神经生长因子的PC12细胞中)， 这个过程是一个“第二信使”，二酰甘油(DAG)，它在这个过程中 环境起着主要的作用。(口述能力- 应用CDP-胆碱减轻卒中所致神经功能障碍 赤字已经在其他两个大规模的“第三阶段”中得到了证明 研究，以及与此用途相关的现在的药物申请[NDA]将 接受FDA的评估。)我们提出的新研究仍在继续 这些研究方向与合成、新陈代谢和 APP的可能功能；胞苷对大脑的来源，以及它的 与胆碱和磷脂的相互作用；DAG的来源 以维持神经突起的生长。像以前一样，我们将尝试 尽可能地将我们的发现应用于人类疾病的治疗。

This application requests continued support for research on two families of chemicals in brain membranes - the phosphatides (e.g., phosphatidylcholine; PC) and amyloid-precursor protein (APP) - which may be involved in causing Alzheimer's disease (AD). Research conducted in our laboratory since this program's last competitive review (June, 1992) has shown, among other things, that the production of APP - like, as we previously showed, its conversion to non-amyloidogenic (i.e. presumably non-toxic) soluble forms - can be controlled by brain neurotransmitters (norepinephrine acting via beta receptors) and second messengers (cyclic AMP); that levels of cytidine in brain and in individual cells can limit the production of PC's immediate precursor, CDP-choline; that-as a consequence - CDP-choline can be used as a drug to treat strokes and memory impairment; and that when some cells are called upon to increase the rate at which they produce new membranes (e.g., neurite outgrowth in PC12 cells exposed to Nerve Growth Factor), the limiting factor in this process is a "second messenger", diacylglycerol (DAG) which in this circumstance acts as a bulk constituent. (The ability of orally- administered CDP-choline to diminish stroke-induced neurological deficits has been demonstrated elsewhere in two large-scale "Phase III" studies, and a Now Drug Application [NDA] relating to this use will undergo evaluation by the FDA.) The new studies that we propose continue these lines of research, and relate to the synthesis, metabolism, and possible functions of APP; the sources of cytidine to the brain, and its interactions with choline and phospholipids; and the sources of the DAG needed to sustain neurite outgrowth. As before, we will attempt to apply our findings to the treatment of human diseases whenever possible.