PSYCHOPHARMACOLOGICAL EFFECTS OF EXOGENOUS CHOLINE

该申请要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， 磷脂酰胆碱（PC）和淀粉样前体蛋白（APP）--它们可能 参与导致阿尔茨海默病（AD）。 进行的研究 我们的实验室自该计划的最后一次竞争性审查（1992年6月） 已经表明，除其他事项外， 先前显示，其转化为非淀粉样蛋白（即推测为 无毒）可溶形式-可由脑神经递质控制 （通过β受体作用的去甲肾上腺素）和第二信使（环 AMP）;脑和单个细胞中的胞苷水平可以限制 PC的直接前体CDP-胆碱的产生;作为一种 结果-CDP-胆碱可用作治疗中风的药物， 记忆障碍;当一些细胞被要求增加 它们产生新膜的速率（例如，神经突生长 在暴露于神经生长因子的PC 12细胞中）， 这个过程是一个“第二信使”，二酰基甘油（DAG），在这个过程中， 环境起着主体成分的作用。 (The口的能力- 给予CDP-胆碱以减少中风引起的神经系统损伤 在两个大规模的“第三阶段”中， 研究，以及与此用途相关的Now Drug Application [NDA]将 经FDA评估）。我们提议的新研究将继续进行 这些研究路线，并涉及合成，代谢， APP的可能功能;胞苷对大脑的来源，以及其 与胆碱和磷脂的相互作用;以及DAG的来源 维持神经突生长所必需的。 和以前一样，我们将尝试 尽可能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.