ETHANOL ACTION ON BRAIN ACIDIC PHOSPHOLIPIDS

乙醇对脑酸性磷脂的作用

• 批准号: 3109919
• 负责人: GRACE Y SUN
• 金额: $ 12.7万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-03-01 至 1993-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3109919
• 关键词: acyltransferase; alcoholic beverage consumption; arachidonate; brain metabolism; cell membrane; drug tolerance; ethanol; gas chromatography; high performance liquid chromatography; ion exchange chromatography; laboratory rat; lipid metabolism; membrane lipids; myelin; phosphatidylinositols; phosphatidylserines; phosphodiesterases; phospholipids; protein kinase; radiotracer; synaptosomes; thin layer chromatography

There is increasing evidence that brain acidic phospholipids (i.e. PS, PA, PI and poly-PI) as well as the receptor-mediated signal transduction mechanism pertaining to turnover of poly- phosphoinositides are altered due to acute and chronic ethanol administration. The overall objective of this research program is to further delineate the molecular site of perturbation of ethanol on the poly-PI- cycle, and to relate the physiological significance of thes changes. We hypothesize that due to an increase in acidic phospholipids (especially phosphatidylserine), chronic ethanol administration is asociated with an increase in the membrane- bound protein kinase C activity. In turn, other cellular changes may occur as a consequence of the alteration of the protein kinase C activity. We will continue to use the Sprague-Dawley rats as an experimental model. The specific aims are: 1. Quantitative determination of metabolites involved in poly-PI metabolsim with respect to acute and chronic ethanol administration. 2. To use the in vivo labeling procedure to examine changes in brain phospholipids (especially poly-PI) with respect to acute and chronic ethanol administration. Label precursors such as (32P)- ATP, (3H)-inositol, (14C)-arachidonic acid and (14C)-acetate will be injected intracerebrally into the rat brain. With this labeling procedure, the effects of ethanol on uptake as well as breakdown of the brain acidic phospholipids will be determined. In addition, attempts will be made to identify brain regions that may exhibit high sensitivity to the effects of ethanol. With brains prelabeled by these various precursors, agents known to alter the response of signal-tranduction mechanism (e.g. lithium) will be evaluated for their effects in the treatment of alcoholism. 3. In vitro experiments will be carried out to investigate the effects of ethonal and other aliphatic alcohols on enzymes responsible for metabolism of poly-PI in brain subcellular membranes. The long-term goal is to understand the molecular action of ethanol on the signal transduction mechanism involving poly-PI turnover. These investigations may give new insights towards explaining the biochemical mechanism(s) of tolerance and the physiological manifestation of hypersensitivity during ethanol withdrawal.

越来越多的证据表明脑酸性磷脂（即 PS、PA、PI 和 Poly-PI）以及受体介导的信号 与多聚体周转有关的转导机制 磷酸肌醇因急性和慢性乙醇而改变 行政。 该研究计划的总体目标是 进一步描绘乙醇扰动的分子位点 聚-PI-循环，并联系其生理意义 这些变化。 我们推测，由于酸性物质的增加 磷脂（尤其是磷脂酰丝氨酸）、慢性乙醇 给药与膜的增加有关 结合蛋白激酶 C 活性。 反过来，其他细胞变化 可能是由于蛋白质改变而发生 激酶 C 活性。 我们将继续使用 Sprague-Dawley 大鼠作为实验模型。 具体目标是： 1. 聚PI相关代谢物的定量测定 急性和慢性乙醇的代谢 行政。 2. 使用体内标记程序来检查 脑磷脂（特别是聚PI）与急性和 长期使用乙醇。 标记前体，例如 (32P)- ATP、(3H)-肌醇、(14C)-花生四烯酸和(14C)-乙酸盐将 脑内注射到大鼠大脑中。 有了这个标签 程序，乙醇对吸收和分解的影响 脑酸性磷脂的含量将被测定。 此外， 将尝试识别可能表现出的大脑区域 对乙醇的影响高度敏感。 大脑预先标记 通过这些不同的前体，已知可以改变反应的试剂 将评估信号转导机制（例如锂） 它们在治疗酒精中毒中的作用。 3. 进行体外实验来研究 乙醇和其他脂肪醇对酶的影响 负责脑亚细胞中聚酰亚胺的代谢 膜。 长期目标是了解分子 乙醇对信号转导机制的作用涉及 聚PI营业额。 这些调查可能会带来新的见解 解释耐受性的生化机制和 乙醇过敏的生理表现 撤回。