ETHANOL ACTION ON BRAIN ACIDIC PHOSPHOLIPIDS

乙醇对脑酸性磷脂的作用

• 批准号: 3109924
• 负责人: GRACE Y SUN
• 金额: $ 11.85万
• 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/3109924
• 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和聚-PI）以及受体介导的信号 转导机制有关的周转聚- 磷酸肌醇由于急性和慢性乙醇 局 本研究计划的总体目标是 为了进一步描绘乙醇扰动的分子位点， 对多PI周期的影响，并将其生理意义 这些变化。 我们假设由于酸性物质的增加 磷脂（特别是磷脂酰丝氨酸），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 可能是蛋白质改变的结果 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. 多聚PI代谢产物的定量测定 急性和慢性乙醇代谢 局 2. 为了使用体内标记程序来检查 脑磷脂（尤其是聚PI）， 慢性乙醇给药。 标记前体，如（32 P）- ATP、（3 H）-肌醇、（14 C）-花生四烯酸和（14 C）-乙酸将 注射到大鼠脑内。 有了这个标签 程序，乙醇对摄取以及分解的影响 将测定脑酸性磷脂的含量。 此外，本发明还提供了一种方法， 将尝试识别可能表现出 对乙醇的影响高度敏感。 大脑被预先标记 通过这些不同的前体，已知可以改变 将评价信号传导机制（如锂）， 在治疗酒精中毒方面的作用。 3. 将进行体外实验以研究 乙醇和其它脂肪醇对酶的影响 负责脑亚细胞中多聚PI的代谢 膜。 长期目标是了解 乙醇对信号转导机制的作用， poly-PI周转率。 这些调查可能会提供新的见解 解释耐受性的生化机制， 乙醇过敏的生理表现 戒断