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ETHANOL ACTION ON BRAIN ACIDIC PHOSPHOLIPIDS

乙醇对脑酸性磷脂的作用

基本信息

批准号：
2855742
负责人：
GRACE Y SUN
金额：
$ 17.77万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-03-01 至 2000-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2855742
关键词：
G protein acyltransferase alcoholic beverage consumption biological signal transduction brain metabolism drug tolerance enzyme activity ethanol high performance liquid chromatography laboratory mouse laboratory rat lipid metabolism membrane lipids phosphatidylinositols phosphatidylserines protein kinase synapses tissue /cell culture

项目摘要

Previous studies provided evidence that chronic ethanol ingestion leads to an increase in levels of the acidic phospholipids in synaptic membranes. Acidic phospholipids (PS, PA, PI, and poly-PI) are known to exert specific effects on membrane proteins due to their anionic properties. The polyphosphoinositides (PIP and PIP2) are of special interest due to their direct involvement in the signal transduction pathway. Using in vivo labeling protocols, our laboratory has obtained evidence that poly-PI turnover in rat and mouse brain was affected by acute and chronic ethanol administration. Furthermore, tolerance to the inhibitory effect of acute ethanol on the poly-PI pathway was observed in mice after chronic ethanol administration. Therefore, specific aim #1 is to further examine the intrinsic factors (e.g. duration and mode of ethanol administration) leading to development of tolerance in this signaling event. PI and PIP kinases are important enzymes in the signaling pathway since they provide the substrate (PIP2) for the receptor-mediated and G-protein coupled phospholipase C reaction. Preliminary studies with rat brain synaptic plasma membranes indicate that PIP kinase is more sensitive to ethanol in vitro than PI kinase. Therefore, specific aim #2 will include experiments to examine the mechanism underlying the action of ethanol on these two kinases and to test the hypothesis that chronic ethanol exposure results in an adaptive change in these kinases. Synaptic plasma membranes will be used to test for (a) effects of ethanol and aliphatic alcohols on the PI and PIP kinase activity in the presence and absence of exogenous substrates, (b) intrinsic changes in enzyme activity occurring in brain membranes after chronic ethanol administration, (c) interaction between the effects of ethanol, acidic phospholipids and cationic amphipathic compounds on purified PIP kinase, and (d) the effects of ethanol on the phosphomonoesterase activity. In order to relate ethanol's action on PI and PIP kinases to metabolism of the poly- PI cycle, specific aims #3 will use an astrocyte cell line as a model system. The effect of ethanol exposure on these enzymes will be related to the ability of these cells to respond to agonists (e.g. bradykinin) known to transduce signals through the poly-PI pathway. Information obtained from this project will be important in understanding the mechanism underlying the development of tolerance and may have the potential of targeting drugs or treatment protocols to alleviate the detrimental effects associated with alcohol withdrawal.

先前的研究提供了证据表明，长期摄入乙醇会导致与突触中酸性磷脂水平的增加有关膜。已知酸性磷脂（PS、PA、PI和聚PI）由于其阴离子性，对膜蛋白产生特异性作用特性. 聚磷酸肌醇（PIP和PIP 2）具有特殊的由于它们直接参与信号转导，通路使用体内标记方案，我们的实验室获得了有证据表明，大鼠和小鼠脑中的聚PI周转受到以下因素的影响急性和慢性乙醇给药。此外，容忍观察急性乙醇对多聚PI通路的抑制作用在慢性乙醇给药后的小鼠中。因此，具体目标 #1是进一步检查内在因素（例如持续时间和模式乙醇管理）导致耐受性的发展，信号事件。 PI和PIP激酶是信号通路中的重要酶，它们为受体介导的G蛋白提供底物（PIP 2）偶联磷脂酶C反应。大鼠脑的初步研究突触质膜表明PIP激酶对乙醇在体外比PI激酶。因此，具体目标#2将包括研究乙醇作用机制的实验这两种激酶，并测试假设，慢性乙醇暴露导致这些激酶的适应性变化。突触浆膜将用于测试（a）乙醇和脂肪族的影响，醇对PI和PIP激酶活性的影响（B）酶活性的内在变化在慢性乙醇给药后发生在脑膜中，（c）乙醇、酸性磷脂和阳离子两亲化合物对纯化的PIP激酶的作用，和（d）所述阳离子两亲化合物对纯化的PIP激酶的作用，乙醇对磷酸单酯酶活性的影响。为了将乙醇对PI和PIP激酶的作用与多聚- PI周期，具体目标#3将使用星形胶质细胞系作为模型系统乙醇暴露对这些酶的影响将是相关的这些细胞对激动剂（如缓激肽）的反应能力已知通过多聚PI途径抑制信号。信息从这个项目中获得的将是重要的理解，耐受性发展的潜在机制，并可能具有靶向药物或治疗方案的潜力，以减轻与酒精戒断有关的有害影响。

项目成果

期刊论文数量（38）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prostaglandin E2 production in astrocytes: regulation by cytokines, extracellular ATP, and oxidative agents.

DOI：
10.1016/j.plefa.2003.08.016
发表时间：
2003-12
期刊：
Prostaglandins, leukotrienes, and essential fatty acids
影响因子：
0
作者：
Jianfeng Xu;M. Chalimoniuk;M. Chalimoniuk;Y. Shu;Á. Simonyi;A. Sun;F. González;G. Weisman;W. Wood;G. Sun
通讯作者：
Jianfeng Xu;M. Chalimoniuk;M. Chalimoniuk;Y. Shu;Á. Simonyi;A. Sun;F. González;G. Weisman;W. Wood;G. Sun

Dietary supplementation of grape polyphenols to rats ameliorates chronic ethanol-induced changes in hepatic morphology without altering changes in hepatic lipids.

向大鼠膳食补充葡萄多酚可改善慢性乙醇诱导的肝脏形态变化，而不改变肝脂质的变化。