ETHANOL AND THE STRUCTURE/FUNCTION OF CELL MEMBRANES

乙醇与细胞膜的结构/功能

• 批准号: 2908421
• 负责人: NATHAN J JANES
• 金额: $ 6.15万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2908421
• 关键词: alcoholic beverage consumption; anions; biological signal transduction; cell membrane; chemical binding; diet; ethanol; intermolecular interaction; laboratory rat; lipid transport; liver; membrane model; membrane structure; microsomes; molecular site; nutrition related tag; phosphatidylinositols; radiotracer; synaptosomes; transport proteins

This proposal is a request for a Research Career Award (K02) which would provide the applicant the means to further his career development by dedicating himself to research on the biochemical effects of alcohol at the level of the cellular membrane. In particular, the applicant plans to examine the effects of ethanol on cellular signaling and the effects of ethanol on membrane structure. Acute and chronic ethanol exposure is known to interfere with polyphosphoinositide signal transduction. Acute ethanol exposure disorders membranes, whereas chronic ethanol exposure promotes an adaptive homeostatic response to the acute disordering effects. In microsomes, the adaptive response is accentuated in the phosphatidylinositol (PI) fraction of phospholipids. Linking these two ethanol sensitive processes is phosphatidylinositol transfer protein (PITP). PITP is an obligatory requirement for polyphosphoinositide signaling and for a variety of vesicular trafficking events. It transports PI from the endoplasmic reticulum or Golgi to the plasma membrane. We have found that the activity of phosphatidylinositol transfer protein (PITP) is enhanced by the presence of clinical concentrations of ethanol or chloroform. We found that PITP activity is exquisitely sensitive to membrane structure (curvature) in ethanol's absence-PITP's sensitivity to membrane order was previously established. This proposal is aimed to elucidate the role of ethanol, PITP, and membrane structure in signal transduction processes. The effects of acute and chronic ethanol exposure upon phospholipid (phosphatidylinositol) mediated by the phosphatidylinositol transfer protein will be investigated. Interference with the binding, transfer and incorporation of newly synthesized phosphatidylinositol into inositol lipid signaling pathways in the plasma membrane by acute or chronic ethanol exposure is likely to alter phosphatidylinositol 4,5-bisphosphate dependent processes. The relationship between domain formation and the effects of ethanol on phosphatidylinositol transfer activity will be investigated. The acute and chronic effects of ethanol on the intrinsic membrane curvature, the ability of the membrane to bind alcohols, and the disordering efficacy will be contrasted within the context of signal transduction.

该提案是颁发研究职业奖（K02）的要求，该奖项将为申请人提供进一步发展其职业发展的手段，以研究蜂窝膜水平上酒精的生化作用。 特别是，申请人计划检查乙醇对细胞信号传导的影响以及乙醇对膜结构的影响。 已知急性和慢性乙醇暴露会干扰多磷酸肌醇信号转导。 急性乙醇暴露障碍膜，而慢性乙醇暴露会促进对急性无序作用的适应性稳态反应。 在微粒体中，自适应反应在磷脂的磷脂酰肌醇（PI）中得到了强调。 将这两个乙醇敏感过程联系起来的是磷脂酰肌醇转移蛋白（PITP）。 PITP是对聚磷酸肌醇信号传导和各种囊泡贩运事件的强制要求。 它将PI从内质网或高尔基体传输到质膜。 我们发现，磷脂酰肌醇转移蛋白（PITP）的活性通过乙醇或氯仿的临床浓度而增强。 我们发现，在乙醇缺乏PITP对膜序列的敏感性中，PITP活性对膜结构（曲率）非常敏感。该建议旨在阐明乙醇，PITP和膜结构在信号转导过程中的作用。 将研究急性和慢性乙醇暴露对由磷脂酰肌醇转移蛋白介导的磷脂（磷脂酰肌醇）的影响。 通过急性或慢性乙醇暴露在质膜中新合成的磷脂酰肌醇的结合，转移和掺入质膜中的肌醇脂质信号通路中，可能会改变磷脂酰肌醇4,5-双异磷酸依赖性过程。 将研究结构域形成与乙醇对磷脂酰肌醇转移活性的影响。 乙醇对固有膜曲率的急性和慢性作用，膜结合醇和无序功效的能力将在信号转导的背景下对比。