Adaptive tissue permeability to alcohol in C. elegans

线虫对酒精的适应性组织渗透性

• 批准号: 8064549
• 负责人: JONATHAN THOMAS PIERCE
• 金额: $ 3.84万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-25 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064549
• 关键词: Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Animals; Behavioral; Brain; Caenorhabditis elegans; Cell membrane; Chronic; Consumption; Development; Diffuse; Drug Delivery Systems; Ethanol; Exposure to; Fetal Alcohol Syndrome; Gene Mutation; Genetic Models; Health; Human; Intoxication; Invertebrates; Kidney; Lead; Lipid Bilayers; Liver; Mediating; Mental Retardation; Modeling; Molecular; Molecular Target; Nematoda; Nerve Tissue; Organ; Osmolar Concentration; Pathway interactions; Permeability; Physiological; Physiological Processes; Placenta; Resistance; Study models; System; Testing; Tissues; alcohol response; alcohol sensitivity; animal tissue; base; binge drinking; gene discovery; in vivo; insight; prevent; public health relevance

DESCRIPTION (provided by applicant): Over consumption of alcohol can permanently damage the liver, kidney and brain. Damage to the nervous tissue incurred during development can lead to fetal alcohol syndrome which is the main preventable form of mental retardation. Although ethanol is widely understood to penetrate these organs and the placenta by diffusing through the lipid bilayer of cell membranes, it is unclear how ethanol penetrates certain tissues more easily than others. It is also unknown what confers these tissues increased permeability to ethanol and whether this can be dynamically altered to prevent damage. We are taking advantage of the powerful genetics of the model nematode C. elegans to provide insight into the molecular basis of alcohol permeability in vivo. This model organism has been used to discover genes involved in fundamental physiological processes including how alcohol elicits intoxication through conserved molecular targets. Previously, we and others have found that C. elegans requires an unusually high concentration of exogenous ethanol (500-1000 mM) to produce intoxication and to raise the internal tissue concentration to a level relevant to human consumption (20-50 mM). We have now discovered that although C. elegans shows this extraordinary resistance to exogenous ethanol when tested in low osmolarity conditions (150 mOsm), the animal reverts to human-like sensitivity to ethanol when tested in higher (physiological) osmolarity conditions (320 mOsm). Moreover, we find that short-term incubation of C. elegans at physiological osmolarity confers human-like sensitivity to alcohol in low osmolarity conditions. We hypothesize that specific conserved molecules allow rapid permeation of ethanol into the tissue of the animal, and these molecules can be dynamically altered to change permeability. To determine the molecular basis for this dynamic permeability to ethanol we propose three specific aims: 1) Test whether mutation of genes in different permeation pathways reduce behavioral responses to ethanol and tissue permeability to ethanol in C. elegans. 2) Discover whether these molecules are dynamically reorganized with chronic exposure to ethanol and/or osmolarity. 3) Determine whether these molecules alter permeation to ethanol in a heterologous system. Identification of the molecules that mediate alcohol permeability in the worm would first show that C. elegans has comparable sensitivity to humans and therefore strengthen its rationale as a model for human alcohol abuse, and second, provide attractive drug targets to prevent tissue damage following binge drinking in humans. PUBLIC HEALTH RELEVANCE: Identification of the molecules that mediate dynamic alcohol permeability in C. elegans is important to human health for two main reasons. First, it would first show that this powerful model invertebrate has equivalent sensitivity to humans, and therefore strengthen rationale for using C. elegans as a model for studying the effects of human alcohol abuse. Second, this would provide attractive drug targets to prevent tissue damage by alcohol after binge drinking in humans.

描述（由申请人提供）：过度食用酒精会永久损害肝脏，肾脏和大脑。发育过程中对神经组织的损害可能导致胎儿酒精综合征，这是智力低下的主要预防形式。尽管乙醇被广泛理解为通过通过细胞膜的脂质双层扩散来渗透这些器官和胎盘，但尚不清楚乙醇如何比其他组织更容易穿透某些组织。尚不清楚这些组织增加了对乙醇的渗透性，以及是否可以动态改变以防止损害。我们正在利用模型线虫秀丽隐杆线虫的强大遗传学，以深入了解体内酒精通透性的分子基础。该模型有机体已用于发现参与基本生理过程的基因，包括酒精如何通过保守的分子靶标引起中毒。以前，我们和其他人发现秀丽隐杆线虫需要异常高的外源乙醇（500-1000 mm）来产生中毒并将内部组织浓度提高到与人类消费相关的水平（20-50 mm）。我们现在发现，尽管在低渗透压条件下（150 MOSM）进行测试时，秀丽隐杆线虫表现出对外源乙醇的极大耐药性，但在在较高（生理）渗透压条件下进行测试时，动物会恢复对人类对乙醇的敏感性（320 MOSM）。此外，我们发现秀丽隐杆线虫在生理渗透压下的短期孵育在低渗透压条件下赋予了对酒精的敏感性。我们假设特定的保守分子可以使乙醇快速渗透到动物的组织中，并且可以动态地改变这些分子以改变渗透率。为了确定这种动态渗透性对乙醇的分子基础，我们提出了三个具体目的：1）测试不同渗透途径中基因的突变是否会减少对秀丽隐杆线虫中乙醇和组织渗透性的行为反应。 2）发现这些分子是否通过长期暴露于乙醇和/或渗透性的状态进行动态重组。 3）确定这些分子是否改变了异源系统中乙醇的渗透。鉴定介导蠕虫中酒精渗透性的分子将首先表明秀丽隐杆线虫对人具有可比的敏感性，因此可以加强其作为人类酒精滥用的模型的理由，其次，提供了有吸引力的药物靶标，以防止人类暴饮暴食后的组织损害。 公共卫生相关性：鉴定介导秀丽隐杆线虫中介导动态酒精渗透性的分子对人类健康很重要，这是两个主要原因。首先，它首先表明，这种强大的模型无脊椎动物对人类具有同等的敏感性，因此可以加强使用秀丽隐杆线虫作为研究人类酒精滥用作用的模型的基本原理。其次，这将提供有吸引力的药物靶标，以防止人类暴饮暴食后酒精损害。