Circadian Modulation of Alcohol Sensitivity and Tissue Injury in Drosophila

急性酒精滥用和酒精依赖通过健康和社会经济影响对个人，家庭和社会造成巨大负担。酗酒和长期饮酒导致多种疾病的发病率增加，并伴有细胞损伤和组织损伤。对酒精的不同敏感性会导致饮酒行为的差异和 酒精毒性在细胞和组织水平。了解和治疗酒精滥用的身体后果，需要确定这些因素的影响差异酒精敏感性和酒精毒性和细胞和分子机制，通过这些因素调节酒精的反应。内源性生物钟允许生物体相对于一天中的时间优化行为和生理过程。最近在几个模型系统中的研究表明，内源性生物钟与对酒精的不同敏感性和毒性之间存在明显的相互作用，然而，这种相互作用的机制仍不清楚。存在对研究的迫切需要，该研究检查生物钟与对酒精的生理和代谢反应的相互作用，以在允许识别这种相互作用的分子机制的系统中进行。果蝇长期以来被认为是研究生物钟核心功能以及代谢、生理和行为输出的昼夜调节的上级模型系统。果蝇也被建立为研究酒精反应行为及其潜在机制的模型系统，因为对酒精的反应在果蝇和人类之间表现出显着的保守性。我们的初步研究表明，昼夜节律系统与果蝇对酒精的急性敏感性密切相关。本申请的目的集中于确定生物钟调节酒精敏感性的分子机制，并确定生物钟调节对酒精诱导的细胞损伤的影响。大量可用的突变体和特定基因表达的转基因技术，结合快速的世代时间和动物维护的实用性，使果蝇成为鉴定参与复杂行为的基因的极好系统。考虑到昼夜节律振荡器背后的进化保守机制以及受酒精影响的信号通路的高度保守性，这项果蝇研究的实验结果将广泛适用于不同物种。因此，这些实验将为未来开发治疗药物和治疗方法以预防与酒精滥用相关的不良健康影响提供基础。

DESCRIPTION (provided by applicant): Project Summary Acute alcohol abuse and alcohol dependence create an enormous burden on individuals, families and society through health and socioeconomic impacts. Binge drinking episodes and long-term alcohol consumption result in the increased incidence of multiple diseases, accompanied by cellular damage and tissue injury. Differential sensitivity to alcohol can result in differences in drinking behavior and variation in alcohol toxicity at the cellular and tissue levels. Understanding and treating the physical consequences of alcohol abuse requires identification of those factors affecting differential alcohol sensitivity and alcohol toxicity and the cellular and molecular mechanisms through which these factors modulate responses to alcohol. Endogenous circadian clocks allow organisms to optimize behavioral and physiological processes relative to the time of day. Recent research in several model systems has shown clear interactions between the endogenous circadian clock and differential sensitivity and toxicity to alcohol, however, the mechanisms through which this occurs remain unclear. There exists a critical need for studies examining the interactions of the circadian clock with physiological and metabolic responses to alcohol to be performed in a system that allows for the molecular mechanisms underlying this interaction to be identified. Drosophila has long been recognized as a superior model system for studies of the core functioning of the circadian clock and the circadian regulation of metabolic, physiological and behavioral outputs. Drosophila also has been established as a model system for the study of alcohol response behaviors and their underlying mechanisms as the response to alcohol appears remarkably conserved between flies and humans. Our preliminary research indicates that the circadian system is tightly intertwined with acute sensitivity to alcohol in Drosophila. Te objectives of this application focus on identifying the molecular mechanisms through which the circadian clock modulates alcohol sensitivity and identifying the impact of circadian modulation on alcohol-induced cellular damage. The tremendous number of available mutants and transgenic techniques for specific gene expression combined with fast generation time and the practicality of animal maintenance have made Drosophila a superb system for the identification of genes involved in complex behaviors. Given the evolutionarily conserved mechanisms underlying circadian oscillators as well as the high degree of conservation in signaling pathways affected by alcohol, the experimental results from this research in Drosophila will be broadly applicable across species. Thus, these experiments will provide a foundation for the future development of therapeutic drugs and treatments for prevention of the adverse health effects associated with alcohol abuse.