Thiamine deficiency and alcohol-induced neurodegeneration

硫胺素缺乏和酒精引起的神经变性

• 批准号: 8966631
• 负责人: JIA LUO
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8966631
• 关键词: Accounting; Adult; Affect; Aging; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic beverage heavy drinker; Alcohols; Animals; Autophagocytosis; Biochemical; Brain; Brain Injuries; Brain region; C57BL/6 Mouse; Cell Survival; Cell physiology; Cells; Cerebellum; Chronic; Data; Dementia; Disease; Enzymes; Etiology; Experimental Models; Genetic; Health; Human; Medial; Metabolic; Nerve Degeneration; Neuraxis; Neurons; Neuropathy; Nutrient; Nutritional status; Organelles; Pathway interactions; Play; Predisposition; Role; Social Impacts; Source; Stress; Testing; Thalamic structure; Thiamine; Thiamine Deficiency; Veterans; Wernicke-Korsakoff Syndrome; alcohol exposure; alcohol response; brain abnormalities; chronic alcohol ingestion; cofactor; cognitive function; combat; economic impact; frontal lobe; glucose metabolism; insight; macromolecule; neurophysiology; neurotoxicity; novel; problem drinker; response

DESCRIPTION (provided by applicant): Excessive alcohol use can cause structural and functional abnormalities of the brain and this has significant health, social and economic impact. Chronic alcohol abuse induces dementia which is associated with morphological, neurophysiological and biochemical changes in the central nervous system (CNS). The most devastating feature of brain damage following chronic alcohol abuse is neurodegeneration. The underlying mechanisms remain unclear. Chronic alcohol consumption is often accompanied by the deficiency of thiamine (vitamin B1). Thiamine deficiency (TD) can damage the CNS. TD in humans may results from chronic alcohol exposure, genetic background, aging or nutritional status. The relationship between thiamine status and neuron susceptibility to alcohol- induced neurodegeneration, however, remains unclear. Autophagy is a lysosomal pathway involved in the turnover of cellular macromolecules and organelles. It provides the cells with an alternative source of intracellular building blocks and energy, thereby enhancing cell survival during nutrient deficiency or stress conditions. We hypothesize that TD may inhibit the autophagic pathways and impair this cellular self-protection mechanism. As a result, neurons are more susceptible to alcohol- induced neurodegeneration after chronic TD. Three specific aims are proposed to test this hypothesis. We will first investigate whether the status of thiamine content determines neuron susceptibility to alcohol-induced neurodegeneration. We will next characterize the effect TD/alcohol on autophagy in the brain. Finally, we will determine the role of autophagy in alcohol/TD interaction and alcohol-induced neurodegeneration. As a unit, the proposal will elucidate the relationship between TD and neuron susceptibility to alcohol neurotoxicity and provide a novel insight into the mechanisms underlying alcohol-induced neurodegeneration.

描述（由申请人提供）： 过量的饮酒会导致大脑的结构和功能异常，这具有重大的健康，社会和经济影响。慢性酒精滥用诱导痴呆，这与中枢神经系统（CNS）的形态，神经生理和生化变化有关。慢性酒精滥用后，脑损伤最具破坏性的特征是神经退行性。基本机制尚不清楚。慢性饮酒通常伴有硫胺素的缺乏（维生素B1）。硫胺素缺乏症（TD）会损坏中枢神经系统。人类的TD可能是由于慢性酒精暴露，遗传背景，衰老或营养状况而引起的。然而，硫胺素状态与神经元对酒精诱导的神经退行性的敏感性之间的关系尚不清楚。自噬是参与细胞大分子和细胞器的营业额的溶酶体途径。它为细胞提供了细胞内构件和能量的替代来源，从而在营养缺乏或应力条件下增强了细胞存活。我们假设TD可能会抑制自噬途径并损害这种细胞自我保护机制。结果，慢性TD后神经元更容易受到酒精诱导的神经退行性的影响。提出了三个特定目标来检验这一假设。我们将首先研究硫胺素含量的状态是否确定神经元对酒精引起的神经变性的敏感性。接下来，我们将表征TD/酒精对大脑自噬的影响。最后，我们将确定自噬在酒精/TD相互作用和酒精诱导的神经退行性中的作用。作为一个单位，该提案将阐明TD和神经元对酒精神经毒性的敏感性之间的关系，并提供对酒精引起的神经变性的机制的新颖见解。