Thiamine deficiency and alcohol-induced neurodegeneration

描述（由申请人提供）： 过量饮酒会导致大脑结构和功能异常，对健康、社会和经济产生重大影响。慢性酒精滥用导致痴呆，这与中枢神经系统（CNS）的形态学、神经生理学和生化变化有关。慢性酒精滥用后脑损伤的最具破坏性的特征是神经变性。其潜在机制尚不清楚。长期饮酒往往伴有硫胺素（维生素B1）缺乏。硫胺素缺乏症（TD）可损害CNS。人类的TD可能是由长期酒精暴露、遗传背景、衰老或营养状况引起的。然而，硫胺素状态和神经元对酒精诱导的神经变性的易感性之间的关系仍不清楚.自噬是参与细胞大分子和细胞器周转的溶酶体途径。它为细胞提供了细胞内结构单元和能量的替代来源，从而在营养缺乏或应激条件下增强细胞存活。我们推测，TD可能会抑制自噬途径，损害这种细胞的自我保护机制。因此，神经元在慢性TD后更容易受到酒精诱导的神经变性的影响。提出了三个具体目标来检验这一假设。我们将首先研究是否硫胺素含量的状态决定神经元对酒精诱导的神经变性的易感性。接下来，我们将描述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变性中的作用。作为一个单元，该提案将阐明TD和神经元对酒精神经毒性的易感性之间的关系，并提供一个新的见解酒精诱导的神经变性的机制。

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.