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的异常，这会对健康、社会和经济产生重大影响。慢性酒精滥用可导致痴呆，痴呆与中枢神经系统(CNS)的形态、神经生理和生化改变有关。慢性酗酒后最具破坏性的脑损伤特征是神经退化。其潜在机制仍不清楚。长期饮酒往往伴随着硫胺素(维生素B1)的缺乏。硫胺素缺乏症(TD)可损害中枢神经系统。人类的TD可能是由于长期接触酒精、遗传背景、年龄或营养状况造成的。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然不清楚。自噬是参与细胞大分子和细胞器周转的溶酶体途径。它为细胞提供了另一种细胞内积木和能量来源，从而在营养缺乏或应激条件下提高细胞存活率。我们推测TD可能抑制了自噬途径，损害了这种细胞自我保护机制。因此，慢性TD后，神经元更容易受到酒精引起的神经变性的影响。为了检验这一假说，本文提出了三个具体目标。我们将首先调查硫胺素含量的状态是否决定了神经元对酒精诱导的神经变性的敏感性。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与神经元对酒精神经毒性的敏感性之间的关系，并为酒精诱导神经变性的机制提供新的见解。

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.