Thiamine deficiency and alcohol-induced neurodegeneration

酗酒会导致许多长期的健康后果；其中之一是认知障碍 其功能被称为酒精相关性痴呆(AAD)。AAD是由形态上的， 大脑中的神经生理和生化变化。脑损伤最具破坏性的特征 长期酗酒会导致神经退化。酗酒经常与 缺乏硫胺素(维生素B1)。除了酒精暴露，其他因素，如遗传背景， 衰老或营养状况也会导致硫胺素缺乏症(TD)。TD和TD之间的关系 酒精引起的神经退行性变仍不清楚。我们的研究表明，TD加重了酒精诱导的 神经退行性变。酒精暴露可引起大鼠脑内内质网ER应激反应。我们 假设TD导致未折叠蛋白反应(UPR)缺陷，而UPR起保护作用 减轻内质网应激所致损伤的反应。MANF是一种进化上保守的神经营养因子， 这是普遍定期审议的一个重要组成部分。我们进一步假设MANF是维持内质网的关键蛋白 动态平衡和TD诱导的MANF缺陷使神经元对酒精诱导的内质网更敏感 压力和神经退化。在这个方案中，我们将首先研究TD对MANF表达的影响。 然后我们将确定MANF在酒精诱导的内质网应激和神经退行性变中的作用。最后，我们会 确定操纵大脑中MANF的表达是否可以改变TD/酒精诱导的行为 赤字。作为一个单位，该提案将调查TD如何加剧酒精诱导的机制 并建立MANF在酒精诱导的神经变性中的保护作用。它不会的 只提供了一种新的洞察力，在AAD的背景下TD和酒精暴露之间的相互作用，但是 还要确定治疗AAD的潜在治疗靶点。

Alcohol abuse causes many long-lasting health consequences; one of which is impaired cognitive functioning known as alcohol-associated dementia (AAD). AAD is caused by the morphological, neurophysiological and biochemical changes in the brain. The most devastating feature of brain damage following chronic alcohol abuse is neurodegeneration. Alcohol abuse is frequently associated with the deficiency of thiamine (vitamin B1). Besides alcohol exposure, other factors, such as genetic background, aging or nutritional status also contribute to thiamine deficiency (TD). The relationship between TD and alcohol-induced neurodegeneration remains unclear. Our studies indicate that TD exacerbated alcohol-induced neurodegeneration. Alcohol exposure caused significant endoplasmic reticulum ER stress in the brain. We hypothesize that TD causes a deficiency in unfolded protein response (UPR) which function as a protective response to alleviate ER stress-induced damage. MANF is an evolutionarily conserved neurotrophic factor and an important UPR component. We further hypothesize that MANF is a key protein that maintains ER homeostasis and TD-induced deficiency in MANF makes neurons more susceptible to alcohol-induced ER stress and neurodegeneration. In this proposal, we will first investigate the effect of TD on MANF expression. We will then determine the role of MANF in alcohol-induced ER stress and neurodegeneration. Finally, we will determine whether manipulation of MANF expression in the brain can alter TD/alcohol-induced behavioral deficits. As a unit, the proposal will investigate the mechanisms of how TD exacerbates alcohol-induced neurodegeneration and establish a protective role of MANF in alcohol-induced neurodegeneration. It will not only provide a novel insight into the interaction between TD and alcohol exposure in the context of AAD but also identify potential therapeutic targets for the treatment of AAD.