Thiamine deficiency and alcohol-induced neurodegeneration

硫胺素缺乏和酒精引起的神经变性

• 批准号: 10082414
• 负责人: JIA LUO
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082414
• 关键词: Accounting; Address; Adult; Affect; Age of Onset; Aging; Alcohol abuse; Alcoholism; Alcohols; Animals; Astrocytes; Attenuated; Behavioral; Biochemical; Blood Circulation; Brain; Brain Injuries; Cell physiology; Chronic; Clinical; Cognitive deficits; Data; Dementia; Diet; Down-Regulation; Endoplasmic Reticulum; Enzymes; Etiology; Experimental Models; Genetic; Health; Homeostasis; Human; Impaired cognition; Impairment; In Vitro; Injections; Knock-out; Knockout Mice; Learning; Memory; Metabolic; Modeling; Morphology; Motor; Mus; Nerve Degeneration; Neuraxis; Neurocognitive Deficit; Neurons; Neuroprotective Agents; Nutritional status; Oral; Oxidative Stress; Play; Population; Process; Proteins; Purkinje Cells; Research; Role; Symptoms; Thiamine; Thiamine Deficiency; Tissues; Veterans; Wernicke-Korsakoff Syndrome; absorption; alcohol abuse therapy; alcohol effect; alcohol exposure; alcohol response; alcohol use disorder; cofactor; cognitive function; endoplasmic reticulum stress; glucose metabolism; in vivo; insight; motor deficit; mouse model; neurophysiology; neurotrophic factor; novel; problem drinker; response; restoration; synergism; therapeutic target

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.

酗酒会造成许多长期的健康后果；其中之一是认知障碍 功能称为酒精相关痴呆（AAD）。 AAD是由形态学引起的 大脑的神经生理学和生化变化。脑损伤最具破坏性的特征 慢性酒精滥用后是神经退行性的。酗酒经常与 硫胺素缺乏（维生素B1）。除了酒精暴露外，其他因素，例如遗传背景， 衰老或营养状况也有助于硫胺素缺乏症（TD）。 TD和TD之间的关系 酒精引起的神经退行性尚不清楚。我们的研究表明，TD加剧了酒精诱导的 神经变性。酒精暴露导致大脑中明显的内质网应激。我们 假设TD会导致展开的蛋白质反应（UPR）的缺乏，该反应起保护性的作用 对减轻ER应力引起的损害的反应。 MANF是一种进化保守的神经营养因素， 重要的UPR组件。我们进一步假设MANF是维持ER的关键蛋白 稳态和TD引起的MANF缺乏使神经元更容易受到酒精诱导的ER 压力和神经变性。在此提案中，我们将首先研究TD对MANF表达的影响。 然后，我们将确定MANF在酒精引起的ER应激和神经变性中的作用。最后，我们会的 确定对大脑中MANF表达的操纵是否可以改变TD/酒精诱导的行为 缺陷。作为一个单位，该提案将调查TD如何加剧酒精诱导的机制 神经变性并确立MANF在酒精诱导的神经退行性中的保护作用。它不会 仅提供对在AAD中TD和酒精暴露之间相互作用的新颖见解，但是 还可以确定用于治疗AAD的潜在治疗靶标。