Cold Inducible RNA Binding Protein and Alcohol Induced Neurosuppression

描述（由申请人提供）：在药物滥用中，酒精是使用最广泛的药物之一。仅在美国，酒精滥用就影响了1800万人，每年因酒精相关疾病造成的直接损失达270亿美元。过量饮酒与认知功能损伤甚至大脑结构退化有关。脑成像技术极大地促进了我们对酒精滥用的影响及其与人类大脑功能和结构变化的关系的理解。脑糖代谢的评估是衡量脑功能的可靠指标。使用正电子发射断层扫描（PET）的研究表明，急性酒精暴露导致脑葡萄糖利用率降低，反映了脑活动的减少。然而,

DESCRIPTION (provided by applicant): Among substance abuse, alcohol is one of the most wildly used substances. Alcohol abuse affects 18 million people with a direct cost of $27 billion annually for alcohol-related illnesses in the United States alone. Excessive alcohol ingestion is associated with the impairment of cognitive function and even structural deterioration in the brain. The brain imaging technique has significantly contributed to our understanding of the effect of alcohol abuse and its correlation to functional and structural changes in the human brain. The assessment of brain glucose metabolism is a reliable measure of cerebral function. Studies using positron emission tomography (PET) have indicated that acute alcohol exposure results in lower brain glucose utilization, reflecting a decrease in brain activities. However, the molecular factor responsible for such neurosuppression has not yet been elucidated. In this project, we propose to test a novel concept that a newly-identified inflammatory mediator, cold-inducible RNA-binding protein (CIRP), is responsible for the reported decrease in neuronal activities in alcoholics. In our preliminary study, we have established the use of the advanced, non-invasive, and real-time microPET imaging technology to monitor brain activities in the mouse. Our results showed that alcohol intoxication in wild-type mice produced significant decrease in brain glucose metabolism. In contrast, CIRP knockout mice were more resistant to the decrease in brain glucose metabolism induced by acute alcohol exposure, suggesting CIRP may mediate central neurosuppression. In addition, CIRP protein levels increased in the hypothalamus of the brain and cerebral spinal fluid in alcohol-exposed wild-type animals. In murine microglia (brain macrophages) BV2 cells, alcohol exposure increased CIRP's mRNA and protein expression as well as its release into the extracellular matrix in a dose-dependent manner. Moreover, recombinant murine CIRP (rmCIRP) caused inflammation and tissue injury. Based on these observations, we hypothesize that alcohol intoxication increases brain CIRP expression and release, which cause the reduction of brain activities. To test this hypothesis, we will further confirm the direct role of CIRP in reducing central neuronal activities after alcohol exposure, and to determine the molecular mechanism responsible for alcohol-induced CIRP expression in the brain. These studies should provide useful information that will allow us to pinpoint the mechanism of alcohol-induced brain damage and central neurosuppression mediated by upregulation of CIRP. PUBLIC HEALTH RELEVANCE: Among substance abuse, alcohol is the most wildly used substance. It is estimated that 50% of Americans 12 years or older consume alcohol at least once a month and 6.8% of them are considered as heavy drinkers. Drinking alcohol at high levels for a long term accounts for over 50,000 hospitalizations with 4% deaths. The direct cost of alcohol-related illnesses in the US has been estimated to be $27 billion annually. Our unique and innovative approach will prove the novel concept that a newly-identified inflammatory mediator called CIRP could be responsible for the reported decrease in brain activities in alcoholics. These studies will provide insights into potential therapeutic approaches in alcohol-induced central neurosuppression. 1