权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cold Inducible RNA Binding Protein and Alcohol Induced Neurosuppression

冷诱导 RNA 结合蛋白和酒精诱导的神经抑制

基本信息

批准号：
8493914
负责人：
PING WANG
金额：
$ 18.61万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8493914
关键词：
Accounting Acute Affect Agonist Alcohol abuse Alcohol consumption Alcohol or Other Drugs use Alcoholic Intoxication Alcoholic beverage heavy drinker Alcohols American Animals Brain Brain Injuries Brain imaging Brain region CCAAT-Enhancer-Binding Proteins Cell physiology Cells Cerebrospinal Fluid Cerebrum Cessation of life Corpus striatum structure Deterioration Direct Costs Dose Extracellular Matrix Family Functional disorder Genes Genetic Recombination Genetic Transcription Glucose Heavy Drinking Hippocampus (Brain)Hospitalization Human Hypothalamic structure Hypoxia Image Imaging Techniques Imaging technology Impairment Inflammation Inflammation Mediators Injury Knock-out Knockout Mice Knowledge Lead Mammalian Cell Measures Mediating Messenger RNA Microglia Molecular Monitor Mus Neurons Peroxisome Proliferator-Activated Receptors Pioglitazone Positron-Emission Tomography Prevention Proteins RNA-Binding Proteins Reaction Time Recombinants Reporting Resistance Role Stimulus Stress Substance abuse problem Testing Thalamic structure Therapeutic Time Tissues Translations United States Up-Regulation Wild Type Mouse alcohol effect alcohol exposure alcohol response base cell injury cognitive function cold shock protein frontal lobe glucose metabolism innovation insight mRNA Expression macrophage neutralizing antibody novel problem drinker promoter protein expression response ultraviolet irradiation

项目摘要

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.

描述（由申请人提供）：在物质滥用中，酒精是使用最广泛的物质之一。仅在美国，酗酒就影响到1800万人，每年因酗酒相关疾病造成的直接损失就达270亿美元。过量饮酒会损害认知功能，甚至导致大脑结构退化。脑成像技术对我们理解酒精滥用的影响及其与人脑功能和结构变化的相关性做出了重大贡献。脑葡萄糖代谢的评估是一个可靠的衡量脑功能。使用正电子发射断层扫描（PET）的研究表明，急性酒精暴露导致大脑葡萄糖利用率降低，反映了大脑活动的减少。但负责这种神经抑制的分子因子尚未阐明。在这个项目中，我们提出了一个新的概念，即一个新发现的炎症介质，冷诱导RNA结合蛋白（CIRP），是负责在酗酒者的神经元活动的报告减少。在我们的初步研究中，我们已经建立了使用先进的，非侵入性的，实时microPET成像技术来监测小鼠的大脑活动。我们的研究结果表明，酒精中毒在野生型小鼠脑葡萄糖代谢显着下降。相反，CIRP基因敲除小鼠对急性酒精暴露引起的脑葡萄糖代谢下降更有抵抗力，表明CIRP可能介导中枢神经抑制。此外，在暴露于酒精的野生型动物中，大脑下丘脑和脑脊液中的CIRP蛋白水平增加。在小鼠小胶质细胞（脑巨噬细胞）BV2细胞，酒精暴露增加CIRP的mRNA和蛋白质的表达，以及其释放到细胞外基质中的剂量依赖性的方式。此外，重组鼠CIRP（rmCIRP）引起炎症和组织损伤。基于这些观察，我们假设酒精中毒增加大脑CIRP的表达和释放，这导致大脑活动减少。为了验证这一假设，我们将进一步证实CIRP在酒精暴露后降低中枢神经元活动中的直接作用，并确定负责酒精诱导的CIRP在大脑中表达的分子机制。这些研究将提供有用的信息，使我们能够查明酒精诱导的脑损伤和CIRP上调介导的中枢神经抑制的机制。