Pathophysiogenomic markers:ethanol-induced brain damage

病理生理基因组标记：乙醇诱导的脑损伤

• 批准号: 7236162
• 负责人: Frank A. Middleton
• 金额: $ 30.46万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7236162
• 关键词: 20 year old; Accidents; Adolescence; Adolescent; Adult; Affect; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Ambulatory Care Facilities; American; Animal Model; Animals; Behavior; Biological Markers; Blood; Blood Screening; Brain; Brain Injuries; Brain region; Cardiac; Cause of Death; Cell Death; Centers for Disease Control and Prevention (U.S.); Cerebellum; Cessation of life; Chronic; Clinical; Collection; Daily; Data; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Driving While Intoxicated; Effectiveness; Ethanol; Exposure to; Family; Friends; Functional disorder; Gene Expression; Generations; Genes; Goals; Health; Health Policy; Heart; Heart Diseases; Hippocampus (Brain); Homicide; Human; Individual; Inflammatory; Injury; Institutes; Intervention; Investigation; Laboratory Rat; Lead; Learning; Leukocytes; Liver; Malignant Neoplasms; Memory; Monitor; Nervous system structure; Numbers; Organ; Patient Self-Report; Pattern; Perinatal Exposure; Peripheral; Personal Satisfaction; Phase; Prevalence; Probability; RNA; Rattus; Reporting; Research Personnel; Risk; Risk Behaviors; Running; Sampling; Screening procedure; Series; Serum; Societies; Somatosensory Cortex; Structure; Substance abuse problem; Suicide; Testing; Therapeutic; Time; Translating; United States; Upper arm; Validation; Vehicle crash; Visuospatial; Week; addiction; alcohol abuse therapy; alcohol effect; alcoholism/alcohol abuse; automobile accident; base; binge drinker; binge drinking; body system; cost; disability; drinking; drinking behavior; high school; human subject; improved; malformation; neurotransmission; peripheral blood; prognostic; programs; research study; tool; underage drinking

DESCRIPTION (provided by applicant): The effects of chronic ethanol abuse on the brain and body can have a devastating impact on health and well-being, and predispose individuals toward risky behaviors that might even result in premature death. In order to reduce the prevalence of alcohol abuse, we need to improve our ability to detect the earliest signs of damage to the central or internal organs, which might enable appropriate interventional or therapeutic strategies to be initiated. The goal of this project is to develop screening tools that could have true translational potential for diagnosing when the earliest signs, of ethanol-induced damage to the brain has occurred. This information will be acquired through a careful series of experiments involving laboratory rats that are engaged in drinking behaviors for variable periods of time, beginning either as adults or adolescents, and are determined to have signs of central or internal organ damage. The peripheral blood of these animals will be monitored for signs of liver or heart damage in order to guard against the possibility that the effects we observe in the blood are not specific for the brain. Total RNA will be extracted from the circulating leukocytes to determine those genes with expression patterns that are significantly correlated (both positively and negatively) with RNA levels in three different brain regions (cerebellum, hippocampus, and somatosensory cortex) of the same animal. In the same animals, we will also assess potential liver or cardiac damage by monitoring serum ALT and AST levels. We will use the expression information as background data for a second phase of investigation, involving the collection of peripheral blood and screening of RNA from human subjects who are currently undergoing treatment for alcohol abuse who are positive or negative for signs of CNS, liver, or heart damage. In the end, we hope to identify a small subset of genes with diagnostic and prognostic utility that could be used to identify at risk individuals in order to commence treatment and tailor this treatment toward their specific pattern of alterations.

描述（由申请人提供）：长期滥用乙醇对大脑和身体的影响可能对健康和福祉产生毁灭性影响，并使个人容易做出危险行为，甚至可能导致过早死亡。为了减少酗酒的发生率，我们需要提高检测中枢或内脏器官损伤的最早迹象的能力，这可能有助于启动适当的干预或治疗策略。该项目的目标是开发具有真正转化潜力的筛查工具，用于诊断乙醇引起的大脑损伤的最早迹象何时发生。这些信息将通过一系列仔细的实验​​获得，这些实验涉及实验室老鼠，这些老鼠在不同的时间段内从事饮酒行为，从成年或青少年开始，并确定有中枢或内脏器官损伤的迹象。将监测这些动物的外周血液是否有肝脏或心脏损伤的迹象，以防止我们在血液中观察到的影响并非针对大脑的特定影响。 将从循环白细胞中提取总RNA，以确定那些表达模式与同一动物的三个不同大脑区域（小脑、海马和体感皮层）的RNA水平显着相关（正相关和负相关）的基因。在相同的动物中，我们还将通过监测血清 ALT 和 AST 水平来评估潜在的肝脏或心脏损伤。我们将使用表达信息作为第二阶段研究的背景数据，包括收集目前正在接受酗酒治疗的人类受试者的外周血和 RNA 筛查，这些受试者的中枢神经系统、肝脏或心脏损伤迹象呈阳性或阴性。最后，我们希望鉴定出一小部分具有诊断和预后效用的基因，可用于识别高危个体，以便开始治疗并根据其特定的改变模式调整治疗方法。