Pathophysiogenomic markers:ethanol-induced brain damage

描述(申请人提供)：慢性酒精滥用对大脑和身体的影响可能会对健康和福祉产生毁灭性的影响，并使个人倾向于危险的行为，甚至可能导致过早死亡。为了减少酗酒的流行，我们需要提高我们发现中枢或内脏受损的最早迹象的能力，这可能使我们能够启动适当的干预或治疗战略。该项目的目标是开发能够真正具有翻译潜力的筛查工具，以诊断乙醇诱导的大脑损伤的最早迹象何时发生。这一信息将通过一系列谨慎的实验获得，这些实验涉及的是实验室大鼠，这些大鼠在成年或青少年时期开始进行不同时期的饮酒行为，并被确定有中枢或内脏损伤的迹象。这些动物的外周血液将被监测肝脏或心脏受损的迹象，以防止我们在血液中观察到的影响不是大脑特有的可能性。 将从循环中的白细胞中提取总RNA，以确定与同一动物三个不同大脑区域(小脑、海马体感觉皮质)的RNA水平显著相关(正负)的基因表达模式。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害。我们将使用表达信息作为第二阶段调查的背景数据，涉及收集外周血液和筛选目前正在接受酒精滥用治疗的人类受试者的RNA，这些受试者的中枢神经系统、肝脏或心脏损害的迹象呈阳性或阴性。最后，我们希望识别出一小部分具有诊断和预后效用的基因，这些基因可以用来识别高危个体，以便开始治疗并针对他们特定的改变模式定制这种治疗。

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.