Pathophysiogenomic markers:ethanol-induced brain damage

描述（由申请人提供）：慢性乙醇滥用对大脑和身体的影响可能对健康和福祉产生破坏性影响，并使个体倾向于危险行为，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器官损害的最早迹象的能力，这可能使适当的干预或治疗策略得以启动。该项目的目标是开发筛选工具，这些工具可以真正转化为诊断乙醇引起的大脑损伤的最早迹象。这些信息将通过一系列涉及实验室大鼠的仔细实验来获得，这些大鼠在不同的时间段内从事饮酒行为，从成年人或青少年开始，并确定有中枢或内部器官损伤的迹象。将监测这些动物的外周血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对大脑不具有特异性的可能性。 将从循环白细胞中提取总RNA，以确定具有与同一动物的三个不同脑区（小脑、海马和体感皮层）中的RNA水平显著相关（正相关和负相关）的表达模式的基因。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，包括收集外周血和筛选来自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CNS、肝脏或心脏损伤体征为阳性或阴性。最后，我们希望确定一小部分具有诊断和预后效用的基因，这些基因可用于识别风险个体，以便开始治疗并针对其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.