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: 7083370
• 负责人: Frank A. Middleton
• 金额: $ 31万
• 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/7083370
• 关键词: age difference; alcoholic beverage consumption; alcoholism /alcohol abuse; behavior test; behavioral /social science research tag; brain disorder diagnosis; brain disorders; brain injury; cardiovascular injury; clinical research; diagnosis design /evaluation; early diagnosis; enzyme linked immunosorbent assay; ethanol; gene expression; genetic markers; human subject; in situ hybridization; laboratory rat; leukocytes; liver disorder; neurogenetics; patient oriented research; polymerase chain reaction; substance abuse related behavior

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）：慢性乙醇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，并使个人倾向于可能导致过早死亡的危险行为。为了减少酒精滥用的患病率，我们需要提高我们检测到对中央或内部器官损害的最早损害迹象的能力，这可能使适当的介入或治疗策略启动。该项目的目的是开发筛选工具，这些工具可能具有真正的翻译潜力，以便在最早发生乙醇引起的大脑损害的迹象时进行诊断。这些信息将通过一系列涉及实验室大鼠的仔细的实验​​来获取，这些实验大鼠从事饮酒行为的时间段，从成年人或青少年开始，并确定具有中央或内部器官损害的迹象。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并非特定于大脑。 将从循环的白细胞中提取总RNA，以确定那些具有表达模式的基因，这些基因与同一动物的三个不同大脑区域（小脑，海马和体感皮层）在三个不同的大脑区域（占积极和负相关）与RNA水平显着相关。在同一动物中，我们还将通过监测血清ALT和AST水平来评估潜在的肝或心脏损伤。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，并从人类受试者中筛选RNA，这些受试者目前正在接受酒精滥用治疗的人类受害者，这些滥用对中枢神经系统，肝脏或心脏损伤的迹象是正面或负面的。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人，以便开始治疗并根据其特定的改变模式来定制这种治疗方法。