Molecular/Genetic Determinants:Alcohol-Induced Apoptosis

分子/遗传决定因素：酒精诱导的细胞凋亡

• 批准号: 7078243
• 负责人: John M Abrams
• 金额: $ 7.85万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7078243
• 关键词: Drosophilidae; RNA interference; alcoholism /alcohol abuse; apoptosis; biological signal transduction; comorbidity; drug tolerance; ethanol; fluorescence microscopy; gene induction /repression; genetic models; lipopolysaccharides; molecular genetics; pathologic process; polymerase chain reaction; Drosophilidae; RNA interference; alcoholism /alcohol abuse; apoptosis; biological signal transduction; comorbidity; drug tolerance; ethanol; fluorescence microscopy; gene induction /repression; genetic models; lipopolysaccharides; molecular genetics; pathologic process; polymerase chain reaction

DESCRIPTION (provided by applicant): It is well established that apoptotic cell death plays an important role during ethanol-induced tissue injury. However, despite a vast literature on this topic, the molecular lesions and signaling mechanisms that underlie alcohol induced pathologies are not well understood. To initiate a rigorous examination of this problem, we established robust assays for alcohol-induced apoptosis in the Drosophila system. This powerful genetic model facilitates conserved mechanistic discoveries at the cellular and whole animal levels. Already, in preliminary studies, we determined that an apical caspase (Drone) is absolutely required for alcohol-induced apoptosis. We wish to leverage this discovery to identify signaling pathways and illuminate candidate sensors that propagate alcohol damage at the molecular level. Specifically, we propose to: 1. Examine the functional status of cells 'genetically rescued' for ethanol-induced apoptosis. 2. Determine how cell-based responses to alcohol-induced apoptosis influence alcohol tolerance at the animal level. 3. Test functional requirements for candidate pathways in alcohol-induced apoptosis. 4. Conduct a pilot RNAi survey to identify novel genes required for ethanol-induced cell death and establish the feasibility of genome scale screens. Alcohol associated injury to organ systems is a widespread public health concern. Together, these projects will answer fundamental questions relating to common molecular mechanisms that cause alcohol-induced tissue damage. This information, in turn, could lead to improved therapies for pathologies associated with excessive alcohol consumption.

描述（由申请人提供）：众所周知，凋亡细胞死亡在乙醇引起的组织损伤中起重要作用。然而，尽管有关于这个主题的大量文献，但尚未很好地了解饮酒诱导病理的分子病变和信号传导机制。为了对此问题进行严格的检查，我们确定了果蝇系统中酒精诱导的凋亡的强大测定法。这种强大的遗传模型促进了在细胞和整个动物水平上的保守机械发现。在初步研究中，我们已经确定了酒精诱导的细胞凋亡绝对需要的顶胱天冬酶（无人机）。我们希望利用这一发现来识别信号通路，并照亮候选传感器，这些传感器在分子水平上传播酒精损害。具体而言，我们建议：1。检查乙醇诱导的细胞凋亡的细胞“遗传营救”的功能状态。 2。确定基于细胞对酒精诱导的凋亡的反应如何影响动物水平的酒精耐受性。 3。测试酒精诱导凋亡中候选途径的功能要求。 4.进行试点RNAi调查，以识别乙醇诱导的细胞死亡所需的新基因，并确定基因组量表筛查的可行性。酒精与器官系统相关的伤害是普遍的公共卫生问题。这些项目将共同回答与造成酒精引起的组织损害的常见分子机制有关的基本问题。反过来，这些信息可能会改善与饮酒过量相关的病理的疗法。