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. ? ? ? ?
