For the past 15-20 years, we have been interested in the cellular and molecular mechanisms that can lead to nerve cell injury or survival resulting from oxygen and/or nutrient deprivation. Tissue hypoxia is a clinically or a physiologically frequent event but the biologic events that take place in and outside cells are not well understood. One very intriguing set of questions pertains to the marked heterogeneity of tissue responses to lack of O2. Anoxia tolerance, for example, is found in certain cell types, in immature cells and in non-mammalian vertebrates such as in the fresh water turtle. However, it is extremely difficult to probe the molecular basis of tolerance in organisms such as the turtle since a number of modern approaches are not currently possible. Recently, we discovered that Drosophila melanogaster, a well studied model organism, is very tolerant to O2 deprivation and can recover from hours or anoxia! Using the Drosophila model system and a genetic screen following mutagenesis, we have obtained very promising and exciting preliminary data. Since it has become clear that biological fundamental pathways are conserved during evolution, we believe that studies on Drosophila have become very relevant to human biology and behavior. Our general hypothesis is that Drosophila melanogaster are endowed with the ability to tolerate prolonged O2 deprivation and genes critical for this tolerance can be identified. In this application, we have 2 specific aims: a) identify, map and clone the genes that seem to be responsible and critical for recovery to O2 deprivation using a genetic mutagenesis screen and b) ascertain the role of these genes at cellular and whole fly levels using several assays (e.g. ectopic expression, cell function under various conditions, etc...).
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