Signalling mechanisms integrating cell survival, organismal growth and stress-resistance in Drosophila

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My goal is to understand the mechanisms that control healthy processes throughout the life of the organism under various conditions. Homeostasis is the ability of a cell, an organ or an organism to generate and maintain a balance of internal processes to function under a range of external factors: we use innovative approaches to explore this in Drosophila melanogaster, the common fruit fly. Prior to starting my group, I demonstrated that loss of a central sub-cellular protein, Akt1, in flies led to widespread cell death. This was my starting point and led to the exploration of the Akt1 kinase and a “master control protein” the foxo transcription factor. My group was the first, of many, to report on foxo in flies and we have examined the effects of foxo activities in response to starvation. Recently, we found that some Akt1 defective flies have an enhanced ability to endure amino-acid starvation due to foxo. These mutants undergo growth compensation during development. We will continue to explore organismal growth and survivability under stress. Secondly, we have evaluated the ability of another sub-cellular protein (minibrain) to influence foxo activity during growth and to regulate degeneration over time. Interestingly, minibrain is the Drosophila version of a Down Syndrome candidate gene. Thirdly, we have initiated the study of the relationship between a protein modification factor atrogin and foxo. In vertebrates, atrogin can act during muscle degeneration and has a complex relationship with the foxo factors. Not only can atrogin contribute to protein breakdown, modification of foxo by atrogin can increase activity. We are evaluating the atrogin protein family in cell and organismal survival. Finally, we have started to examine the relationship between foxo and spargel along with other members of the parkin-Pink1 pathway. Through the work described here, we will focus upon a number of processes including the maintenance of the mitochondrial balance in healthy cells and organisms. Our research goal to develop a full understanding of the mechanisms that lead to survivorship under various stress conditions, including the “natural” effects of ageing upon an individual. It is possible that the precise control of foxo may lead to an enhanced level of homeostasis, the ability to survive, and perhaps benefit, from the challenges of various stress. Overall, the proposed research program is expected to contribute in a transformative manner to our knowledge of the fundamental biological mechanisms of homeostasis and have applications in the development of innovative concepts applicable to a wide range of biological systems. Finally, in terms of training, implementation of this research program will help train a substantial number of undergraduate and graduate students in molecular cellular biology and genetics thus contributing to the scientific knowledge of Canadians in academics and applied sciences.