Gene expression in programmed cell death

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Our research proposal entitled “Gene expression in programmed cell death” investigates the molecular mechanisms by which animal cells undergo an essential process of cellular suicide. In multicellular organisms, programmed cell death (otherwise known as apoptosis) is essential for normal development and the elimination of excessive or damaged cells. Classical examples of the crucial nature of apoptosis include the elimination of cells in between fingers and toes during development, death of damaged skin cells after sunburn, and the elimination of white blood cells that would otherwise attack our own bodies. Our team has discovered a new cellular pathway termed the TAF6delta pathway that can dictate life versus death decisions in animal cells. The TAF6delta pathway, unlike all previously described pathways of apoptosis, is also essential for normal cell growth. We propose a series of experiments designed to shed further light on this fascinating new TAF6delta cell death pathway. We have shown that the TAF6delta protein drives changes in the expression of genes that force cells to commit cellular suicide. We will now seek to understand what triggers TAF6delta expression by a process known as alternative splicing. We further propose to define in molecular detail which genes are controlled directly by TAF6delta and by what mechanisms. Finally we will investigate a previous unknown role for TAF6delta in the cellular death by inducing changes in the alternative splicing of recently identified cell death genes. Our research program will provide training opportunities for the future generation of young Canadian researchers in a multidisciplinary environment. Furthermore, our results will have far-reaching impacts in understanding how animal cells respond to their environment by the extremely different outcomes of growth versus cell death. In addition to advancing our understanding of the mechanism by which animal cells interpret life versus death signals, the long-term outcomes or our research have the potential to impact diseases that are linked to defective cell death, including diseases of aging (for example neurodegenerative disorders) as well as cardiovascular disease, cancer and viral infections. By building knowledge in our fundamental understanding of gene expression in cell death, we are convinced that our work will contribute to a dynamic Canadian knowledge-based economy.