Gene expression in programmed cell death

我们的研究计划题为“程序性细胞死亡中的基因表达”，研究动物细胞经历细胞自杀的基本过程的分子机制。在多细胞生物中，程序性细胞死亡（也称为细胞凋亡）是正常发育和消除过多或受损细胞所必需的。细胞凋亡至关重要的经典例子包括发育过程中手指和脚趾间细胞的消失，晒伤后受损皮肤细胞的死亡，以及白细胞的消失，否则白细胞会攻击我们自己的身体。我们的团队发现了一种新的细胞通路，称为TAF6delta通路，它可以决定动物细胞的生死。与所有先前描述的凋亡途径不同，TAF6delta途径也是正常细胞生长所必需的。我们提出了一系列的实验，旨在进一步阐明这个迷人的新的TAF6delta细胞死亡途径。我们已经证明，taf6蛋白驱动基因表达的变化，迫使细胞进行细胞自杀。现在，我们将通过一种被称为选择性剪接的过程来了解是什么触发了TAF6delta的表达。我们进一步建议在分子细节上确定哪些基因直接受TAF6delta控制，以及通过什么机制控制。最后，我们将通过诱导最近发现的细胞死亡基因的选择性剪接变化来研究TAF6delta在细胞死亡中的未知作用。

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.