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”，研究动物细胞进行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（也称为凋亡）对于正常发育和消除过多或受损细胞至关重要。细胞凋亡的重要性质的经典例子包括在发育过程中消除手指和脚趾之间的细胞，晒伤后受损皮肤细胞的死亡，以及消除白色血细胞，否则它们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TAF6 δ通路，它可以决定动物细胞的生死决定。TAF6 δ途径，不同于所有先前描述的细胞凋亡途径，也是正常细胞生长所必需的。我们提出了一系列旨在进一步阐明这一迷人的新TAF6 δ细胞死亡途径的实验。我们已经证明，TAF6 δ蛋白驱动基因表达的变化，迫使细胞进行细胞自杀。我们现在将试图了解是什么触发TAF6 δ表达的过程称为选择性剪接。我们进一步提出，在分子上详细定义哪些基因是由TAF6 δ直接控制的，以及通过什么机制。最后，我们将通过诱导最近鉴定的细胞死亡基因的选择性剪接的变化来研究TAF6 δ在细胞死亡中先前未知的作用。 我们的研究计划将为未来一代的年轻加拿大研究人员在多学科环境中提供培训机会。此外，我们的研究结果将对理解动物细胞如何通过生长与细胞死亡的极端不同结果对其环境作出反应产生深远的影响。除了推进我们对动物细胞解释生命与死亡信号的机制的理解外，我们的研究的长期结果有可能影响与缺陷细胞死亡有关的疾病，包括衰老疾病（例如神经退行性疾病）以及心血管疾病，癌症和病毒感染。通过建立我们对细胞死亡中基因表达的基本理解的知识，我们相信我们的工作将有助于建立一个充满活力的加拿大知识经济。

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.