Mechanistic insight into a novel TIF-IA-NF-kB nucleolar stress response pathway and elucidation of its role in senescence

这项提议关注的是细胞内一种叫做核仁的结构。这种结构在许多常见疾病中都是功能失调的，包括阿尔茨海默氏症、帕金森氏病和癌症。众所周知，它在衰老过程中也起到了作用。如果细胞的环境发生变化，例如营养物质减少或细胞暴露在有毒物质中，核仁会做出反应并向细胞的其他部分发送信号，以改变生长/死亡的速度和许多其他细胞过程。然而，核仁如何感知环境的变化，以及它们向细胞其他部分发送的信号，仍然知之甚少。我们最近发表了一种新的方法，通过这种方法，核仁对压力做出反应，这涉及到一种名为TIF-IA的关键核仁蛋白的降解。我们还证明了这种降解会导致核仁大小增加，并在细胞的另一部分模拟一种称为核因子-kB的蛋白质。由于核仁大小增加和核因子-kB的刺激与衰老有关，我们使用一种名为癌基因诱导衰老(OIS)的模型来观察TIF-IA-NF-kB是否在这一过程中发挥重要作用。在这里，我们的目标是充分了解应激是如何降低TIF-IA的。我们有令人兴奋的初步数据表明，这种降解是通过一种新的机制发生的，因此，这将是这些研究的重点。我们还旨在确定TIF-IA水平变化与核仁大小变化和核因子-kB刺激之间的联系。同样，我们有初步数据显示，一些候选人可能参与这一进程。最后，也是重要的一点，我们的目标是确认TIF-IA-NF-kB在衰老中的作用。鉴于核仁功能障碍和核因子-kB途径激活都是衰老的标志，并导致健康状况不佳，这些研究具有非常真实的潜力，可以增加我们对这一过程的理解，并识别可用于识别疾病或衰老细胞的生物标志物。它们还可能为一类新的药物开辟途径，这些药物通过同时针对这两个途径发挥作用。

This proposal focuses on a structure inside the cell called the nucleolus. This structure is dysfunctional in many common disease, including Alzheimer's, Parkinsons disease and cancer. It is also known to play a role in aging. If the environment of a cell changes, for example if nutrients are decreased or the cell is exposed to toxic agents, nucleoli respond and send signals to other parts of the cell to change the rate of growth/death and many other cellular processes. However, how nucleoli sense changes in the environment, and the signals they send to the other parts of the cell, remain poorly understood. We have recently published a new method by which nucleoli respond to stress that involves degradation of a critical nucleolar protein called TIF-IA. We have also demonstrated that this degradation causes an increase in nucleolar size and simulates a protein in another part of the cell called NF-kB. Since increased nucleolar size and NF-kB stimulation are connected with ageing, we looked to see if TIF-IA-NF-kB may be important in this process using a model called oncogene-induced senescence (OIS). Here we aim to gain full understanding of how stresses degrade TIF-IA. We have exciting preliminary data to suggest that this degradation occurs by a novel mechanisms and so, this will be the focus of these studies. We also aim to identify the signals that link changed levels of TIF-IA to altered nucleolar size and NF-kB stimulation. Again we have preliminary data that has revealed some candidates that may be involved in this process. Finally, and importantly, we aim to confirm the role of TIF-IA-NF-kB in senescence. Given that nucleolar dysfunction and NF-kB pathway activation are both markers of ageing and contribute to poor health, these studies have the very real potential of increasing our understanding of this process and identifying biomarkers that could be used to identify diseased or ageing cells. They may also open up avenues for a new class of drugs that act by targeting both these pathways simultaneously.