RESETTING AND SCULPTING THE NOTCH RESPONSE

细胞之间的交流是身体的基本组成部分，对构建和维持我们的组织至关重要。这种沟通的失败是许多疾病的原因，特别是许多类型的癌症。细胞沟通的一个关键途径是通过Notch受体。当Notch接收到信号时，根据细胞以前的历史，指令被不同地解释。例如，一个细胞是否会继续繁殖将取决于它的基因组如何设置以接收信号。在正常情况下，系统中存在检查和平衡，以确保细胞正确反应。然而，在一些类型的癌症中，Notch信号不能正常发挥作用。在许多这样的情况下，包括t细胞急性淋巴细胞白血病和乳腺癌，产生过多的信号导致细胞过度繁殖，形成肿瘤。令人惊讶的是，在其他一些类型的癌症中，情况正好相反。这使得了解细胞如何在特定的组织环境中解释Notch信号变得非常重要。这也使得使用仅仅关闭Notch信号的药物治疗变得更加困难，因为它们可能对某些组织产生破坏性影响。通过回答两个关键问题，我们将更好地了解细胞环境，这将增加Notch活性致癌的可能性。这些信息对于制定最佳的患者治疗策略和确定可用于开发靶向药物或药物组合的途径，以避免当前治疗的问题，将是有价值的。首先，我们的目标是发现通常是什么重置了细胞解释Notch信号的方式，以确保它们不会因为不受控制地分裂而成为癌症干细胞而行为不当。其次，我们将发现基因组的哪些结构特征有助于引导信号，以便在基因开启时产生正确类型的产物。为了做到这一点，我们将使用果蝇和人类细胞，并将使用使我们能够实时可视化基因组重置方式的策略，以帮助Notch挑选哪些基因开启，并在细胞中找到促进这一过程的成分。我们还将进行大规模分析，使我们能够检测正常组织和生长过多的组织中基因组结构的全局变化，因为它们具有额外的Notch活性。我们使用果蝇是因为它们有一个更简单的系统，我们可以很容易地在生物体中研究，使其更直接地破译信息，但它们有超过75%的人类致病基因。然后，我们将果蝇的发现转化为更复杂的人类癌细胞，以显示它们与疾病的相关性，并确定临床应用的最佳途径。

Communication between cells, the building blocks of the body, is essential to build and maintain our tissues. Failures in this communication are the cause of many diseases, especially many types of cancers. One key way cells communicate is via the Notch receptor. When a signal is received by Notch, the instructions are interpreted differently depending on the previous history of the cell. For example, whether or not a cell will go on to multiply will be based on how its genome is set up to receive the signal. Under normal conditions there are checks and balances in the system to ensure that the cells respond correctly. However, in several types of cancers Notch signalling doesn't function properly. In many of these conditions, including T-cell acute lymphoblastic leukaemia and breast cancers, too much signal is produced causing the cells to multiply excessively, forming tumours. Surprisingly, in some other types of cancer the converse is the case. This makes it important to know how the cells will be interpreting the Notch signal in a particular tissue context. It also makes it more difficult to use drug treatments that simply shut off the Notch signal as they could have damaging effects in some tissues. By answering two key questions we will acquire a better understanding of cell circumstances that will increase the probability that Notch activity will be oncogenic. This information will be valuable in working out the best strategies for patient treatments and to identify avenues that could be used to develop targeted drugs or drug combinations to avoid problems with current treatments. First we aim to discover what normally resets the way that cells interpret Notch signals, to ensure that they do not behave inappropriately by dividing unchecked and becoming cancer stem cells. Second, we will find out what architectural features of the genome help guide the signal so that the right types of product are made when the genes are turned on. To do this we will use both the fruit fly and human cells and will use strategies that enable us visualize in real time the way the genome is reset to help Notch to pick out which genes to turn on and to find the components in cells that facilitate this. We will also undertake large-scale analysis that allows us to detect global changes in the genome architecture in normal tissue and in tissues that grow too much because they have extra Notch activity. We use fruit flies because they have a simpler system that we can easily study in the living organism, making it more straightforward to decipher the information, yet they have over 75% of the human disease-causing genes. We then translate our discoveries from fruit-flies into the more complex human cancer cells to show their relevance for disease and to identify the best routes towards uses in the clinic.