RESETTING AND SCULPTING THE NOTCH RESPONSE

细胞之间的交流是人体的组成部分，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。细胞交流的一个关键方式是通过Notch受体。当Notch接收到信号时，根据单元的先前历史，指令的解释会有所不同。例如，一个细胞是否会继续繁殖将取决于它的基因组是如何设置来接收信号的。在正常情况下，系统中有制衡机制，以确保细胞正确响应。然而，在几种类型的癌症中，Notch信号不能正常工作。在许多这样的情况下，包括T细胞急性淋巴母细胞性白血病和乳腺癌，产生太多的信号，导致细胞过度增殖，形成肿瘤。令人惊讶的是，在一些其他类型的癌症中，情况正好相反。这使得了解细胞将如何在特定的组织环境中解释Notch信号变得重要。这也使得使用简单地切断Notch信号的药物治疗变得更加困难，因为它们可能会对某些组织产生破坏性影响。通过回答两个关键问题，我们将对细胞环境有更好的了解，这将增加Notch活性致癌的可能性。这些信息将在为患者治疗制定最佳战略以及确定可用于开发靶向药物或药物组合以避免当前治疗问题的途径方面具有价值。首先，我们的目标是找出正常情况下是什么重置了细胞解释Notch信号的方式，以确保它们不会通过未经检查的分裂而成为癌症干细胞而表现不当。其次，我们将找出基因组的哪些结构特征有助于引导信号，以便在基因启动时产生正确类型的产品。为了做到这一点，我们将同时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挑选出哪些基因可以打开，并找到细胞中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由于Notch活性过高而过度生长的组织基因组结构的全球变化。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活的有机体中进行研究，使破译信息变得更简单，但它们拥有超过75%的人类致病基因。然后，我们将我们在果蝇身上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，并确定临床使用的最佳路线。

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.