Programming the Notch Response

为了构建和维持我们的组织，使它们具有正确的形状和大小，至关重要的是构建模块，即细胞，能够彼此交谈。他们通过专门的通信设备这样做，其中一个使用称为Notch的接收器。当Notch接收到一个信号时，它会给细胞指示该做什么，例如是否要相乘。在正常情况下，系统中存在检查和平衡，以确保细胞正确地发出信号。然而，在几种类型的癌症中，Notch信号传导功能不正常。在许多这些情况下，包括T细胞急性淋巴细胞白血病和乳腺癌，最终会有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。这意味着Notch收到信号时发送的指令必须不同。这也使得使用简单地关闭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，我们希望确定可用于开发更多靶向药物的策略，以避免这些问题。首先，我们的目标是发现什么是防止Notch途径失控的正常检查，以及这些检查是如何被损坏的。其次，我们将找出Notch收到信号后，负责编码Notch发送的指令的原因。为了做到这一点，我们将使用果蝇和人类细胞，并进行大规模分析，使我们能够阅读所有的指令，以“打开”的基因的形式，在正常组织和生长过多的组织中，因为它们具有额外的Notch活性。与此同时，我们将使用一些策略，使我们能够找到细胞中的成分，帮助Notch挑选出哪些基因被激活。我们使用果蝇，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，然而它们拥有超过80%的人类致病基因。然后，我们将我们从果蝇中的发现转化为更复杂的人类乳腺细胞，以显示它们与疾病的相关性，并确定临床应用的最佳途径。

To build and maintain our tissues so that they are the correct shape and size it is vital that the building blocks, the cells, are able to talk to one another. They do so via specialized communication devices, one of which uses a receiver called Notch. When Notch receives a signal it then gives the cell instructions about what to do, for example whether or not to multiply. Under normal conditions there are checks and balances in the system to ensure that the cells signal correctly. However, in several types of cancers Notch signalling doesn't function properly. In many of these conditions, including T-cell acute lymphoblastic leukemia and breast cancers, there ends up being too much signal causing the cells to multiply excessively, forming tumours. Surprisingly, in some other types of cancer the converse is the case. This means that the instructions sent by Notch when it receives the signal must be different. 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 hope to identify strategies that could be used to develop more targeted drugs so avoiding these problems. First we aim to discover what are the normal checks that prevent the Notch pathway running out-of control and how these get damaged. Second we will find out what is responsible for coding the instructions sent by Notch once it receives the signal. To do this we will use both the fruit fly and human cells and will undertake large scale analysis that allows us to read all of the instructions, in the form of the genes that are "turned on", in normal tissue and in tissues that grow too much because they have extra Notch activity. In parallel we will use strategies that enable us to find the components in cells that help Notch to pick out which genes to turn on. 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 80% of the human disease-causing genes. We then translate our discoveries from fruit-flies into the more complex human breast cells to show their relevance for disease and to identify the best routes towards uses in the clinic.