RESETTING AND SCULPTING THE NOTCH RESPONSE

点击翻译按钮获取中文摘要

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.