Characterising and targeting Cyclin D stabilisation in development and disease.

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The growth of organisms, and organs such as the brain, fingers and toes, occur by cells dividing and changing from simple precursors into complex cells with specific functions through a series of carefully regulated processes. The cell cycle controls cell division by requiring the cell to pass multiple checkpoints to ensure only a healthy cell can divide. Another important ability for a cell is to be able to stop dividing. When no more cells are required in the developing brain, cells exit the cycle resulting in no more cells being produced than are needed. Failure to exit the cell cycle can lead to excessive cell numbers, and so-called overgrowth disorders, whereby organs are too big and often do not have the correct structure. In the brain this results in the disorder megalencephaly. While brains generally stop growing once fully developed, the brains of people with overgrowth disorders continue to grow. This growth persists even after surgical intervention, resulting in further complications. Interestingly in over-growth syndromes, some patients, also have an extra finger and/or toe. Taken together, these observations tell us that precise management of the cell cycle is required for development of the brain and formation of limb digits.The aim of this study is to investigate a family of proteins called D-type Cyclins (CCND), which act as a molecular switch for the cell cycle. This will help to understand the molecular processes that control the cell cycle and how these lead to developmental defects when they don't work correctly. When CCND levels are high, cells continue to divide to create more cells, however when CCND is switched off the cells stop dividing. I am interested in disorders that occur which CCND2 does not get switched off, meaning cells continue to divide even when they're not supposed to. In particular, I want to learn more about the molecules that control this switch, what happens in a cell when the switch cannot be turned off and to develop molecules that overcome high levels of CCND2 in order to stop the cells dividing. Using this information, I hope to learn how cells signal to stop cell division normally and therefore how they coordinate the development of complex structures such as the brain. Currently there are no cures or therapies available that can overcome the post-natal effects of CCND2 stabilisation. In some cases surgery is attempted, but with limited success. As well as CCND2, other D-type Cyclins such as Cyclin D1 also cause disease, such as breast cancer, when they cannot be switched off. By gaining new insights into the mechanisms governing the cell cycle, my aim is to not only identify new disease genes which cause these conditions and understand the roles they play, but also develop novel treatments in order to improve the quality of life for patients and their families.