Mutational analysis of the regulation of Notch receptor trafficking and signalling

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In humans numerous cancer-associated mutations in Notch have been identified in different tumours and genetic diseases such as the dementia causing CADASIL disease. The links between the mutations, the affect on Notch signalling and misregulation arising in CADASIL are poorly understood because we lack sufficient understanding of functional contributions of large portions of the Notch receptor to its regulation. Through Drosophila genetics many mutations of Notch have been identified which cause an up or down regulation of Notch signalling, which have been linked to developmental phenotypes in the fly and whose mechanism of misregulation is also unclear. Some of those mutations such as the nd3 allele, resemble the kind of mutation identified in CADASIL patients. Combining these human and Drosophila data sets there is considerable resource of information regarding the locations of different functionally important regions of the Notch receptor structure. This project will combine studies in human and insect cell culture, and in vivo in Drosophila tissues, to understand the fundamental mechanisms of activation or inhibition resulting from different Notch mutations to provide a basic understanding of Notch structure and function and how it relates to the regulation of Notch trafficking which plays a key role in controlling the level of signalling.