Grant: Doctoral: Vanier Canada Graduate Scholarships

In many inherited diseases, a mutation present in virtually every cell in the body causes dysfunction in only one or a few tissues or organs. For example, in Huntington's disease, a mutation to the huntingtin gene causes a neurodegenerative syndrome originating in the brain, while sparing most other organs, despite the fact that the mutated protein is expressed in many different types of cells. To understand why this is the case, it is important to realize that genes (and their protein products) do not operate in isolation. Rather, proteins accomplish normal cellular tasks by interacting with other proteins. The protein-protein interactions within a cell form a large and complex network. Mapping this network of interactions-known as the interactome-is essential to understanding both how proteins interact with one another to accomplish biological functions in healthy organisms, and how these interactions are disrupted in disease. However, studies that have mapped the interactome in humans or model organisms have rarely taken into account tissue or cell type. Recent developments in mass spectrometry have made it possible to map the interactome in individual tissues. This new data has the potential to significantly improve our understanding of human biology in general, and of disease more specifically. I propose to conduct computational analyses to reveal how cells separate interactions required for tissue-specific functions from interactions that occur in all cells. I will identify cellular pathways underlying tissue-specific pathologies in hereditary diseases. Finally, I will identify the protein-protein interactions disrupted by genetic mutations associated with inherited diseases in each tissue affected by the disease, to identify molecular mechanisms for many hereditary diseases and new targets for therapy. The analysis proposed here promises to leverage a unique new dataset to develop insights into human biology and the mechanisms underlying human disease.