Title of the presentation:

The systems biology of protein trafficking diseases.

Biography:

David Thomas is Chair of the Department of Biochemistry, McGill University and holds the tier 1 Canada Research Chair in Molecular Genetics. Dr. Thomas has made original research contributions in mitochondrial genetics, protein processing, protein folding in the ER, heterotrimeric G protein signaling, and MAP kinase signaling cascades. His research is currently funded by the NCIC, CIHR, and the US and Canadian Cystic Fibrosis Foundations. He has served on many national and international scientific committees and is on the SAB of biopharmaceutical and venture capital companies in Montreal. He is a consultant to companies in the areas of signal transduction, protein trafficking diseases and genomics. He serves on national and international committees. He is leading the Canadian Chemical Biology Network that provides chemical libraries for the Canadian research community, particularly for infectious, orphan and neglected diseases. He is a Fellow of the Royal Society of Canada and was the Director of the Life Sciences Division of the Royal Society of Canada and was President of the Canadian Society for Biochemistry Cellular and Molecular Biology. His present research interests are on the mechanism of ER quality control and its impact on protein trafficking diseases using a variety of approaches.

Abstract:

Protein misfolding diseases are a significant and increasing problem and generally result from the recognition of a mutant protein by the cellular protein quality surveillance system. In protein trafficking diseases, such as the respiratory disease cystic fibrosis, some mutant, but otherwise functional, proteins are recognized by the protein quality control system and retained in the endoplasmic reticulum, retrotranslocated from the ER and degraded by the cytosolic proteasomal system. We are using the respiratory protein trafficking disease cystic fibrosis (CF) to investigate the mechanism of this protein quality control system. From a cell-based high throughput screen of >120,000 compounds we have identified 40 chemically diverse "corrector" compounds that allow the mutant proteins to escape the ER and traffic to the plasma membrane. We are determining the cellular targets and mechanism(s) of action of these correctors with the goal of building a comprehensive model of the cellular and ER protein quality control system. We have used genomics and systems biology tools to achieve this. Using microarrays we have transcriptionally profiled the action of the corrector compounds on human bronchial cells and identified genes that are specific for each class of correctors. We have also a complete genome siRNA screen for genes that are correctors of trafficking. We are combining this data together with disease specific data to derive and test a predictive model of the mechanism of ER protein quality control.

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