Glycoscience: Glycoscience is a research area in which various scientific methods, including those from both chemistry and biology, are used to understand the roles of specialized carbohydrates linked to proteins and lipids. Within humans 10 different monosaccharide building blocks are conjugated to proteins and lipids. These glycoconjugates are emerging as central players that regulate diverse cellular processes and act as the first line of defense against pathogens. Glycoscience has emerged as a frontier area of molecular biology with the National Academy of Sciences calling for the creation of new chemical tools that can be exploited to further our understanding of the roles of these structures.
Chemical Biology Tools: A major thrust of what we do is to chemical synthesize and create new biochemical research tools that enable the general research community. We developed the first selective inhibitors of O-GlcNAcase and various other glycosidases. We have created orally available picomolar O-GlcNAcase inhibitors that are active in brain. We pioneered the creation of metabolic inhibitors of glycosyltransferases that are active in cells, including inhibitors for O-GlcNAc transferase and fucosyltransferases. We have created proteomics probes to profile O-GlcNAc modified proteins and activity based proteomics probes for profiling glycosidases in cell lysates. More recently we have initiated efforts to synthesize new substrates that permit quantitative live cell imaging of glucocerebrosidase and other glycoside hydrolases. We have also developed unbiased chemical methods to map sites of post-translational modifications including O-GlcNAc to sites on the genome using chemical methods combined with next generation sequencing.
New Biological Insights: Using these new chemical and biochemical tools we contribute to understanding the roles of glycoconjugates in health and disease. A few examples include our work showing that increased O-GlcNAc modification protects against protein aggregation for toxic proteins such as tau. Correspondingly, we have found that blockade of O-GlcNAcase protects against neurodegenerative diseases in tau and amyloid models of Alzheimer's. We also found that O-GlcNAc serves to stabilize the nuclear pore complex, which is the key portal between the nucleus and cytoplasm of cells, from inappropriate degradation. We further showed that O-GlcNAc also occurs co-translationally to protect select nascent chains against premature degradation. And we helped show that O-GlcNAc transferase is a key general regulator of gene expression. We have worked to determine the catalytic mechanism of the enzymes regulating O-GlcNAc, uncovered factors contributing to their substrate specificity, and rationally design inhibitors and proteomic probes that act both in cells as well as in vivo.
We are focused on developing new chemical biology research tools and understanding the roles of glycoconjugates implicated in fundamental cellular processes ranging from regulation of gene expression through to autophagy. We are also working to uncover the roles of these carbohydrates in major human diseases including Alzheimer's, Parkinsons's, cancer, and bacterial infections.
Of particular interest to us is the role of glycoproteins and glycolipids in neurodegenerative diseases like Parkinson's and Alzheimer's. We have made a range of contributions to understanding the O-GlcNAc protein modification, which is implicated in diverse cellular processes ranging from regulation. We continue to develop new chemical tools and methods, as well as to collaborate with other laboratories, to address the roles of O-GlcNAc in gene expression to protein stability.
A new research theme for the laboratory is focused on quantitative live cell imaging of enzyme activity. Recently we developed the first live cell imaging agents to monitor endogenous glucocerebrosidase activity in live cells. And more recently we pioneered the creation of a general approach to monitor the activity of a range of glycoside hydrolases. We are now using these tools to understand why this enzyme is the greatest genetic risk factor for Parkinson's. As well, we continue to develop new chemical probes and inhibitors, as well as new imaging modalities for other glycan processing enzymes including both fluorescence and positron emission tomography agents.
IMPACT of research
Several of our research tools including inhibitors and antibodies have been adopted by researchers within the community. Our fundamental research also has high translational potential. A major portion of our research is funded by agencies with a translational focus including, for example, the Michael J. Fox Foundation for Parkinson Research, the Alzheimer Drug Development Foundation, the Weston Foundation, and the Alzheimer Society of Canada. Group members are inventors of over 20 patents filed in most major jurisdictions. Most patents have been licensed or optioned. Our research and patents were foundational technology for establishing Alectos Therapeutics, which pioneered the development of O-GlcNAc modulators for neurodegenerative diseases including Alzheimer's. The significance of this work is illustrated by Alectos and Merck forming a major partnership and having recently moved OGA modulators and Positron Emission Tomography (PET) agents into Phase I clinical trials.