Structure-Based Immunogen Design
Malaria and HIV-1 are two of the most devastating and ongoing health burdens, particularly in the developing world. Protective vaccines against these pathogens remain elusive, in part because of our inability to induce by vaccination high-neutralizing antibody titers against conserved antigenic sites.
We use epitope-selective, structure-based protein design strategies to generate novel immunogens that elicit antibodies blocking the function of critical malaria and HIV-1 proteins.
We study the fundamentals of protein nanoparticle assembly and use protein engineering and biophysical techniques to broaden the development of stable glycoprotein nanocages. Our objective is to uncover the fundamentals of protein nanoparticle self-assembly to engineer the transport of multimerized glycoproteins on vehicles with loaded cargo.
Over half of human proteins have modifications that lead to their glycosylation. Their multimerization regulates a variety of biological processes including gene expression, activity of receptors, and cell-cell adhesion. Our research in protein design and glycobiology has previously shown that self-assembling protein cages can be used for the external display of viral glycoproteins.
Structural Delineation of B cell Receptors
B cells are central to immunity. They protect hosts against pathogens primarily through the production of neutralizing antibodies. As such, surface receptors on B cells are prominent targets for the design of vaccines that can elicit high titers of neutralizing antibodies.
Conversely, dysregulation of B cell homeostasis can lead to autoimmune diseases, as well as devastating blood cancers, such as leukemias and lymphomas. B cell surface receptors are therefore also targets for the development of therapeutics that can deplete dysregulated B cells. Molecular structures of key B cell receptors are critically lacking, preventing a deep understanding of their functions and hindering the rational design of next-generation biologics.
We use integrative structural biology techniques to provide molecular details into the function and targeting of B cell receptors.
Platforms for Studies of Antibody-Antigen Complexes
We have assembled high-throughput platforms in glycoprotein biochemistry and structural biology to study antibodies and glycoproteins in health and disease. These include high-capacity incubator/shakers and high-performance purification equipment for the isolation of homogeneous glycoproteins from expression in mammalian/insect cells; high-throughput and micro-volume systems for the biophysical characterization of glycoproteins and their interactions with antibodies; and an automated crystallography infrastructure.
The SickKids Research Institute offers some of the most complete specialized core facilities in Canada, including the Nanoscale Biomedical Imaging Facility to perform structural analysis by cryo-electron microscopy on the revolutionary K2 summit direct-detector.