Gairdner Symposium - Dr. Ronald Vale and Dr. Bruce Stillman

“New approaches for addressing the effect of genetic variation at scale,” by Douglas M. Fowler, Associate Professor, Department of Gnome Sciences, University of Washington, School of Medicine.

How does a protein’s sequence encode its fold and function?  How do changes in sequence influence disease risk, prognosis and treatment? How do gene expression patterns combine with protein activity to define cellular processes like growth, migration and communication? The Fowler lab is interested in developing new ways to probe the relationship between genotype and phenotype, enabling us to better answer these questions. In particular, we have applied large-scale mutagenesis to reveal a new mechanism of kinase regulation, to better understand the meaning of variants in human genomes, and to better predict the impact of mutations.

Monday, October 7, 1019, at 2:30 pm, LSC #3

Hosted: by Christian Kastrup

“Physical Perturbations to the Gut Microbiota During Health and Disease,” by Carolina Tropini, PhD, Assistant Professor, School of Biomedical Engineering and Department of Microbiology & Immunology, UBC.

The consortium of microbes living in and on our bodies is intimately connected with human biology and deeply influenced by physical forces. Despite incredible gains in describing this community, and emerging knowledge of the mechanisms linking it to human health, understanding the basic physical properties and responses of this ecosystem has been comparatively neglected. Most diseases have significant physical effects on the gut; diarrhea alters osmolality, fever and cancer increase temperature, and bowel diseases affect pH. Furthermore, the gut itself is comprised of localized niches that differ significantly in their physical environment, and are inhabited by different commensal microbes. Understanding the impact of common physical factors is necessary for engineering robust microbiota members and communities; however, our knowledge of how they affect the gut ecosystem is poor.

We are investigating how changes in osmolality affect the host and the microbial community and lead to mechanical shifts in the cellular environment. Osmotic perturbation is extremely prevalent in humans, caused by the use of laxatives, lactose intolerance, or celiac disease. In our studies we monitored osmotic shock to the microbiota using a comprehensive and novel approach, which combined in vivo experiments to imaging, physical measurements, computational analysis and highly controlled microfluidic experiments. By bridging several disciplines, we developed a mechanistic understanding of the processes involved in osmotic diarrhea, linking single-cell biophysical changes to large-scale community dynamics. Our results indicate that physical perturbations can profoundly and permanently change the competitive and ecological landscape of the gut, and affect the cell wall of bacteria differentially, depending on their mechanical characteristics.

Monday, September 9, 2019 at 2:30 pm, LSC#3
Host: Dr. Christian Kastrup

“Charting metabolism in health and disease by activity metabolomics and nanostructure imaging mass spectrometry,” by Amelia Palermo, post-doctoral scientist.

Department of Biochemistry and Molecular Biology and BC Children’s Hospital presents Amelia Palermo, candidate for joint Faculty position in BMB and BCCHRI. Amelia is currently a post-doctoral scientist at The Scripps Research Institute Center for Metabolomics in San Diego, working in the group of Professor Gary Siuzdak.  Her research interests focus on the characterization of the metabolic determinants of resistant cancer phenotypes by activity metabolomics  and on the development of novel mass spectrometry-based approaches for metabolomic sand systems biology.

Wednesday, September 4th at 9:30 am
Michael Smith Laboratories, Lecture Theatre, Room 102
2185 East Mall

“Small Molecules Effective for Disruption of HIV-1 Latency“, by Seyedeh Pargol Hashemi, PhD candidate in Sadowski Lab.

Tuesday, August 20, 2019 at 9:00 am, Room 203, Graduate Student Centre, 6371 Crescent Road.

Abstract  

Although antiretroviral therapies have improved the outlook of the HIV epidemic by controlling virus replication, they do not provide a cure. The major barrier to development of a cure lies in the virus’s ability to become transcriptionally silent as chromosomally integrated provirus. The presence of latently infected cells that harbor transcriptionally repressed viral genomes, predominately consisting of long-lived memory CD4⁺ T cells, gives rise to cellular reservoirs that are impenetrable by current therapies. Therefore, devising ways to selectively target these latent reservoirs is imperative for the long-term management of the disease. My thesis focuses on the shock phase of a proposed cure strategy known as “shock and kill,” which aims to induce latent HIV-1 reservoirs that could then be purged via a boosted immune response, specific targeting of infected cells, or by viral-induced apoptosis. To this end, I identified five novel small molecule compounds, of a class commonly referred to as latency reversing agents (LRAs), that are capable of reversing HIV latency without affecting the general T cell activation state. These compounds exhibit synergy for reactivation of latent provirus with other LRAs, in particular, ingenol-3-angelate. One compound, designated PH02, was efficient at reactivating viral transcription in several cell lines bearing HIV-1 reporters at different integration sites. Furthermore, this compound was capable of reversing latency in resting CD4⁺ T lymphocytes from patients on antiretroviral therapy, while producing minimal cellular toxicity. The combination of PH02 and ingenol-3-angelate produces a strong synergistic effect of reactivation, as demonstrated by a quantitative viral outgrowth assay on CD4⁺ T lymphocytes from HIV-1-infected individuals. A comparison of similar efforts from other groups is provided, with the goal of illustrating the diversity of molecular scaffolds that can produce HIV-1 latency reversing activity. I expect these results will contribute to a deeper understanding of mechanisms regulating HIV-1 latency but also will provide insight towards design of optimized structures for development of highly effective LRAs capable of forcing a purge of the persistent HIV-1 infection.

“Moonlighting tRNA synthetases as extracellular targets of matrix metalloproteinases, ” by Parker Jobin, MD/PhD Candidate, Overall Lab.

Wednesday, May 22, 2019 at 9:00 am in Room 200 of the Graduate Student Centre, 6371 Crescent Road.