"Cell and Cell Based Gene Therapies for Cardio-Pulmonary Disease:
Regulation of Cell Phenotype by Extracellular Matrix"

Host:  Prof. Maurice Ringuette <maurice.ringuette@utoronto.ca>

Abstract:
The loss of peripheral vasculature is the hallmark of serious cardiovascular diseases and can lead to peripheral and myocardial ischemia or if occurring in the lung pulmonary hypertension (PH), an often progressive and fatal disease culminating in right heart failure. Autologous cells derived from the circulation and modified in culture to take on an endothelial phenotype hold promise for the regeneration of lost vasculature. The therapeutic application of these putative endothelial progenitor cells (EPCs) may provide some benefit, yet preclinical studies suggest that patient derived autologous cells are less effective stimulators of vascular repair. We have therefore pioneered the development of gene enhanced autologous cell based treatments for pulmonary hypertension and myocardial ischemia. Our first-in-human clinical trials are on going, with early results demonstrating safety and efficacy in PH patients.  A major limitation of these cell therapies is the extremely low rate of cell engraftment and survival in the target organ. We have hypothesized that modifying the cell surface by either growth on selected matrices or by encapsulation in an engineered provisional matrix will enhance cell survival, differentiation, and targeted organ engraftment ultimately leading to improved tissue regeneration. We found that eNOS expression in these EPCs is regulated by extracellular matrix. Thus the combination of autologous EPCs, gene therapy, and matricellular protein conditioning could be a promising method of  developing a cell therapy with increased potency for vascular regeneration.

Video Conferencing at UTM (DV3138) & UTSc (MW229)

"Origins of Pandemic Cholera from Environmental Gene Pools (and its Fate within Patients)"

Host:  Prof. David Guttman <david.guttman@utoronto.ca>

Abstract:
Some microbes can transition from an environmental lifestyle to a pathogenic one. This ecological switch typically occurs through the acquisition of horizontally acquired virulence genes. However, the genomic features that must be present in a population prior to the acquisition of virulence genes and emergence of pathogenic clones remain unknown. We hypothesized that virulence adaptive polymorphisms (VAPs) circulate in environmental populations and are required for this transition. We developed a comparative genomic framework for identifying VAPs, using Vibrio cholerae as a model. We then characterized several environmental VAP alleles to show that, while some of them reduced the ability of clinical strains to colonize a mammalian host, other alleles conferred efficient host colonization. These results show that VAPs are present in environmental bacterial populations prior to the emergence of virulent clones. We propose a scenario in which VAPs circulate in the environment, they become selected and enriched under certain ecological conditions, and finally a genomic background containing several VAPs acquires virulence factors that allows for its emergence as a pathogenic clone.

"Nuclear Pore Complex: Simple Biophysics of a Complex Biomachine"

Host:  Prof. Tony Harris <tony.harris@utoronto.ca>

Abstract:

Nuclear Pore Complex (NPC) is a key cellular transporter that controls nucleocytoplasmic transport in eukaryotic cells, and is involved in large number of regulatory processes. It is a remarkable device that combines high selectivity with robustness and speed. Its unique transport mechanism is still not fully understood. The centerpiece of NPC transport is the assembly of intrinsically disordered polypeptides, known as FG nucleoporins, lining its passageway, which serve as a template for binding of the cargo-carrying transport proteins. Their conformations and collective dynamics during transport are difficult to assess in vivo. In vitro investigations provide partially conflicting results, lending support to different models of transport, which invoke various conformational transitions of the FG nucleoporins induced by the cargo-carrying transport proteins. Recently, the Nuclear Pore Complex transport mechanism inspired creation of artificial selective nano-channels that mimic its structure and function for nano-technology applications.

I will present a theoretical and computational framework that provides rigorous biophysical underpinnings for the mechanism of transport through the Nuclear Pore Complex. It shows that the spatial organization of FG nucleoporin assemblies with the transport proteins can be understood within a first principles biophysical model with a minimal number of key physical variables, such as the average protein interaction strengths and spatial densities. The model provides a general physical mechanism for selectivity based on the differences in the interaction strength of the transported molecules with the flexible disordered proteins within the NPC. In particular, the model explains how the NPC and related channels can remain selective in the presence of vast amounts of non-specific noise. These results reconcile some of the outstanding controversies and suggest how molecularly divergent NPCs in different species can perform essentially the same function. The theoretical predictions have been verified in experiments with in vitro NPC mimics.

Video Conferencing at UTM (DV3138) & UTSc (MW229)

"Dynamic Temporal Control and Predictive Modeling of Signaling-activated Gene Regulation"

Abstract:
Signal transduction and gene regulatory pathways exhibit dynamic profiles that cause distinct cellular phenotypes. Manipulating these profiles required genetic and drug perturbations of known proteins. We propose an orthogonal approach to perturb and control dynamic signaling and gene regulatory pathways, without genetic or drug perturbations, using extracellular temporal concentration profiles. To demonstrate the feasibility of this approach we interrogate and control the osmotic stress response in yeast, enabling the manipulation of signaling intensity, duration, and shape. Combining quantitative single cell and single molecule experiments with predictive modeling, enables the quantification of thresholds for signal transduction activation, signal transduction saturation and gene expression activation. This approach is independent of the biological pathway or organism and presents a general methodology to interrogate and control signal transduction and gene expression pathways non-invasively.

Host:  Prof. Alan Moses <alan.moses@utoronto.ca>

Video Conferencing at UTM (DV3138) & UTSc (MW229)

"Network Oscillations Coordinate Neuronal Ensembles
during Sleep-dependent Memory Consolidation"

Host:  Prof. John Peever <john.peever@utoronto.ca>

Abstract:
A major feature of mammalian sleep is the presence of low-frequency oscillations
of highly synchronous activity between the cortex and thalamus, and between
thalamocortical circuits and the hippocampus. We find that consolidation of fear
memories and consolidation of plasticity in the visual system are blocked by disruption
of these sleep-dependent oscillations (in hippocampal and thalmocortical circuits, respectively)
in the hours following a learning experience. Our current data suggest that network oscillations
are necessary to promote the stable reactivation of neuronal ensembles, which in turn drives
long-term memory storage across brain circuits.

Video Conferencing at UTM (DV3138) & UTSc (MW229)

"Understanding the Disease – Modifying Effects of Sirtuin 3 in Parkinson’s Disease"

Host:  Maurice Ringuette <maurice.ringuette@utoronto.ca>

Video Conferencing at UTM (DV3138) & UTSc (MW229)

"Molecular Mechanisms of Polarization and Cell Guidance for Collective Migration"

Friday, September 16, 2016
Ramsay Wright Building, Room 432 at 2 p.m.

Host:  Sergey Plotnikov <sergey.plotnikov@utoronto.ca>

Abstract
I will be presenting our recent work on how cells coordinate their cytoskeletal and signaling machineries to be able to collectively migrate. Particularly, we have been employing live cell imaging and a HUVEC endothelial cell model to understand cell polarization and guidance. I will focus my talk on an intriguing discovery we made of an engulfed tubular structure "cadherin fingers" that have a critical role in cell guidance and the coordination of collective migration.