Development of pre-clinical stroke models

Project Leader:

Michael Tymianski, Toronto Western Research Institute

Project Team:

R. Loch Macdonald, St. Michael’s Hospital, Toronto
David Mikulis, Toronto Western Research Institute
Michael W. Salter, Hospital for Sick Children
Yu-Tian Wang, University of British Columbia
Andy Tasker, University of Prince Edward Island
Michelle Aarts, University of Toronto
Douglas Cook, Toronto Western Research Institute
Hong Cui, Toronto Western Research Institute
Hong-Shuo Sun, Toronto Western Research Institute
Jinglu Ai, St. Michael’s Hospital
Lucy Teves, Toronto Western Research Institute
Michael D. Hill, University of Calgary
Nicholas Hatsopoulos, University of Chicago

Project Summary:

Among its missions, the CSN is dedicated to translating fundamental research to the point of clinical utility. Since its inception, CSN scientists have studied stroke mechanisms and neuroprotective strategies, of which some are in clinical trials. But progress has been slow because research has been restricted to tools comprising genetic and biochemical assays, cell based assays, and rodent models of stroke. Historically, these tools have failed to translate stroke treatments to human use even though fundamental biology is unlikely to differ between humans and rodents. This indicates that rodents and humans differ at one or more critical levels that cannot be evaluated using current tools. While acknowledged, these unknowns have never been adequately addressed. Thus, the Project Team PIs have agreed to jointly participate in elucidating stroke mechanisms in more relevant models (RM).

The long-term goal is to test the feasibility of treating acute ischemic stroke in RMs. To achieve this, a practical stroke model must be established in which rodents and RMs are evaluated simultaneously at the levels of molecules (e.g., expression of stroke-related genes and proteins), cells (relevant neurophysiological processes), the neurovascular unit, higher levels of anatomical organization and, importantly – surrogate measures of stroke outcome such as imaging and neurobehaviour. The first task is development of an RM of focal ischemic stroke that can be evaluated at all levels of biological organization, but also all surrogate outcome measures used in humans. This proposal provides an unprecedented opportunity in Canada to obtain knowledge on stroke mechanisms in RMs, thus moving basic stroke research as close as possible to the human situation.

Targeting Cell Death

Project Leaders:

David Park, University of Ottawa
Brian MacVicar, University of British Columbia
John MacDonald, University of Toronto

Project Team:

Michael W. Salter, Hospital for Sick Children
Michael Tymianski, Toronto Western Research Institute
Peter K. Stys, University of Calgary
Tim H Murphy, University of British Columbia
Ruth S. Slack, University of Ottawa
Roger Thompson, University of Calgary
Yu-Tian Wang, University of British Columbia
Serge Rivest, Université Laval
Jiming Kong, University of Manitoba
Christian Naus, University of British Columbia
Steffen-Sebastian Bolz, University of Toronto
Michelle Aarts, University of Toronto

Project Summary:

The purpose of this work is to understand how signaling cascades that are initiated and maintained by ion channel proteins lead to the loss of brain cells following ischemic stroke; and, to develop potential therapies to prevent this cell death. Although the loss of blood flow during ischemia results in the inevitable death of many nerve cells in what is called the “ischemic core,” there is an even greater region (“the penumbra”) where the cells do not die until long after the stroke has finished. This resulting loss of cells has a devastating effect on the functioning and quality of life of stroke victims. The objective of this project is to stop the death of cells in the penumbra, minimize the severity of the stroke and to greatly improve the recovery of stroke patients. The approach is to bring together a group of outstanding Canadian fundamental and clinical neuroscientists who have major ideas about how to prevent cell loss. There are also very strong international collaborators, and the project provides promise for the development of effective agents or drugs for the treatment of ischemic stroke. Most importantly, the group will act as a research incubator for the development and implementation of new stroke drugs. Several group members have formed a Canadian biotechnology firm that has taken a discovery into Phase 2 clinical trials.