Drs Freda Miller and Nobuhiko Tokuriki receive CIHR funding

Congratulations to Drs Freda Miller and Nobuhiko Tokuriki for receiving funding from the Canadian Institutes of Health Research (CIHR) for their research projects at the Michael Smith Laboratories! The CIHR Project Grant program is “…designed to capture ideas with the greatest potential to advance health-related fundamental or applied knowledge, health research, health care, health systems, and/or health outcomes”. We look forward to supporting these important projects focused on brain repair (Miller) and antibiotic resistance and novel therapies (Tokuriki) and seeing where the research leads these talented scientists and their teams.

Learn more about each project

Principal investigator: Dr. Freda Miller

Building and rebuilding brain white matter with endogenous neural stem cells

Abstract: Damage to brain white matter occurs following injury and in disorders like multiple sclerosis, and results in a wide variety of neurological issues, including sensory, movement, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation. Brain white matter is comprised of the axons of the nerve cells that conduct information, surrounded by a type of insulation called myelin that ensures signals are sent in a timely and faithful manner. This myelin is made by another brain cell type, oligodendrocytes, and in many of the aforementioned disorders these oligodendrocytes die, myelin is lost, and normal brain information transfer is disrupted. How might we repair this deficiency? Here, we propose a strategy based upon replacing the lost oligodendrocytes, thereby enabling myelin repair and restoration of normal circuitry. To do this, we will take advantage of the fact that our brains contain resident neural stem cells that normally make oligodendrocytes throughout life. We propose to perform studies asking how these stem cells make oligodendrocytes under optimal conditions during development and then to ask if we can recreate these optimal conditions again in the adult injured brain. We will attempt to do this using bioactive agents we define and/or repurposed drugs that we have identified. Ultimately, we hope that these studies will lead to new treatments for human white matter damage.

Principal investigator: Dr. Nobuhiko Tokuriki

Project 1:

Comprehensive characterizations for the molecular and evolutionary mechanisms of beta-lactam ‘resistome’

Abstract: Bacteria, such as P. aeruginosa. E. coli, K. pneumonia, and A. baumannii, can cause serious infectious diseases, including pneumonia, urinary tract infections, and diarrhea. During the past decade, the increasingly rapid spread of bacteria that are resistant to multiple antibiotics has become a real threat to our health systems. A major underlying cause for bacterial resistance is the action of a group of enzymes called beta-lactamases, which destroy beta-lactam antibiotics. Our overall understanding of those enzymes is still limited despite extensive studies in the past decades. We must develop our comprehensive understanding of beta-lactamases, in particular, ‘hidden’ potentials and limitations of the reservoir of beta-lactam resistance that provide future resistance, in particular, our newly developed last resort antibiotics. In this research project, we aim to develop a comprehensive understanding for beta-lactamases. In particular, we will investigate evolutionary potentials and limitations of beta-lactam ‘resistome’ against newly developed clinical and preclinical beta-lactam antibiotics and lactamase inhibitors. We will combine large scale bioinformatics and cutting-edge genetic technology to unveil the sequence-function relationships for all four major classes of beta-lactamases (class A, B, C and D), with an emphasis on beta-lactamases that have been spread among pathogens and non-pathogenic environmental microbes. We will also conduct high-throughput beta-lactamase characterizations and experimental evolution to unveil evolutionary potentials and limitations of several major clinically associated beta-lactamase types. Our research program will greatly advance our understanding of beta-lactamases, and the information obtained in this research will be used to develop robust surveillance programs and mitigation strategies for controlling and preventing further evolution and dissemination of beta-lactamases. 

Project 2:

Novel antibiotic therapies that target bacterial energetic systems

Abstract: Antimicrobial resistance is one of the biggest health, economic and security threats to mankind. Without more effective therapies, it is estimated that 10 million people will die from previously treatable infections by 2050. New therapeutic options are urgently needed, yet antibiotic development has stalled. This proposal seeks to comprehensively characterize bacterial energetic systems, a relatively unexplored antibiotic target, in order to discover, design and optimize more effective antibiotic therapies for multidrug-resistant pathogens. We, and others, have recently revealed that clinical drugs for conditions such as heart disease and diabetes can be repurposed as antibiotics due to their effects on bacterial energetics. In this proposal, we will systematically explore the mechanisms through which these drugs disrupt bacterial energy systems, and examine the ways through which resistance could evolve against them. Furthermore, we will examine the antibiotic efficacy of these drugs in in vitro and in vivo infection models to validate their potential as effective clinical therapies. With promising preliminary results to date, our proposal provides a realistic and feasible path toward the development of new therapeutic options for bacterial infections. The FDA-approved status of these drugs, the protection of intellectual property, and current negotiations with commercial partners, offers promise for rapid progression into the clinic, which is urgently needed to combat this global emergency. 

Learn more about the Canadian Institutes of Health Research (CIHR)