Research in my lab is centered around the cellular and molecular mechanisms of neuronal damage during stroke and other injuries such as epilepsy and trauma. Our focus is on calcium-regulated signaling pathways that cause neurons to die when injured. Our main contributions to this field has been the determination that acute damage to neurons is mediated by distinct signaling pathways that are specifically associated with certain types of cell membrane receptors and ion channels. We are working on elucidating these pathways, with the goal of finding rate-limiting steps that might be amenable to modulation by pharmacological or genetic means. The ultimate goal therefore, is to design rational therapeutic strategies for neuronal injury based on a concrete understanding of the molecular mechanisms that cause it.
1) We are working on mechanisms of coupling of Ca2+ influx through the NMDA subtype of glutamate receptors to intracellular second messengers that trigger neurotoxic signaling pathways. This project is centered around an understanding and modulation of the molecular organization of synapses, and the treatment of neuronal injury triggered by postsynaptic glutamate receptors.
2) We are working on mechanisms of anoxic cell damage that are independent of postsynaptic glutamate receptors. Current projects involve the elucidation of Ca2+-dependent intracellular signaling pathways that result in cell death in the absence of excitotoxicity (glutamate-receptor-mediated damage).
3) We are working on protein-protein interactions in the postsynaptic density of neurons that affect learning, memory, pain behaviors and ischemic vulnerability.
The scope of each project includes studies in tissue culture and in-vivo models. Techniques most commonly used are neurophysiological, including Ca2+ imaging, confocal imaging, electrophysiology, molecular biology, protein chemistry and animal models of stroke and neurotrauma.
Keywords Stroke, cerebral ischemia, synaptic mechanisms, glutamate, transient receptor potential channels, TRPM7, animal models, rats, primates, protein-protein interactions.
Dr. Tymianski is a cerebrovascular neurosurgeon-scientist. Hi is the Head of the Division of Neurosurgery, University Health Network, Toronto. He is a Senior Scientist, Toronto Western Hospital Research Institute, a Professor, Dept of Surgery, University of Toronto, Medical Director, Neurovascular Therapeutics Program, University Health Network, a and a Canada Research Chair (Tier 1) in Translational Stroke Research.
Dr. Tymianski Trained in Neurosurgery at the University of Toronto, and Graduated from the residency training program in 1995. During his residency, he also obtained a PHD in Neuroscience from the University of Toronto.
He completed two cerebrovascular fellowships, one at the University of Toronto, and one at the Barrow Neurological Institute in Phoenix, AZ.
He has been an attending neurosurgeon and a stroke researcher since he joined the Department of Surgery, U of T, in 1997.
Dr. Tymianski practices cerebrovascular and skull base neurosurgery, with a specific interest in minimally-invasive aneurysm surgery, and in brain revascularization. He has popularized the use of minicraniotomy approches to aneurysms, and practices day surgery for unruptured anterior circulation aneurysms. He also uses the ELANA technique (Excimer Laser-Assisted Nonocclusive Anastamosis) for long vein bypass surgery, and has a significant interest in Moya-Moya disease.
His long-term research goal is to devise pharmacological strategies to protect the brain following acute or chronic neurological insults, and especially ischemic insults. To this end, Dr. Tymianski heads a research laboratory dedicated to the understanding of the cellular and molecular mechanisms of neurodegeneration. The lab possesses expertise ranging from protein chemistry and molecular biology, through to in-vitro assays, drug screening methods, neurophysiology (including fluoresent ion imaging and electrophysiology), and animal models of disease including models in rodents (rats and mice) and in non-human primates. Two main projects in his lab comprise the development of two novel classes of agents that inhibit ischemic cell damage. The first are termed "PSD95 inhibitors", which are peptides that uncouple glutamatergic signalling from deleterious cell death pathways. The second is centered on the Transient Receptor Channels, especially TRPM2 and TRPM7, which play a key role in ischemic cell damage. Inhibiting these channel imparts mammalian cells, including CNS neurons, with resilience to ischemia and other insults.
Dr. Tymianski is regarded as an expert on the role of TRP channels in ischemic cell death, and has published the world’s most cited articles on the subject. He discovered that the TRPM7 channel comprises the main mechanism by which neurons die from anoxia (Aarts et al., Cell, 2003), and subsequently showed that suppressing TRPM7 in-vivo renders brain neurons resistant to stroke (Sun et al., Nature Neuroscience, 2009).
Dr. Tymianski’s most advanced contribution relates to the development of PSD95 inhibitors. In 1999 he described that PSD95, and abundant protein found in neuronal synapses, may constitute an important therapeutic target (Sattler et al., Science, 1999). By 2002, he developed a drug, now termed “NA-1”, that inhibits PSD95 and reduces ischemic brain damage in rats (Aarts et al, Science, 2002). This finding has been reproduced by several investigators worldwide. Over the next decade, the Tymianski lab focused on translating NA-1 to the point of clinical utility through extensive target validation (Cui et al, J Neurosci, 2007), testing in rodent models (Sun et al., Stroke, 2008) and, ultimately, in primate models of stroke (Cook et al., Nature, 2012; Cook et al., Science Translational Medicine, 2012).
Concomitantly with the academic studies of NA-1, Dr. Tymianski founded a biotechnology company, NoNO Inc. (named after the mechanism of action of NA-1, which inhibits Nitric Oxide production in the brain). Dr. Tymianski has been the president and CEO of NoNO Inc since its inception, and has raised in excess of $30M in capital. Through NoNO, Tymianski’s team conducted the GMP and GLP studies required by Health Canada and the FDA to enable NA-1 to be tested in human clinical trials. A Phase 1 trial of the safety of NA-1 was completed in 2007.
In 2012, Tymianski and his team published the first and only clinical trial of a stroke neuroprotectant that had shown efficacy in human beings (Hill et al., Lancet Neurology, 2012). This was a Phase 2 multicenter, randomized placebo-controlled trial of NA-1 conducted in 185 patients in 14 centers in Canada and the USA. It was the culmination of the academic work conducted in the Tymianski research lab, and the preclinical safety, pharmacology and PK studies conducted by NoNO Inc. The results of the trial received significant attention from both the lay and academic media (e.g., Nature Medicine, 2012).
Dr. Tymianski’s team has just received approval from Health Canada and the FDA to conduct a pivotal, Phase 3 trial of NA-1 in stroke patients. This will be a multi-center trial conducted in Toronto, Vancouver, and Los Angeles. If the trial is successful, this will be the first time since the invention of insulin that a basic scientific discovery made by a researcher in Toronto will have been translated to clinical utility by the same researcher.
Additionally, due to his extensive expertise in both fundamental and translational stroke research, Tymianski has become an influential figure in translational stroke research and clinical stroke trials, and contributes influential reviews of these topics (Tymianski, Stroke 2013; Tymianski, Nature Reviews Neurology, 2014). He has an H-index of 81 (Google Scholar), and is among the most frequently cited neurosurgeons worldwide (23,780 citations as of March 2, 2014). He is currently the inventor on >95 patents, has trained > 30 trainees at the MSc, PhD, and Post-Doctoral levels in his lab, and has had extensive peer-review research funding from the Heart and Stroke Foundation of Canada, the Canadian Institutes of Health Research, the Canadian Stroke Network, and the Ontario Ministry of Research and Innovation. His most recent research grant on which he is the principal investigator has just been awarded by the National Institutes of Neurological Disorders and Stroke (NINDS) of the NIH, consisting of approximately USD $5M to develop next generation PSD95 inhibitors. Funding by NIH to a foreign PI is extremely rare (<2% of all foreign applicants are funded), and speaks to the worldwide recognition and expertise that Dr. Tymianski has garnered throughout his career.
Cell and tissue culture: Neurons, primary neuronal cultures and cell lines.
Procedures: Adenovirus, behavioural tests, electrophysiology, HPLC, gene expression analysis, induction of cerebral ischemia in animals, immunohistochemistry, immunocytochemistry, in vitro electrophysiology, high throughput screening, microarrays, patch clamp, qRT-PCR, RT-PCR, signal transduction characterization, siRNA, stereotaxic brain surgery, vessel cannulation, voltage clamp, western blot.
Amplifier, analytical balances, benchtop centrifuge, blotting apparatus, calcium imaging system, confocal microscope, culture hood, culture incubators, cryostat, departmental beta and gamma counters, digidata, digital microscope, dissecting microscope, electrophysiology rig, fluorescence microscope, fresh tissue sectioning systems, gel apparatus, HPLC, infusion apparatus, low- and high-speed centrifuge, low and ultralow freezers, micropipette puller, microwave oven, mini vortexer, monochromator, motorized micromanipulators, ProBlot Hybridization Oven, Real-time/Thermocycler, setups for electropherosis, stimulator, stirrer/hot plate, vibratome, water baths.