Area:
Stroke, NMDA receptors, TRP channels
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High-probability grants
According to our matching algorithm, Michael Tymianski is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
1999 — 2001 |
Tymianski, Michael |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Mechanisms of Calcium-Dependent Excitotoxicity @ Toronto General Hospital
disease /disorder model; laboratory mouse; tissue /cell culture
|
1 |
2004 — 2008 |
Tymianski, Michael |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Targeting Psd Proteins in the Treatment of Cns Injury @ Toronto Western Hospital
DESCRIPTION (provided by applicant): My goal is to find a treatment for stroke and CNS injury. Such injuries are partly mediated by synaptic glutamate receptors, which are also essential for CNS function. Curtailing synaptic function with glutamate antagonists is harmful and is a failed approach to treating stroke in humans. We have shown that toxic glutamatergic signals are restricted to distinct pathways, indicating that they might be blocked selectively, without affecting essential synaptic activity. This grant pursues our discovery of the molecular mechanism for neurotoxic signaling, which depends on NMDA receptor (NMDAR) interactions with submembrane scaffolding proteins. A key interaction is that of NMDARs with the scaffolding protein PSD-95. We have suppressed neuronal PSD-95, which uncoupled NMDARs from nitric oxide synthase, an enzyme tethered to NMDARs by PSD-95. This blocked NMDAR toxicity without blocking synaptic activity. More recently, using cell-permeant peptides that disrupt NMDAR/PSD-95 coupling, we treated stroke in animals. The treatment reduced focal ischemic brain damage in rats and improved their neurological outcome without blocking synaptic function. Our approach avoids the negative consequences of blocking NMDARs and may constitute a practical stroke therapy. We propose to pursue this promising approach further. In AIM 1 we will determine the mechanism of action of the therapeutic molecules that we discovered. In AIM 2 we will focus on the therapeutic limits (therapeutic window, duration of effect, neurobehavioral consequences) and toxicity of treating stroke and CNS trauma by dissociating NMDAR/ PSD-95 interactions. In AIM 3 we will identify novel therapeutic targets for neurological disease based on downstream interactions of PSD-95. The results will provide knowledge on mechanisms of disease and synaptic function, and validate a stroke treatment with the future intention of proceeding to human trials.
|
1 |
2014 — 2017 |
Tymianski, Michael |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Development of a Next-Generation Psd95 Inhibitor For the Treatment of Acute Ische @ University Health Network
DESCRIPTION (provided by applicant): The mission of NINDS is to reduce the burden of neurological disease. Stroke is a leading cause of mortality and disability, affecting 795,000 people annually in the US at a direct and indirect cost of $38.6 billion. Stroke i a rapidly progressive disorder, with brain damage being near complete by 3 hours after stroke onset. There is a major unmet need for safe stroke treatments to reduce the burden of stroke and improve stroke victims' outcomes. We will address this need by developing an emergency stroke medication that is safe enough to be given to stroke victims in the community even before arrival to a hospital (e.g., by paramedic), or immediately on hospital arrival, thus arresting stroke progression within the first golden hour and preferaby no later than 3h after stroke onset. This will be achieved by developing a safe and effective drug that targets neuronal postsynaptic density 95 protein (PSD95), termed a PSD95 inhibitor. We have already developed a prototype (termed NA-1) that reduces stroke damage in animals and humans, but that has the side effect of producing hypotension. This makes NA-1 unsuitable for use in emergency situations. To improve on NA-1 we identified 7 potential related candidates. Our objective is to evaluate each in order to select the optimal Lead Candidate for further development in future clinical trials. This will be done through the followin steps: In vitro lead selection: The 7 candidates will be evaluated in vitro for optimal properties that are predictive of efficacy in animal stroke models and for clinical utility; Lad selection in animals: The same candidates will be evaluated in rats for lack of hypotension and then advanced to more detailed animal studies that include evaluations of the drugs' efficacy in experimental strokes. The most effective and safe single candidate will be advanced to the next steps; Manufacturing and formulation studies: The lead PSD95 inhibitor will be manufactured to regulatory (FDA/ICH) standards and used to create a formulation in a drug vial that protects the drug from degrading and that can be used in an ambulance or a hospital; Safety Pharmacology and Toxicity testing. This lead candidate will then be tested in the necessary studies to demonstrate safety in animals, and to confirm that it is appropriate for advancement to a filing of an IND for a Phase 1 human trial. Filing of an IND: The project will culminate with a filing of an IND with the FDA for a Phase 1 human trial. We have already successfully translated NA-1 all the way from its discovery to a successfl phase 2 human clinical trial and are experienced in the process of developing a PSD95 inhibitor and the filing of IND submissions. We are thus confident that this project will provide a safe emergency neuroprotectant for further development in order to reduce the extraordinary burden of stroke on our society.
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0.94 |