Grant: Operating Grant

Stroke is the third leading cause of death in North America, and the leading cause of disability and represents a huge economic and social cost. Stroke is a brain attack from a sudden loss of blood supply to the brain that occurs when the blood supply to a specific part of the brain is suddenly interrupted (ischemic) or when a blood vessel in the brain either bursts or is blocked. Cells in the affected brain die when they no longer receive oxygen and nutrients from the blood, leading to the symptoms and disabilities of stroke patients. However, effective pharmacotherapy that directly protects brain cells from stroke insults is still lacking. Our objectives are to achieve a better understanding of the molecular mechanisms by which stroke insults produce brain cell damage, and thereby develop novel pharmacotherapies. Using cellular models of stroke, we have identified a molecule called PTEN (a lipid phosphatase) as an essential step in the signaling cascade initiated by stroke insults that causes brain cells to die. By understanding the mechanisms by which stroke insults causes the PTEN nuclear translocation, we have been able to devise a novel drug to specifically disrupt this stroke-induced PTEN nuclear translocation, and thereby to reduce stroke-induced brain cell death. We propose further validation using several animal models of stroke if the new drug we developed can be used as a new and effective post-stroke pharmacotherapy. We expect that the completion of our proposed study will help to bring this drug to the point where it can be tested in human stroke patients. Because this therapeutic is specifically designed to target the stroke-related neuronal death process, without affecting normal function of the brain cells in affected areas, it is expected to have minimal side effects. Studies as such can be expected to lead to better stroke therapies and hence, will directly impact the health of Canadians and reduce mortality and morbidity from stroke.