Grant: Project Grant

Canadian life expectancy is increasing but with this improvement the rates of cardiovascular disease, stroke and vascular dementia are rising. Dementia is a devastating condition that causes loss of memory, cognitive decline, impaired thought processes and social isolation. It is often associated with cardiovascular disease. The emotional, physical and economic impact of dementia to the individual, their families and communities is enormous. 60 million people worldwide live with dementia and this will double every 20 years. In Canada 2 million people have dementia and it is estimated that the current economic burden of $40 billion will increase by 275%. Despite its high prevalence, the exact causes still remain unknown and there are no effective cures. Moreover, drugs to slow progression of dementia are lacking. New research indicates that damage of small blood vessels in the brain is an important factor associated with vascular dementia. However, the processes causing this need to be uncovered. It is only through the understanding of these processes that specific new treatments can be identified. We will study a condition called CADASIL, where patients have vascular dementia due to abnormal and damaged small blood vessels. CADASIL is known- this is due to a mutation of a gene called NOTCH3. We discovered some factors (called Rho kinase and ER stress) that are associated with the abnormal NOTCH3 gene that causes damage to blood vessels leading to dementia. Our objective is to better understand the pathology of vascular dementia, and to discover new molecules specifically Rho kinase and ER stress as potential treatment targets. We will study various experimental models, including cells, blood vessels and mice. We aim to show that inhibiting Rho kinase and ER stress pathways restores vascular function and slows cognitive decline. Our ultimate goal is to propose a Rho kinase inhibitor as a potential new therapy in CADASIL and other disorders of small blood vessels.