Grant: Catalyst Grant: Environments, Genes and Chronic Disease

An environmental factor that causes chronic compromised brain function is maternal alcohol exposure. Prenatal alcohol exposure leads to Fetal Alcohol Spectrum Disorders (FASD). FASD refers to neurological disorders that affect 1-3% of live born children and is associated with intellectual disabilities, facial-growth abnormalities and impaired brain function. FASD is the most preventable and life-long brain disease in the Western world, with an estimated annual cost of 5.3 billion CAD for health services and activity loss in Canada. In mice FASD models, MeCP2 protein levels are reduced in the brain of offspring. Precise expression levels of MeCP2 are highly critical for normal brain development and function. Currently, FASD has no cure or prevention, underscoring an urgent need for innovative therapeutic and preventive strategies. This application is a collaborative and new initiative designed to understand the compromised gene expression program of brain cells affected in FASD. The highest MeCP2 levels are detected in brain, but how this is controlled is unclear. In brain, MeCP2 levels are highest in neurons compared to cells that support neurons (e.g. astrocytes). Currently, the biological reasons of such high levels of MeCP2 in neurons are unknown. This is an important scientific question that has not been previously addressed. We reported the first generation of preclinical human MeCP2 gene therapy viruses as well as the cell type-specific MeCP2 expression in the developing and adult brain. As a team with expertise in brain development and disease, combined with control of gene expression expertise in another discipline (cancer research), we propose a collaborative multidisciplinary project to study the molecular mechanisms that regulate MeCP2 expression in brain cells. The outcome will be beneficial for future preventive and therapeutic strategies for FASD as a chronic life-long disease with no cure that is caused by an environmental factor.