Mechanisms underlying a decline in neural stem cell migration during aging

PROJECT SUMMARY Aging is the main risk factor for a variety of brain diseases, such as stroke and neurodegenerative diseases. Additionally, recovery from stroke and other types of brain injury declines with age. There is an unmet need for the development of more effective therapies centered on aging to counter the decline in repair capacity and the onset of neurodegenerative diseases. The adult brain contains neurogenic stem cell niches that have the potential to generate new progeny that migrate to distal sites, which could play a critical role for repair in age- related disease and injury. During aging, neural stem cells show a progressive loss in their ability to proliferate and give rise to new neurons (neurogenesis), and this is accompanied with a decline in repair ability. However, the mechanisms underlying this deficit are not well understood. My preliminary findings suggest that aging leads to changes in cell migration and adhesion abilities in neural stem cells, with activated neural stem cells and their progeny becoming less migratory with age. Based on these findings, my specific hypothesis is that with age, activated neural stem cells undergo reversible changes in cell migration and adhesion that lead to decreased neurogenesis. My proposal aims to elucidate the mechanisms underlying the age-related decline in migration in activated neural stem cells and uncover therapeutic strategies to mitigate this. Aim 1 will identify specific genes and regulatory factors that underlie the migratory defect in old activated neural stem cells and perturb them to boost the migration of old cells. Aim 2 will evaluate the therapeutic potential of blocking a signaling pathway that is important for regulation of cell migration and adhesion for repair upon stroke injury and explore the mechanisms by which it does so. Together, these independent aims will contribute to the field by giving a mechanistic understanding of how age causes a decline in neural stem cell function through dysregulation in cell migration and adhesion as well as provide a potential therapeutic avenue for improving neurogenesis and recovery from stroke in old brains. Through this work, I will be trained in the field of aging and neural stem cells as well as gain diverse expertise in cutting-edge experimental approaches. My scientific training coupled with mentoring by physician-scientists will help me in building a career as a physician-scientist interested in brain aging and treating patients with neurological diseases.