Stroke induces the generation of new neurons and their migration to sites of ischemic damage in the brain. This process of post-stroke neurogenesis occurs in rodents, primates, and humans, and may contribute to functional recovery. After stroke, new neurons (neuroblasts) preferentially migrate to, and intimately associate with, the remodeling (angiogenic) vasculature in peri-infarct cortex. Previous work has shown that neurogenesis and angiogenesis are causally linked in this peri-infarct niche, though the signals derived from angiogenic blood vessels that mediate the migration of neuroblasts are not known. As part of the preliminary studies for this grant, we have identified a set of gene systems uniquely upregulated in peri-infarct angiogenic vessels during the process of neuroblast in-migration after stroke. These systems encode for secreted or membrane-bound products that are in a position to signal to neuroblasts and guide their migration into peri- infarct cortex. The overarching goal of this proposal is to determine the causal role of two of the most promising candidate signaling systems - the cytokine oncostatin M and neurotrophic protein pigment epithelium-derived factor - in post-stroke neuroblast migration and functional recovery. Although post-stroke neurogenesis may represent an attempt by the brain for endogenous neural repair, the role of this process in functional recovery has been unclear. Modulation of angiogenic signaling to neuroblasts may potentiate post- stroke neurogenesis and promote functional recovery after stroke. In the proposed experiments, we will utilize a local protein delivery system to enhance and supress OSM and PEDF signaling in peri-infarct cortex in order to determine their causal role in post-stroke neurogenesis. Moreover, we will assess the ability of these interventions to influence functional recovery after stroke, and determine whether their effects are dependent on adult neurogenesis by conditionally ablating post-stroke neurogenesis. Our goal is to demonstrate that these two signaling systems serve as endogenous mediators of post-stroke neurogenesis, and through this role improve functional recovery after stroke. As there are currently no treatments to promote post-stroke functional recovery, such signaling systems may be valuable targets for neural repair in human stroke.
Stroke causes damage to the brain by interrupting blood flow, and is the leading cause of adult disability in the United States. This proposal will investigate signals in the brain that may recruit new brain cells to regions of damage after stroke and thereby improve functional recovery. Since there are currently no effective treatments to improve functional recovery after human stroke, knowledge of the mechanisms that new cells use to reach and repair damaged regions of the brain after stroke may help to design new treatments to reduce the devastating burden of this disease.
