Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatment strategies for stroke primarily focus on reducing the size of ischemic damage and on rescuing dying cells early after occurrence. Treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, or even weeks after stroke occurs, which might provide a second window for treatment. Our preliminary data suggests that in vivo delivery of sonic hedgehog (shh) peptide into the CNS of stroke animals improves their functional recovery. We hypothesize that the shh signaling pathway is involved in the regulation of neuroregeneration after stroke and that modulating the shh signaling pathway will lead to better functional outcome in stroke recovery. We will test this hypothesis in a combined pharmacological and genetic approach in an animal model of stroke (middle cerebral artery occlusion MCAo). Towards this goal, we have developed a proposal that consists of three specific aims. In specific aim 1 and 2, we will investigate the role of the shh signaling pathway in stroke-induced neurogenesis by cell-type specific modification of shh or smo gene in adult neural progenitor cells and local reactive astrocytes. In specific aim 3, we will test the efficacy of shh- signaling pathway stimulation in a animal stroke model by pharmacological methods. Together, the pharmacological and genetic combined approach of this proposal will generate data that will provide insights on the precise role of shh signaling in the process of injury-induced neuroregeneration. The data gained will be directly applicable to developing novel therapeutic interventions in treating cerebral ischemia through the manipulation of the cellular microenvironment in the CNS. We anticipate that the animal resources and results generated from our study will open new avenues in neuroregeneration research and lead to the identification of molecular therapeutic targets.