Traumatic brain injury (TBI) afflicts an estimated 1.5 million people each year in the US. Survivors often suffer persistent neurological dysfunction, compromising their quality of life and productivity. Despite the expanding base of knowledge regarding the complex pathophysiology of TBI, no clinically proven therapeutic interventions have been identified. TBI produces acute neurovascular damage and cell death, resulting in early functional deficits. Recovery of function may be limited by the inability of the injured brain to adequately harness endogenous repair mechanisms. The central hypothesis of this proposal is that treatment with insulin-like growth factor-1 (IGF-1) will improve neurobehavioral function through the attenuation of neurovascular damage and the augmentation of posttraumatic neurogenesis and angiogenesis. We previously showed that administration of recombinant human IGF-1 (rhIGF-1) improves motor and cognitive function in brain-injured rats. However, no studies have examined the neuroprotective or neurorestorative capabilities of IGF-1 in the traumatized brain. We propose to conduct the first comprehensive investigation of the multiple, potentially synergistic mechanisms underlying the behavioral efficacy of IGF-1. Importantly, we will evaluate the efficacy of rhIGF-1 treatment initiated within a clinically relevant therapeutic window of 8 hr and demonstrate sustained protection up to 5 weeks postinjury. In the setting of TBI, IGF-1 is a promising therapeutic candidate, as it has neuroprotective properties and helps to sustain or enhance myelination. Therefore, after demonstrating in Aim 1 that a 7 day systemic infusion of rhIGF-1, initiated at 15 min, 3 hr or 8 hr postinjury, improves motor and cognitive function in mice subjected to cortical impact brain injury, in Aim 2 we will test the hypothesis that IGF-1 protects against neuronal loss and axonal degeneration. IGF-1 is also known to stimulate proliferation of progenitor cells, promote neuronal, oligodendroglial and endothelial differentiation, and increase angiogenesis in the brain. Therefore, in Aim 3 we will test the hypothesis that infusion of rhIGF-1 enhances neurogenesis in the subgranular and subventricular zones. In Aim 4, we will employ novel vascular perfusion techniques to quantify densities of total and angiogenic vessels in brain- injured mice treated with rhIGF-1 or vehicle to test the hypothesis that IGF-1 effectively enhances posttraumatic angiogenesis. Finally, in Aim 5 we will test the hypothesis that rhIGF-1 administration delayed 48 hr can selectively enhance neurogenesis and angiogenesis resulting in cognitive recovery in the absence of acute neuroprotection. These data will provide unique and valuable insights into the neurovascular targets for IGF-1 in the injured brain. By establishing long term (up to 5 wks postinjury) histological benefits and correlating these with behavioral responses, the proposed studies have the potential for high clinical impact. Ultimately our goal is to provide a catalyst to accelerate the translation of IGF-1 therapy into clinical application in order to improve the health and well-being of individuals burdened with TBI. PUBLIC HEALTH RELEVANCE: Project Narrative In light of the high incidence and devastating socioeconomic costs of traumatic brain injury, development of an effective treatment strategy is of utmost importance. Our proposed studies will provide multiple lines of evidence that treatment with insulin-like growth factor-1 initiated within a clinically feasible therapeutic window improves functional outcome and reduces brain damage following contusion brain injury. These studies will provide new insights into how this growth factor protects the traumatized brain, yielding information critical to translating this treatment into clinical trials.