PROJECT SUMMARY: Repetitive, mild traumatic brain injury (TBI) is increasingly seen in soldiers deployed to combat areas and linked to persistent, debilitating neurological symptoms in Veterans. There is increasing evidence that a major outcome of repetitive, mild TBI is chronic traumatic encephalopathy (CTE). This slowly developing neurodegenerative condition is characterized by neuroinflammation and brain atrophy. Importantly, CTE is also accompanied by cognitive impairment. A compound that could mitigate these pathologies and is amendable to delivery to the brain could be the basis of a much needed pharmacotherapy. All trans retinoic acid (ATRA) is an anti-inflammatory with neuromodulatory actions. We hypothesize that ATRA delivery to mice months after receiving repetitive, mild TBIs will improve cognition and this will be linked to improved brain pathology. To test this hypothesis we have developed nanoparticles for nose-to-brain drug delivery of ATRA (ATRA-NP). We will test the efficacy of ATRA-NP using an established model of repetitive, mild TBI in mice. Importantly, cognitive impairment is not apparent immediately after a series of head impacts, but ensues in the weeks and months afterwards, mimicking the human condition. We will test the ability of intranasal ATRA-NP to reverse cognitive impairment in these mice and investigate links to brain pathology postmortem. There are two specific aims. The first aim will test the hypothesis that ATRA-NP delivery during the chronic phase after TBI will improve cognitive impairment. The second aim will test the hypothesis that ATRA-NP delivery during the chronic phase of TBI will improve brain pathology. The potential for impact of this work is high. A pharmacotherapy that improves cognition could revolutionize care for Veterans and the general population. In addition to ATRA being a strong candidate as a neuromodulator, it is also one of the most prescribed medications in the United States. In addition, the nanoparticle drug carrier (PLG) is implemented in 19 FDA approved drug formulations. Thus, if ATRA-NP is successful, getting this therapy to Veterans may be faster and less expensive than developing new drugs. Finally, the delivery system is versatile, able to accommodate new or additional pharmaceutics or new administration schedules, if necessary. Given that the investigative team has the required expertise to carry out the proposed work, we are confident that the project will bring us closer to realizing a pharmacotherapy for Veterans suffering from the persistent debilitating neurological symptoms secondary to traumatic brain injury.