Project Details

Early Career

Status: Funded - Open

The role of arginase in neuroinflammation after neonatal hypoxic-ischemic brain injury

Jana Krystofova, MD, PhD

Summary

BACKGROUND: Hypoxic-ischemic brain injury (HI) is a major cause of longterm disabilities in children resulting from neuroinflammatory pathways of oxidant stress, inflammation, and excitotoxicity. Therapies targeting developing brain are critically needed since current therapies remain largely supportive and mostly focused on adults.

GAP: ARG is a key regulatory enzyme of inflammation and tissue repair through its effects on NO and polyamine pathways. In neuroinflammation, ARG has been shown to activate microglia, stimulate axonal regeneration, participate in glial scar formation, however its impact on brain HI has not been explored.

HYPOTHESIS: We hypothesize that ARG accumulates at the injury site at different timepoints and mediates the local neuroinflammatory pathways. Therefore, timed pharmacologic inhibition of ARG is neuroprotective.

METHODS: After defining the spatiotemporal localization of ARG in brain and determining the dynamics of ARG response to HI, we will evaluate the effects of genetic knockout and pharmacologic inhibition of ARG on the extent of neuroinflammation, neuronal loss and severity of injury over time using immunohistochemistry and western blot. Samples for our studies will be obtained from neonatal mouse brains exposed to the Vannucci model of brain HI.

RESULTS: Pending.

IMPACT: Our proposed research will comprehensively elucidate the novel pathway of HI brain injury at different stages of brain development in greatly understudied pediatric population. Since modulation of the ARG pathway has already been the subject of clinical trials in different conditions associated with inflammation, our pre-clinical data and feasibility of ARG pathway modulation represent an attractive opportunity for new neuroprotective therapies of HI brain injury applicable on pediatric population.

Website Link: http://neurology2.ucsf.edu/neoneur/