BLRD Research Career Scientist Award Application

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Research in the Chen lab focuses on alleviating the neurological sequelae of traumatic brain injury (TBI) and ischemic stroke, which diminish our veterans’ quality of life. Our goals are to help identify and/or develop pharmacologic agents that can leverage phylogenetically conserved tissue-repair mechanisms to alleviate acute and secondary brain damage and sustain functional recovery. TBI is a major concern for US military veterans. In TBI survivors, white matter injury is associated with long-term functional deficits, including sensorimotor, cognitive, and psychiatric impairments. The Chen lab will continue to develop restorative therapies that augment endogenous repair processes. Supported by VA Merit Review, we found that the functional phenotypes of brain innate immune cells, including resident microglia and infiltrating blood-borne macrophages, critically regulate the microenvironment in white matter and impact both white matter injury and repair. We have recently identified salt-inducible kinase-1 (SIK1), an evolutionarily conserved protein kinase, as a key molecular switch that governs the functional states of innate immune brain cells after TBI. Thus, in the next four years, we will test the new hypotheses that genetic deletion or pharmacological inhibition of SIK1 improves white matter restoration and long-term TBI outcomes through dual mechanisms: 1) protecting against early synaptic and axonal injury by inflammation-resolving microglia/macrophage responses, and 2) enhancing chronic-stage white matter repair. Our preliminary data suggest that SIK1 inhibition not only reduces TBI-induced sensorimotor and cognitive deficits, but also the psychiatric symptoms relevant to post-traumatic stress disorder (PTSD). We believe that continued positive outcomes of this research will accelerate the development of novel therapies to promote successful rehabilitation of veterans with TBI. Stroke is a leading cause of long-term disability in elderly US veterans. Approximately 11,000 veterans are hospitalized annually with new strokes. Although survival has increased with improvements in emergency care and new recanalization therapy, the population with disabilities continues to climb. Optimal care of our veterans will require therapies that not only ameliorate brain injury—but also lead to regeneration of brain tissue and restoration of neurological function. Post-stroke immune responses have a substantial impact on the progression of ischemic brain injury and brain recovery, but there are no clinical treatments that successfully harness the restorative power of the immune system while also tempering inflammation-induced secondary injuries. The reasons for this gap are multifactorial, but include a preclinical overemphasis on young adult animals, which do not display the same pathophysiological mechanisms underlying brain ischemia as the aged. Using a clinically relevant stroke model in 20-month old aging mice, our VA-funded research helped us make two key discoveries: 1) the remarkably reduced ability of aged brains to recover from stroke is, at least in part, due to microglial aging and the impaired reparative functions of microglia; 2) aged microglia and post-stroke brain-repair functions of microglia can be rejuvenated by activating the retinoid X receptor (RXR) in the aged brain. In the new VA-funded research, we will test the ability of bexarotene, an FDA-approved RXR agonist with excellent safety profiles, to reactivate the brain repair-enhancing functions of microglia, thereby improving long-term stroke outcomes and functional recovery in aged animals. Thus, our long-term goals are to improve veterans’ lives after stroke and reduce the socioeconomic burden of their disabilities.