Document text
Principal Investigator: Jun Chen
Organization: VETERANS HEALTH ADMINISTRATION
Fiscal Year: 2024
Funding agency: Veterans Affairs
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.
Terms: <3-methyl TTNEB><9-cis-Retinoic Acid Receptor><ATP-protein phosphotransferase><Acceleration><Acquired brain injury><Acute><Affect><Aging><Agonist><Alteplase><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Apoplexy><Area><Attention><Award><B cell growth factor><B-Cell Differentiation Factor-1><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><BBB disruption><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF1><Bexarotene><Binetrakin><Biological><Blood Vessels><Body Tissues><Brain><Brain Injuries><Brain Ischemia><Brain Nervous System><Brain Trauma><Brain Vascular Accident><Caring><Cell Body><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Circulation><Cerebrovascular Stroke><Chronic><Clinical Treatment><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Collaborations><Data><Development><Disturbance in cognition><ED care><ER care><Economic Burden><Elderly><Emergency Care><Emergency Department care><Emergency Room care><Emergency health care><Emergency healthcare><Emergency medical care><Encephalon><FDA approved><Funding><Future><Generalized Growth><Generations><Genetic><Goals><Grant><Grant Review><Growth><HSP27><HSPB1><HSPB1 gene><Health><Health system><Healthcare><Heat Shock 27 kD Protein 1><Heat Shock 27kD Protein 1 Gene><Heat Shock Protein 27><Heat-Shock Protein 27 Gene><Hortega cell><Hospital Admission><Hospitalization><IL-4><IL4 Protein><Immune><Immune response><Immune system><Immunes><Immunity><Immunological response><Impaired cognition><Impairment><Infiltration><Inflammation><Injury><Institution><Interleukin-4><Interleukin-4 Precursor><Intermediary Metabolism><Investigators><Ischemic Brain Injury><Ischemic Encephalopathy><Ischemic Stroke><Journals><Kinase Family Gene><Level of Evidence><Long term disability><Lymphocyte Stimulatory Factor 1><MCGF-2><Macrophage><Magazine><Manuscripts><Mast Cell Growth Factor-2><Medical Rehabilitation><Medical center><Metabolic Processes><Metabolism><Mice><Mice Mammals><Microglia><Molecular><Moods><Murine><Mus><Mφ><NIH><NINDS><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><National Institutes of Health><Natural regeneration><Nervous System Physiology><Neurologic><Neurologic function><Neurological><Neurological function><Omega-3 Fatty Acids><Omega-3 PUFA><Omega-3 Polyunsaturated Fatty Acid><Omega3><Outcome><Outcomes Research><PTSD><Paper><Peer Review><Personal Satisfaction><Phenotype><Phylogenetic Analysis><Phylogenetics><Population><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Process><Protein Kinase><Publications><QOL><Quality of life><RXR><RXR Protein><Recombinant Tissue Plasminogen Activator><Recovery><Recovery of Function><Regeneration><Regulatory T-Lymphocyte><Rehabilitation><Rehabilitation therapy><Rejuvenation><Reporting><Research><Research Personnel><Researchers><Retinoic Acid Receptor RXR><Retinoid X Receptors><Role><Safety><Scientific Publication><Scientist><Stroke><Survivors><Synapses><Synaptic><System><T-Cell Growth Factor 2><T-Plasminogen Activator><TBI recovery><TBI therapy><TBI treatment><Targretin><Testing><Therapeutic><Thinking><Tissue Activator D-44><Tissue Growth><Tissue Plasminogen Activator><Tissue-Type Plasminogen Activator><Tissues><Trauma><Traumatic Brain Injury><Traumatic Brain Injury recovery><Treg><United States National Institutes of Health><Universities><Veterans><Work><adult animal><adult youth><advanced age><after stroke><aged><aged animal><aged animals><aged brain><aging brain><animal old age><axon damage><axon injury><axonal damage><axonal injury><biologic><blood flow in brain><blood-brain barrier disruption><bloodbrain barrier disruption><brain attack><brain blood circulation><brain blood flow><brain cell><brain damage><brain repair><brain tissue><brain-injured><career><cerebral blood flow><cerebral circulation><cerebral vascular accident><cerebrocirculation><cerebrovascular accident><cerebrovascular blood flow><clinical investigation><clinical relevance><clinically relevant><cognitive defects><cognitive dysfunction><cognitive function><cognitive loss><cytokine><developmental><disability><disabled><effective therapy><effective treatment><elderly animal><female subjects><functional recovery><geriatric><gitter cell><glial activation><glial cell activation><glycogen synthase a kinase><health care><host response><hydroxyalkyl protein kinase><immune system response><immunoresponse><improved><indexing><injuries><injury and repair><injury recovery><ischemic brain damage><long term recovery><male><mature animal><mesoglia><microglial cell><microgliocyte><military veteran><n-3 Fatty Acids><nervous system function><neurological recovery><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><old animals><omega-3><ontogeny><perivascular glial cell><pharmacologic><phosphorylase b kinase kinase><post stroke><post-trauma stress disorder><poststroke><posttrauma stress disorder><pre-clinical><preclinical><programs><psychiatric symptom><recovery after TBI><recovery after injury><recovery after traumatic brain injury><recovery following injury><recovery post injury><regenerate><regulatory T-cells><rehab therapy><rehabilitative><rehabilitative therapy><repair><repair function><repaired><reparative function><response><restoration><salt-inducible kinase><senior citizen><social role><socio-economic><socio-economically><socioeconomically><socioeconomics><stroke model><stroke outcome><stroke victims><stroked><strokes><substantia alba><synapse><t-PA><thoughts><tissue repair><traumatic brain damage><traumatic brain injury therapy><traumatic brain injury treatment><traumatic neurosis><trial regimen><trial treatment><vascular><veteran population><well-being><wellbeing><white matter><white matter injury><women subjects><young adult><young adulthood><ω-3 fatty acids>