Document text
Principal Investigator: Mariana Angoa-Perez
Organization: JOHN D DINGELL VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Project Summary/Abstract
Traumatic brain injury (TBI) has been referred to as the “signature injury” of recent military combat operations
in Iraq and Afghanistan. The form of TBI that is most prevalent among military service members and Veterans
is repetitive, mild TBI, or rmTBI. Apart from the immediate effects of a head injury, rmTBI is also associated
with a number of significant and chronic co-morbid conditions including cognitive dysfunction, sleep disorders,
alterations in visual function, and psychiatric complications (e.g., depression, suicide, anxiety). rmTBI and its
co-morbid conditions exact a steep toll on military personnel and Veterans and the cost to the nation of TBI is
estimated to be $60 billion annually. The mechanisms by which rmTBI alters brain function are not well
understood and all clinical trials of new therapies for TBI thus far have failed. Therefore, an effective treatment
for TBI does not exist. Perhaps the most alarming aspect of rmTBI is the possibility that repeated mild impacts
to the head do not cause clinically significant or recognizable symptoms but set in motion a cascade which has
an endpoint of neurodegeneration and psychiatric illness. The primary goals of this application are to 1) refine
and validate a humanized mouse model of rmTBI and 2) test two new mechanism-based therapies for the
long-term consequences of rmTBI. These goals will be achieved by employing a new model of rmTBI that is
very mild, even after as many as 20 head impacts, and which does not result in any behavioral or neuronal
pathology at the end of the treatment period. We include preliminary data showing that rmTBI results in a
delayed and progressive emergence of increased reactive gliosis and inflammation along white matter tracts,
and increases in the pathologic form of tau, a microtubule stabilizing molecule. In addition, this model of rmTBI
results in slowly developing cognitive deficits and psychiatric-like disorders (e.g., anxiety and depression),
neither of which are evident immediately after the rmTBI course of treatment. These neuronal and behavioral
outcomes are hallmark signs of chronic traumatic encephalopathy (CTE) and have been observed in
postmortem brains of military service members exposed to rmTBI. Two new drugs will be tested as therapies
for rmTBI and include an inhibitor of histone deacetylase 6 (HDAC6) and a colony-stimulating factor 1 receptor
(CSFR1) inhibitor that ablates CNS microglia. The rationale behind the use of an HDAC6 inhibitor for treating
rmTBI is compelling for several reasons. First, modification of tau by acetylation protects it from aggregation
(i.e., its pathological form) by inhibiting its phosphorylation. Second, HDAC6 has been identified as the specific
enzyme that deacetylates tau. Deacetylation of tau allows for modification of tau by phosphorylation. Third,
inhibition of HDAC6 should shift the balance of acetylation/phosphorylation to favor acetylation and thereby
protect tau against pathological aggregation in brain. The rationale behind the use of a CSF1R inhibitor is
likewise compelling and strong because rmTBI results in significant increases in microglial activation which
then causes a secondary activation of astrocytes. This increased glial reactivity results in neuronal damage. By
ablating microglia, a CSF1R inhibitor should prevent activation of both microglia and astrocytes and reduce the
CTE-like damage that occurs in CTE. The effects of rmTBI will be studied over a chronic time-frame in mice to
simulate the slow-developing neuropathologies and behavioral disorders seen in humans after repeated head
injuries. Treatment will not begin until after exposure of mice to repetitive head impacts in order to simulate a
clinical situation more closely. It is hypothesized that inhibition of HDAC6 or CSF1R after rmTBI will prevent or
reduce the development of CTE-like tau pathology. It is hypothesized further that prevention of the formation of
tauopathies with these treatments will reduce the chronic co-morbid conditions that develop with high
frequency after rmTBI to include cognitive dysfunction, alterations in vision and sleep, and depression- and
anxiety-like behavioral disorders. This project has high translational relevance for the VA health care mission.
Terms: <Ablation><Acetylation><Acute><Afghanistan><Anxiety><Appearance><Armed Forces Personnel><Astrocytes><Astrocytus><Astroglia><Autopsy><Behavior Disorders><Behavioral><Brain><Brain Nervous System><Brain Trauma><CD115><CD115 Antigens><CD115 Gene><CSF-1 Receptor><CSF-1-R><CSF1R><CSF1R Gene Product><CSF1R gene><CSFMR><Chronic><Clinical><Clinical Trials><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Colony Stimulating Factor 1 Receptor><Colony Stimulating Factor 1 Receptor Gene><Complex><Craniocerebral Injuries><Craniocerebral Trauma><Data><Deacetylation><Development><Disease><Disorder><Disturbance in cognition><Dysfunction><Encephalon><Enzyme Gene><Enzymes><Equilibrium><Exposure to><Frequencies><Functional disorder><Gliosis><Goals><HDAC Agent><HDAC inhibitor><HDAC6><HDAC6 gene><Head><Head Injuries><Head Trauma><Health><Healthcare><Histone Deacetylase Inhibitor><Histone deacetylase inhibition><Hortega cell><Human><Impaired cognition><Individual><Inflammation><Injury><Iraq><KIAA0901><Lead><Long-Term Effects><Longterm Effects><M-CSF Receptors><MT-bound tau><MTBI><Macrophage Colony Stimulating Factor I Receptor><Macrophage Colony-Stimulating Factor Receptor><Medical><Mental Depression><Mental disorders><Mental health disorders><Mice><Mice Mammals><Micro-tubule><Microglia><Microtubules><Military><Military Personnel><Mission><Modeling><Modern Man><Modification><Motion><Murine><Mus><Nature><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neurocyte><Neurologic outcome><Neurological outcome><Neuron Degeneration><Neurons><Outcome><Paralysis Agitans><Parkinson><Parkinson Disease><Pathologic><Pathology><Pb element><Phosphorylation><Physiopathology><Prevention><Primary Parkinsonism><Protein Phosphorylation><Proto-Oncogene Protein fms><Psychiatric Disease><Psychiatric Disorder><Publishing><Research><Sight><Sleep><Sleep Disorders><Suicide><Symptoms><TBI therapy><TBI treatment><Tauopathies><Testing><Therapeutic Intervention><Time><Traumatic Brain Injury><Traumatic encephalopathy><Treatment Period><Veterans><Vision><Work><astrocytic glia><balance><balance function><behavior outcome><behavioral disorder><behavioral outcome><c-FMS><c-fms Genes><c-fms Protein><c-fms Proto-Oncogenes><chronic traumatic encephalopathy><clinical significance><clinically significant><co-morbid><co-morbidity><cognitive defects><cognitive dysfunction><cognitive loss><combat arena><combat operations><combat situation><combat zone><comorbidity><cost><depression><developmental><effective therapy><effective treatment><experiment><experimental research><experimental study><experiments><fatal attempt><fatal suicide><gitter cell><glial activation><glial cell activation><head impact><health care><heavy metal Pb><heavy metal lead><histone deacetylase 6><humanized mice><humanized mouse><inhibitor><injuries><intent to die><intervention therapy><mental illness><mesoglia><microglial cell><microgliocyte><microtubule bound tau><microtubule-bound tau><mild TBI><mild brain trauma><mild traumatic brain injury><military member><military population><military service><military veteran><mouse model><murine model><necropsy><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal><neuronal degeneration><neuropathologic><neuropathologic tau><neuropathological><neuropathological tau><neuropathology><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><outcome forecast><p-tau><p-τ><pathophysiology><perivascular glial cell><phospho-tau><phospho-τ><phosphorylated tau><post-translational modification of tau><postmortem><posttranslational modification of tau><prevent><preventing><psychiatric illness><psychological disorder><service member><sleep diseases><sleep dysfunction><sleep illness><sleep problem><substantia alba><suicides><tau><tau Proteins><tau associated neurodegeneration><tau associated neurodegenerative process><tau factor><tau induced neurodegeneration><tau mediated neurodegeneration><tau neurodegenerative disease><tau neuropathology><tau phosphorylation><tau posttranslational modification><tau-1><tauopathic neurodegenerative disorder><tauopathy><traumatic brain damage><traumatic brain injury therapy><traumatic brain injury treatment><treatment days><treatment duration><veteran population><virtual><visual function><white matter><τ Proteins><τ phosphorylation>