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Principal Investigator: BRIAN P HEAD
Organization: VA SAN DIEGO HEALTHCARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
Age-related neurodegenerative diseases such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis
(ALS) are the most common cause of morbidity in the Veteran population. Medical costs for U.S. Veterans of
Iraq and Afghanistan could be enormous because of differences between these wars and previous conflicts
due to today’s Veterans surviving injuries that would have been fatal in previous wars, and "polytraumatic"
injuries that require decades of costly physical and social rehabilitation. With no prevention or treatment,
individuals with neurodegenerative conditions could reach 11-16 million by 2050. In addition to age-related
neurodegeneration, depression among the elderly has been estimated to increase health care costs by 50%
and increase outpatient costs by 43 to 52% in these individuals compared to non-depressed patients. With this
growing Veteran population is an increase in chronic health conditions, and social and financial burdens on
their families and the health care system. Neurodegeneration diseases are closely associated with decreased
neuronal signaling, mitochondrial dysfunction, loss of synapses and neuromuscular junctions. Since receiving
the VA CDA in 2009, the Head laboratory has focused on targeting molecular mechanisms (via genetic and/or
pharmacologic interventions) to evoke functional neuronal and synaptic plasticity to improve cognitive and
motor function in the neurodegenerative brain and spinal cord respectively. As a result of continuous funding
from the VA (3 Merits since 2011) and NIH (NINDS R01 2011), in 2012 Dr. Head was bestowed the
Presidential Early Career Awards for Scientists and Engineers (PECASE) through the Department of Veterans
Affairs, which is the highest honor given by the United States Government to early-stage scientist and
engineers. Specifically, the Head laboratory investigates how caveolin (Cav), a cholesterol binding and
scaffolding protein within membrane/lipid rafts (MLRs), regulates synaptic signaling, mitochondrial function,
and neuroplasticity in neuronal models in vitro using human neurons derived from iPSCs and in animal models
of neurodegeneration such as AD and ALS. Cav-1 is a cholesterol-binding and membrane protein that is
essential for MLR formation and MLR-localization of neurotrophin receptors and synaptic proteins necessary
for synaptic function and neuroplasticity. Dr. Head engineered a genetic construct that contains a neuron-
targeted promoter (synapsin) to drive the expression of Cav-1 (termed SynCav1) specifically in neurons to
evoke neuroprotection and functional plasticity in the setting of disease or following traumatic injury (work
funded by NINDS, VA, and DoD). Dr. Head patented this novel gene therapy through the U.S. Patent Office in
March 2015 (U.S. Patent No. 8,969,077 B2: Neuronal specific targeting of caveolin expression to restore
synaptic signaling and improve cognitive function in the neurodegenerative brain and motor function in spinal
cord) of which the VA and UCSD are owners. The Head laboratory published several seminal studies
demonstrating that exogenous delivery of SynCav1 (using AAV9) promotes hippocampal synaptic and
neuroplasticity, significantly improves learning and memory in aged mice and in AD mice, the latter
independent of reducing amyloid plaques. More recently, Dr. Head’s group showed that spinal cord delivery of
AAV9-SynCav1 protects and preserves spinal motor neuron and neuromuscular junction morphology, motor
function, delays disease onset, and extends longevity in a mouse model of familial (F)ALS, without reducing
the toxic monogenic component (mutant hSOD1). Furthermore, SynCav1 delivery preserved neuromuscular
function in a rat model of FALS. The latter findings strongly indicate the therapeutic applicability of SynCav1 to
treat ALS attributed to monogenic (FALS) and potentially in sporadic cases (i.e., SALS). Dr. Head’s long-term
goal is to translate this gene therapy to the clinical setting to treat Veterans suffering from neurodegenerative
conditions such as AD and ALS.
Terms: <22kD Caveolae Protein><3'5'-cyclic ester of AMP><AAV9 delivery><AAV9 mediated delivery><AAV9 vector delivery><AAV9 viral delivery><AAV9 virus to deliver><AD dementia><Acquired brain injury><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Afghanistan><Age><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Ammon Horn><Amputation><Amyloid (Aβ) plaques><Amyloid Plaques><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Animal Model><Animal Models and Related Studies><Award><Biology><Blindness><Brain><Brain Injuries><Brain Nervous System><CNS Diseases><CNS Nervous System><CNS disorder><CNS plasticity><Capsid><Cardiac><Caveolin 1, Caveolae Protein, 22kD><Caveolin Proteins><Caveolins><Cell Body><Cell Communication and Signaling><Cell Membrane Lipid Rafts><Cell Signaling><Cells><Cellular Matrix><Central Nervous System><Central Nervous System Diseases><Central Nervous System Disorders><Cerebrum><Chronic><Circulation><Clinical><Cognitive><Common Rat Strains><Contrast-Enhancing Lesion><Cornu Ammonis><Crystal Meth><Crystal methamphetamine><Cyclic AMP><Cytoskeletal System><Cytoskeleton><DNA Therapy><Degenerative Neurologic Disorders><Deoxyephedrine><Desoxyephedrine><Disease><Disorder><Dose><Elderly><Encephalon><Engineering><Enhancing Lesion><Exhibits><Face><Family><Fellowship><Financial Hardship><Funding><G Protein-Coupled Receptor Signaling><GPCR Signaling><Gadolinium-Enhancing Lesion><Gd-Enhancing Lesion><Gehrig's Disease><Gene Delivery><Gene Transfer Clinical><Generalized Growth><Genetic><Genetic Intervention><Goals><Grant><Growth><Head><Health><Health Care Costs><Health Care Systems><Health Costs><Healthcare Costs><Healthcare Systems><Hippocampus><In Vitro><Individual><Induced pluripotent stem cell derived human neuron><Injury><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigators><Iraq><Journals><Knowledge><Laboratories><Learning><Legal patent><Length of Life><Longevity><Lou Gehrig Disease><Magazine><Medical Care Costs><Medulla Spinalis><Membrane><Membrane Microdomains><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Memory><Mental Depression><Methamphetamine><Methylamphetamine><Mice><Mice Mammals><Mitochondria><Modeling><Molecular Target><Morbidity><Morbidity - disease rate><Morphology><Motor><Motor Cell><Motor Neurons><Multiple Injuries><Multiple Trauma><Murine><Mus><Myoneural Junction><N-Methylamphetamine><NGF Receptors><NINDS><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><Nerve Cells><Nerve Degeneration><Nerve Growth Factor Receptors><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Physiology><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neuritic Plaques><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurohumor Receptors><Neurologic Degenerative Conditions><Neurologic function><Neurological function><Neuromediator Receptors><Neuromuscular Junction><Neuron Degeneration><Neuronal Plasticity><Neuronal Transmission><Neurons><Neuroregulator Receptors><Neurotransmitter Receptor><Neurotrophic Factor Receptor><Neurotrophin Receptors><Onset of illness><Out-patients><Outpatients><PTSD><Paper><Patents><Patients><Physical Rehabilitation><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Postdoc><Postdoctoral Fellow><Posttraumatic Neuroses><Prevention><Primary Senile Degenerative Dementia><Principal Investigator><Proteins><Provincial Government><Publishing><Rat><Rats Mammals><Rattus><Research><Research Associate><Research Peer Review><Research Personnel><Researchers><Risk Factors><Route><Scaffolding Protein><Scientist><Seminal><Senile Plaques><Signal Transduction><Signal Transduction Systems><Signaling><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><Spinal><Spinal Cord><State Government><Surface Proteins><Synapses><Synapsins><Synaptic><Synaptic plasticity><Therapeutic><Time><Tissue Growth><Transgenic Mice><Translating><Trauma><Traumatic injury><Treatment Efficacy><Tropism><United States><United States Department of Veterans Affairs><United States Veterans Administration><VIP21><VIP21 protein><Veterans><Veterans Administration><Veterans Affairs><War><Work><accelerated aging><accelerated biological age><accelerated biological aging><adeno-associated viral vector 9 delivery><adeno-associated virus 9 delivery><adenosine 3'5' monophosphate><advanced age><age acceleration><age associated neurodegeneration><age associated neurodegenerative disease><age associated neurodegenerative disorder><age dependent neurodegeneration><age dependent neurodegenerative condition><age dependent neurodegenerative disease><age dependent neurodegenerative disorder><age related neurodegeneration><age-driven neurodegenerative disorders><age-related neurodegenerative disease><age-related neurodegenerative disorder><aged mice><aged mouse><ages><aging associated neurodegeneration><aging associated neurodegenerative disease><aging related neurodegeneration><aging related neurodegenerative disease><aging related neurodegenerative disorder><amyloid beta plaque><amyloid-b plaque><axon signaling><axon-glial signaling><axonal signaling><aβ plaques><biological signal transduction><brain damage><brain injury and spinal cord injury><brain-injured><brain/spinal cord injury><cAMP><career><caveolin 1><central nervous system plasticity><cerebral><cholesterol-binding protein><co-morbid><co-morbidity><cognitive function><comorbidity><cored plaque><cost><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><depression><diffuse plaque><disease onset><disorder onset><elderly mice><fALS><faces><facial><familial ALS><familial amyotrophic lateral sclerosis><financial adversity><financial burden><financial distress><financial insecurity><financial strain><financial stress><functional plasticity><functional restoration><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><geriatric><glia signaling><glial signaling><hiPSC-derived neurons><high risk><hippocampal><human iPSC-derived sensory neuron><iPSC-derived human neuron><improved><improved motor function><in vitro Model><in vivo><injured><injuries><intervention efficacy><interventional strategy><intracellular skeleton><ischemia injury><ischemic injury><lipid raft><medical costs><medical expenses><membrane structure><meth><mid life><mid-life><middle age><middle aged><midlife><military service><military veteran><mitochondrial><mitochondrial dysfunction><model of animal><motoneuron><motor function improvement><mouse model><murine model><mutant><nerve signaling><nervous system function><neural degeneration><neural inflammation><neural plasticity><neural signaling><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neuromuscular function><neuronal><neuronal degeneration><neuronal signaling><neuroplastic><neuroplasticity><neuroprotection><neuroprotective><neurotransmission><neurotrophic factor><neurotrophin><neutrophin><novel><old mice><ontogeny><overexpress><overexpression><pharmacologic><physical rehab><polytrauma><post-doc><post-doctoral><post-doctoral trainee><post-trauma stress disorder><posttrauma stress disorder><preservation><primary degenerative dementia><promoter><promotor><receptor-mediated signaling><research associates><restore function><restore functionality><restore lost function><sALS><senile dementia of the Alzheimer type><senior citizen><social><social rehab><social rehabilitation><spinal cord and brain injury><sporadic ALS><sporadic amyotrophic lateral sclerosis><synapse><synapse function><synaptic function><theranostics><therapeutic efficacy><therapy efficacy><traumatic neurosis><trend><vesicular integral membrane protein 21 kDa><veteran population><vision loss><visual loss>