BLR&D MERIT REVIEW RESEARCH CAREER SCIENTIST AWARD APPLICATION

BLR

• 批准号: 10701474
• 负责人: BRIAN P HEAD
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701474
• 关键词: Acceleration; Afghanistan; Age; Aging; Alzheimer' s Disease; Amputation; Amyotrophic Lateral Sclerosis; Animal Model; Award; Biology; Blindness; Brain; Brain Injuries; Capsid; Cardiac; Caveolins; Cells; Central Nervous System; Central Nervous System Diseases; Cerebrum; Chronic; Circulation; Clinical; Cognitive; Cyclic AMP; Cytoskeleton; Disease; Dose; Elderly; Engineering; Enhancing Lesion; Exhibits; Face; Family; Fellowship; Financial Hardship; Funding; G Protein-Coupled Receptor Signaling; Gene Delivery; Genetic; Goals; Grant; Growth; Head; Health; Health Care Costs; Healthcare Systems; Hippocampus; Human; In Vitro; Individual; Induced pluripotent stem cell derived neurons; Injury; Intervention; Iraq; Journals; Knowledge; Laboratories; Learning; Legal patent; Longevity; Medical Care Costs; Membrane; Membrane Microdomains; Membrane Proteins; Memory; Mental Depression; Methamphetamine; Mitochondria; Modeling; Molecular Target; Morbidity - disease rate; Morphology; Motor; Motor Neurons; Multiple Trauma; Mus; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Nerve Growth Factor Receptors; Nervous System Physiology; Neurodegenerative Disorders; Neuromuscular Junction; Neuronal Plasticity; Neurons; Neurotransmitter Receptor; Onset of illness; Outpatients; Paper; Patients; Physical Rehabilitation; Post-Traumatic Stress Disorders; Postdoctoral Fellow; Prevention; Principal Investigator; Proteins; Publishing; Rattus; Research; Research Peer Review; Research Personnel; Risk Factors; Route; Scaffolding Protein; Scientist; Seminal; Senile Plaques; Signal Transduction; Spinal; Spinal Cord; State Government; Synapses; Synapsins; Synaptic plasticity; Therapeutic; Time; Transgenic Mice; Translating; Trauma; Traumatic injury; Treatment Efficacy; Tropism; United States; United States Department of Veterans Affairs; Vertebral column; Veterans; War; Work; age related neurodegeneration; aged; career; caveolin 1; cholesterol-binding protein; cognitive function; comorbidity; cost; familial amyotrophic lateral sclerosis; functional plasticity; functional restoration; gene therapy; high risk; improved; in vitro Model; in vivo; injured; ischemic injury; middle age; military service; military veteran; mitochondrial dysfunction; motor function improvement; mouse model; mutant; neuroinflammation; neuromuscular function; neuroprotection; neurotransmission; neurotrophic factor; novel; overexpression; pharmacologic; preservation; promoter; receptor-mediated signaling; social; social rehabilitation; spinal cord and brain injury; sporadic amyotrophic lateral sclerosis; synaptic function; theranostics; trend

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.

与年龄相关的神经退行性疾病，如阿尔茨海默病（AD）和肌萎缩侧索硬化症