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.

阿尔茨海默病（AD）和肌萎缩侧索硬化症等阿尔茨海默病相关的神经退行性疾病 (ALS)是退伍军人发病的最常见原因。美国退伍军人的医疗费用 伊拉克和阿富汗战争可能是巨大的，因为这些战争和以前的冲突之间的差异 由于今天的退伍军人幸存下来的伤害，将是致命的，在以前的战争，和“多创伤” 这些伤害需要数十年昂贵的身体和社会康复。如果没有预防或治疗， 到2050年，患有神经退行性疾病的人数可能达到1100万至1600万。除了与年龄有关的 据估计，老年人的神经退行性疾病、抑郁症会使医疗保健费用增加50%。 与非抑郁症患者相比，这些患者的门诊费用增加了43%至52%。与此 不断增长的退伍军人人口是慢性健康状况的增加，以及社会和财政负担， 他们的家庭和医疗保健系统。神经退行性疾病与减少 神经元信号传导、线粒体功能障碍、突触和神经肌肉接头的丧失。自从收到 在2009年的VA CDA中，首席实验室专注于靶向分子机制（通过遗传和/或 药理学干预）以唤起功能性神经元和突触可塑性，从而改善认知和 运动功能在神经退行性脑和脊髓分别。由于持续供资， 从VA（自2011年以来的3个优点）和NIH（NINDS R 01 2011），在2012年博士头被授予 通过退伍军人部颁发的科学家和工程师总统早期职业奖（PECASE） 这是美国政府授予早期科学家的最高荣誉， 工程师具体来说，首席实验室研究了小窝蛋白（Cav），一种胆固醇结合蛋白， 膜/脂筏（MLR）内的支架蛋白，调节突触信号传导，线粒体功能， 在使用源自iPSC的人神经元的体外神经元模型和动物模型中的神经可塑性 AD和ALS等神经退行性疾病Cav-1是一种胆固醇结合膜蛋白， 对MLR形成和神经营养因子受体和突触必需蛋白的MLR定位至关重要 突触功能和神经可塑性。海德博士设计了一种基因结构它含有一个神经元 靶向启动子（突触蛋白）驱动Cav-1（称为SynCav 1）在神经元中特异性表达， 在疾病或创伤性损伤后引起神经保护和功能可塑性（工作 由NINDS，VA和DoD资助）。Head博士于年通过美国专利局为这种新型基因疗法申请了专利。 2015年3月（美国专利号8，969，077 B2：神经元特异性靶向小窝蛋白表达以恢复神经元的功能） 突触信号传导和改善神经退行性脑的认知功能和脊髓运动功能 其中，曹操和曹操都是曹操的亲信。首席实验室发表了几项开创性的研究， 证明SynCav 1的外源性递送（使用AAV 9）促进海马突触， 神经可塑性，显着改善老年小鼠和AD小鼠的学习和记忆，后者 与减少淀粉样斑块无关。最近，海德博士的研究小组表明， AAV 9-SynCav 1保护和保存脊髓运动神经元和神经肌肉接头形态、运动神经元和神经肌肉接头结构。 在家族性（F）ALS的小鼠模型中， 毒性单基因组分（突变体hSOD 1）。此外，SynCav 1递送保留了神经肌肉 在大鼠模型中的功能。后一项发现强烈表明SynCav 1在治疗上的适用性， 治疗归因于单基因的ALS（FALS）和潜在的散发病例（即，SALS）。海德医生的长期 我们的目标是将这种基因疗法转化为临床环境，以治疗患有神经退行性疾病的退伍军人。 如AD和ALS。