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.

老年性神经退行性疾病，如阿尔茨海默病(AD)和肌萎缩侧索硬化症 肌萎缩侧索硬化症(ALS)是退伍军人中发病的最常见原因。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病在以前的战争中是致命的，而且是“多发性创伤” 需要数十年昂贵的身体和社会康复的伤害。在没有预防或治疗的情况下， 到2050年，神经退行性疾病患者可能达到1100-1600万人。除了与年龄有关的 据估计，老年人中的神经退化、抑郁症会使医疗费用增加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%。有了这个 退伍军人人数的增加意味着慢性疾病的增加，以及社会和经济负担的增加 他们的家庭和医疗保健系统。神经退行性疾病与神经功能减退密切相关 神经元信号、线粒体功能障碍、突触丢失和神经肌肉连接。自收到 自2009年退伍军人事务部CDA以来，首席实验室一直专注于靶向分子机制(通过遗传和/或 药物干预)以唤起功能神经元和突触的可塑性，以改善认知和 神经退行性脑和脊髓的运动功能。作为持续资助的结果 来自退伍军人事务部(自2011年以来的3项功绩)和NIH(NINDS R01 2011)，在2012年，Head博士被授予 退伍军人事务部颁发的总统科学家和工程师早期职业奖 事务，这是美国政府给予早期科学家和 工程师。具体地说，首席实验室研究了小窝蛋白(Cav)，一种胆固醇结合蛋白和 膜/脂筏(MLRs)内的支架蛋白，调节突触信号，线粒体功能， 在体外用来自ipscs的人神经元和动物模型建立神经元模型中的神经可塑性 神经退行性变，如阿尔茨海默病和肌萎缩侧索硬化症。Cav-1是一种胆固醇结合和膜蛋白，它是 神经营养因子受体和突触蛋白的MLR形成和定位所必需的 用于突触功能和神经可塑性。海德博士设计了一种包含神经元的基因结构- 靶向启动子(突触素)驱动Cav-1(称为SynCav1)在神经元中的特异性表达 在疾病背景下或在创伤(工作)后唤起神经保护和功能可塑性 由NINDS、弗吉尼亚州和国防部资助)。年，海德博士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 突触信号与改善神经退行性脑的认知功能和脊髓的运动功能 Corde)，退伍军人事务部和UCSD是其所有者。首席实验室发表了几项开创性的研究 证明外源性传递SynCav1(使用AAV9)促进海马区突触和 神经可塑性，显著改善老年小鼠和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，脊髓传递的 AAV9-SynCav1保护和保存脊髓运动神经元和神经肌肉接头形态、运动 在家族性(F)ALS小鼠模型中，在不减少的情况下，发挥作用，延迟疾病发病，并延长寿命 有毒的单基因成分(突变体hSOD1)。此外，SynCav1的交付保存了神经肌肉 在FALS大鼠模型中发挥作用。后者的发现有力地表明了SynCav1在治疗上的适用性 治疗可归因于单基因ALS的ALS(FALS)，并可能治疗散发性ALS(即SALS)。海德博士的长期 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变的退伍军人 AD和ALS等情况。