BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10587736
• 负责人: Bruce A. Citron
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587736
• 关键词: ALS patients; Accidents; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Applications Grants; Area; Astrocytes; Attention; Award; Binding; Biochemical Pathway; Biological Models; Brain; CASP3 gene; Caspase; Cells; Central Nervous System; Cessation of life; Characteristics; Chronic; Clinical; Clinical Research; Clinical Trials; Cognitive; Complex; Conflict (Psychology); DNA-Binding Proteins; Development; Disease; Down-Regulation; Family; Gene Expression; Gene Expression Profile; General Population; Genes; Goals; Gulf War; Health; Healthcare; Healthcare Systems; Human; Human Resources; Incidence; Inflammatory; Injury; Intervention; Investigation; Ketones; Knowledge; Laboratories; Life; Measures; Memory; Microglia; Military Personnel; Modeling; Molecular; Molecular Biology; Molecular Genetics; Motor Neuron Disease; Motor Neurons; NF-kappa B; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Neurosciences; Paralysed; Pathway interactions; Patients; Peptide Hydrolases; Performance; Persian Gulf; Persian Gulf Syndrome; Pharmacologic Substance; Predisposition; Prevalence; Prevention; Problem behavior; Process; Proteins; Publishing; Quality of life; Regulation; Regulatory Pathway; Research; Rest; Risk; Sampling; Scientist; Services; Signal Transduction; Societies; Spinal Cord; Spinal cord injury; Sports; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Regulation; Transgenic Mice; Translating; Traumatic Brain Injury; Traumatic CNS injury; Traumatic injury; Up-Regulation; Veterans; behavior test; bench to bedside; career; cognitive function; cognitive testing; combat; combat zone; cost; cytokine; effective therapy; experience; experimental study; falls; functional loss; improved; improved outcome; military veteran; neuron loss; neuroprotection; neuropsychiatry; new therapeutic target; novel; operation; therapeutic target; therapeutically effective; therapy development; tissue culture; transcription factor; transgenic model of alzheimer disease; treatment optimization; treatment strategy

Traumatic brain injury and other neurodegenerative disorders, e.g., Alzheimer’s Disease (AD), amyotrophic lateral sclerosis (Lou Gehrig’s disease, ALS), and related conditions, have an especially significant and increasing prevalence in the Veteran population. Gulf War illness has a high incidence among Veterans that served in the 1990-1991 Persian Gulf conflict and neurologic problems are common. It is essential that the underlying mechanisms that contribute to these conditions are understood so that treatments can be developed to improve the outcomes for Veterans and others. I have been studying the molecular genetic aspects of neurons and glia in the brain and spinal cord to determine how we can best modulate regulatory pathways to block and reverse neurodegenerative signaling that results in behavioral problems. In the course of these investigations, we examine human CNS samples obtained from brain banks, animal models, and model neurons in tissue culture. We evaluate gene expression changes and interactions that occur during the course of neurodegeneration in a variety of brain and spinal cord samples and model systems to compare alterations that are specific to the various disorders so that we can characterize factors that can be targeted to obtain neuroprotection and improved functional performance. I have determined key mechanisms responsible for central nervous system neurodegeneration. Areas of current discovery include Alzheimer's disease, important to the aging Veteran and general population, and traumatic brain injury which is becoming increasingly understood in terms of injury exposures in sports and importantly, is unfortunately the signature affliction of recently deployed military forces. In this arena I have, for example, identified therapeutic targets by defining neurodegenerative mechanisms and demonstrating that attacking these targets results in reduced activation of caspase- 3, improved neuroprotective gene expression in the brain, and reduced functional deficits, measured with behavioral and cognitive tests, by treatment after injury. We have found that several genes responsible for the loss of neuronal function are influenced significantly by a handful of inflammatory responsive regulatory factors that control the transcription rates, or gene expression, of the proteins important to neuronal health. For example, we found that inflammatory responsive regulatory transcription factors can be modulated to produce neuroprotective levels of intracellular proteins through selective upregulation and downregulation. By treating models with our intracellular, regulatory modulators, we have not only positively influenced biochemical pathways, we have demonstrated improved memory function in neurodegenerative conditions compared to untreated controls. We are currently extending this research to additional neurological problems that occur more frequently in Veterans and are seeking to advance beneficial therapeutic strategies.

创伤性脑损伤和其他神经退行性疾病，例如阿尔茨海默病 (AD)、 肌萎缩侧索硬化症（Lou Gehrig 病，ALS）及相关病症尤其严重 海湾战争退伍军人中患病率显着且不断增加。 1990-1991 年波斯湾冲突中服役的退伍军人中的发病率和神经系统疾病 问题是常见的，至关重要的是造成这些问题的根本机制。 了解情况，以便开发治疗方法来改善退伍军人的治疗结果 我一直在研究大脑中神经元和神经胶质细胞的分子遗传学方面。 脊髓以确定我们如何最好地调节调节途径以阻断和逆转 在此过程中导致行为问题的神经退行性信号传导。 调查中，我们检查从脑库、动物模型获得的人类中枢神经系统样本， 我们评估组织培养中的模型神经元。 在各种大脑和脊髓样本和模型的神经变性过程中 系统来比较各种疾病特有的变化，以便我们能够表征 可以针对获得神经保护和改善功能表现的因素。 确定了中枢神经系统神经变性的关键机制。 目前的发现包括阿尔茨海默病，这对老年退伍军人和普通人群很重要， 和创伤性脑损伤，人们越来越多地通过伤害暴露来了解这一点 不幸的是，体育运动是最近部署的军队的标志性问题。 例如，在这个领域，我通过定义神经退行性疾病来确定治疗目标 机制并证明攻击这些目标会导致 caspase 激活减少 3、测量发现，改善了大脑中的神经保护基因表达，并减少了功能缺陷 通过行为和认知测试，通过受伤后的治疗，我们发现了几个基因。 导致神经功能丧失的因素受到少数炎症的显着影响 控制蛋白质转录速率或基因表达的响应性调节因子 例如，我们发现炎症反应调节。 可以调节转录因子以产生神经保护水平的细胞内蛋白质 通过选择性上调和下调通过用我们的细胞内治疗模型， 调节调节剂，我们不仅对生化途径产生了积极影响，我们还 与未经治疗的神经退行性疾病相比，记忆功能得到改善 我们目前正在将这项研究扩展到发生的其他神经系统问题。 在退伍军人中更常见，并且正在寻求推进有益的治疗策略。