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）， 肌萎缩性侧索硬化症（Lou Gehrig病，ALS）和相关病症具有特别的 在退伍军人群体中的患病率显著增加。海湾战争疾病发病率高 在1990-1991年波斯湾冲突中服役的退伍军人和神经系统疾病的发病率 问题是常见的。至关重要的是，有助于这些的基本机制 了解情况，以便开发治疗方法，以改善退伍军人的结果 等人我一直在研究大脑中神经元和神经胶质的分子遗传学方面， 脊髓，以确定我们如何能够最好地调节调节途径，以阻止和逆转 导致行为问题的神经退行性信号。在这些过程中， 研究中，我们检查了从脑库，动物模型和 组织培养中的模型神经元。我们评估基因表达的变化和相互作用， 在各种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， 这些因素可以被靶向以获得神经保护和改善的功能表现。我有 确定了中枢神经系统神经退行性变的关键机制。领域 目前的发现包括老年痴呆症，对老年退伍军人和普通人群很重要， 和创伤性脑损伤，这是越来越多地了解在伤害暴露方面， 体育，更重要的是，不幸的是，是最近部署的军事力量的标志性痛苦。在 例如，在这个竞技场中，我通过定义神经退行性疾病， 机制，并证明攻击这些目标的结果减少激活半胱天冬酶- 3，改善大脑中的神经保护基因表达，并减少功能缺陷， 通过行为和认知测试，通过受伤后的治疗。我们发现有几个基因 负责神经元功能丧失的神经元受到少数炎性细胞因子的显著影响。 控制蛋白质转录速率或基因表达的响应性调节因子 对神经元健康很重要。例如，我们发现炎症反应性调节 转录因子可以被调节以产生神经保护水平的细胞内蛋白质 通过选择性的上调和下调。通过用我们的细胞内， 调节调节剂，我们不仅积极影响生化途径， 在神经退行性疾病中，与未治疗的相比， 对照我们目前正在将这项研究扩展到其他神经系统问题， 更频繁地在退伍军人和正在寻求推进有益的治疗策略。