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，例如阿尔茨海默氏病（AD）， 肌萎缩性侧索硬化症（Lou Gehrig氏病，ALS）及其相关疾病特别有 退伍军人人口的严重和越来越多的患病率。海湾战争疾病很高 1990 - 1991年波斯湾冲突和神经系统的退伍军人的发病率 问题很常见。至关重要的是，有助于这些的基本机制 理解条件，以便可以开发治疗以改善退伍军人的结果 还有其他。我一直在研究大脑中神经元和神经胶质的分子遗传方面， 脊髓以确定我们如何最好地调节调节途径以阻止和逆转 神经退行性信号导致行为问题。在这些过程中 调查，我们检查了从脑库，动物模型和 在组织培养中建模神经元。我们评估基因表达变化和发生的相互作用 在各种大脑和脊髓样品中的神经变性过程中 比较特定于各种疾病的更改的系统，以便我们可以表征 可以针对获得神经保护和提高功能性能的因素。我有 确定负责中枢神经系统神经变性的关键机制。区域 当前的发现包括阿尔茨海默氏病，对老化的退伍军人和一般人群很重要， 和创伤性脑损伤，从损伤暴露中越来越了解 不幸的是，体育和重要的是最近部署军事力量的签名感。 例如，我有这个领域通过定义神经退行性来识别治疗靶标 机制并证明攻击这些目标导致caspase-激活降低 3，改善了大脑中神经保护基因的表达，并减少了功能性缺陷，测量了 通过行为和认知测试，受伤后的治疗。我们发现几个基因 导致神经元功能丧失的损失受到少数炎症的显着影响 控制蛋白的转录速率或基因表达的响应式调节因素 对神经元健康很重要。例如，我们发现炎症响应式调节 可以调节转录因子以产生细胞内蛋白的神经保护水平 通过选择性上调和下调。通过用我们的细胞内处理模型 监管调节器，我们不仅对生化途径产生积极影响，而且还具有 与未经治疗相比，在神经退行性条件下的记忆功能改善了 控件。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 在退伍军人中更频繁地寻求提高有益的治疗策略。