BLRD RESEARCH CAREER SCIENTIST AWARD APPLICATION

BLRD 研究职业科学家奖申请

• 批准号: 10514611
• 负责人: FIONA C. CRAWFORD
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514611
• 关键词: Acute; Address; Adopted; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Animal Model; Anti-Inflammatory Agents; Antihypertensive Agents; Area; Attention; Autopsy; Award; Awareness; Behavioral; Biochemical; Biological Availability; Biological Markers; Blood; Blood specimen; Brain; Cell model; Cells; Cerebrovascular system; Chronic; Clinical; Clinical Trials; Collaborations; Data; Development; Diagnostic; Dihydropyridines; Disease; Dose; Drug Kinetics; Ensure; Evaluation; Exposure to; Formulation; Functional disorder; Funding; Future; Genes; Genomics; Genotype; Goals; Healthcare; Heterogeneity; Human; I-kappa B Proteins; Immune; Inflammatory; Injury; Intervention; Investigation; Laboratories; Lead; Life; Longevity; Military Personnel; Modeling; Molecular; Molecular Target; Mus; Nervous System Trauma; Neurodegenerative Disorders; Neuroimmunomodulation; Neurosciences Research; Nutraceutical; Outcome; Pathogenicity; Pathologic; Patients; Persian Gulf Syndrome; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Post-Traumatic Stress Disorders; Productivity; Property; Publications; Rationalization; Recording of previous events; Research; Research Personnel; Role; Route; SYK gene; Sampling; Scientist; Signal Pathway; Signal Transduction; Stress; Therapeutic; Therapeutic Intervention; Time; Tissue Sample; Toxic effect; Toxicant exposure; Translations; Traumatic Brain Injury; Veterans; Work; aged; brain tissue; career; clinical application; clinically relevant; dietary supplements; disease-causing mutation; drug discovery; effective therapy; experience; genetic manipulation; inhibitor; mild traumatic brain injury; military veteran; mouse model; nervous system disorder; neuroinflammation; neuropsychiatric disorder; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; oleoylethanolamide; patient population; pre-clinical; programs; research clinical testing; research study; response; response to injury; severe injury; tau Proteins; therapeutic target; treatment response; verification and validation

The overarching goal of my research is to apply molecular neuroscience research to identify better treatments for Veterans conditions for which there are currently no effective treatments. Specifically, my work has focused on Alzheimer’s Disease (AD), Traumatic Brain Injury (TBI), Gulf War Illness (GWI) and Posttraumatic Stress Disorder (PTSD). Primarily, I use mouse models of these conditions, in order to explore the pathobiology of each condition over the mouse lifespan at the behavioral, biochemical and pathological level, and therein identify key targets for potential therapeutic intervention. Mouse models of AD, created using human AD-causing mutations (including those which I discovered), are commercially available; the mouse models of TBI, GWI and PTSD I have developed in-house. Using brain tissue and blood samples from these mice, we investigate cellular and molecular level changes that correlate with behavioral and pathological outcomes, in order to identify i) in the brain, potential molecular targets to intervene in the pathobiological sequelae; and ii) in the blood, potential diagnostic and theragnostic signatures. I work closely with many clinical collaborators to inform and direct the development and characterization of these models and to ensure that they have clinical relevance, in order to facilitate translation into clinical applications. This includes obtaining human blood and autopsied brain samples which can be used to verify and validate findings from our mouse models. Neuroinflammatory and neuroimmune mechanisms are emerging as key contributors in all of these conditions, but those umbrella terms encompass a multitude of detail into which we are now delving, including cell-specific and timing- specific responses. One of the unique aspects of my research programs has been our attention to lifelong consequences of the insults/exposures experienced in TBI, GWI or PTSD. These lengthy studies have resulted in e.g. 1) characterization of the lifelong (27 months old) consequences of single and repetitive mild TBI in mice aged 3 months at the time of injury – critically important data to understand the chronic effects of neurotrauma and provide a platform for studies of potential therapeutics; 2) characterization of the lifelong (25 months old) consequences of early life (3 months old) exposure to agents known to be contributory to GWI – very important for the current patient population who are suffering Today from GWI, more than 28 years after their toxic exposures; 3) demonstration of behavioral, biochemical and pathological outcomes in our novel PTSD mouse model 6 months after stress exposure –a translationally relevant preclinical platform in which to model our military and veteran populations with persisting PTSD. In these relevant laboratory models, we are identifying cell signaling pathways which, when modulated, mitigate against the negative outcomes of these various exposures. In GWI we have shown that the PPARa agonist, and dietary supplement, oleyoylethanolamide (OEA) is an effective treatment in our model, and have advanced into a Phase II human trial of OEA (ongoing). We have demonstrated that Nilvadipine (our lead anti-AD drug with anti-amyloid, anti-tau and anti-inflammatory properties) and Anatabine (a potent NFkB inhibitor / anti-inflammatory agent, previously available as a nutraceutical) each show positive outcomes in our mTBI models, including when administered at delayed timepoints post-injury (again highly relevant to the human mTBI patient population). My goal over the next ten years is to advance validated, well rationalized, novel treatments, derived from these research studies, into human clinical trials for AD, TBI, GWI and PTSD.

我研究的总体目标是应用分子神经科学研究以识别 对当前没有有效治疗的退伍军人条件的更好的治疗方法。 具体而言，我的工作集中于阿尔茨海默氏病（AD），创伤性脑损伤（TBI），海湾 战争疾病（GWI）和创伤后应激障碍（PTSD）。主要是我使用的鼠标模型 这些条件是为了探索小鼠寿命上每种状况的病理生物学 行为，生化和病理水平，并确定潜在的关键目标 治疗干预。使用人类广告突变创建的AD的鼠标模型 （包括我发现的），可商购； TBI，GWI和 PTSD我在内部开发。使用这些小鼠的脑组织和血液样本，我们 研究与行为和病理相关的细胞和分子水平变化 结果，为了识别i）在大脑中，潜在的分子靶标以干预 病原体后遗症； ii）在血液中，潜在的诊断和热特征。我的工作 与许多临床合作者紧密联系，以告知和指导的发展和表征 这些模型并确保它们具有临床相关性，以便将 临床应用。这包括获得人类血液和尸体型大脑样本 用于验证和验证我们的鼠标模型的发现。神经炎症和神经免疫性 在所有这些条件下，机制都成为关键因素，但是这些伞 涵盖了我们现在正在研究的大量细节，包括特定于细胞的和时机 - 具体响应。 我的研究计划的独特方面之一是我们关注终身 TBI，GWI或PTSD中经历的事件/暴露的后果。这些漫长的研究 导致了例如1）表征终身（27个月大）的单身和 受伤时3个月大的小鼠重复轻度TBI - 至关重要的数据以了解 神经瘤的慢性作用，为潜在治疗的研究提供了一个平台； 2） 终身（25个月大）早期（3个月大）的后果的表征 已知代理人对GWI有贡献 - 对于目前的患者人群非常重要 今天遭受GWI的痛苦，在其有毒暴露后28年； 3）演示 在我们的新型PTSD小鼠模型中，行为，生化和病理结果6个月后 压力暴露 - 翻译相关的临床前平台，在其中对我们的军事和 经验丰富的PTSD的退伍军人人口。 在这些相关的实验室模型中，我们正在识别细胞信号通路，当 调节，减轻这些各种暴露的负面结果。在GWI中，我们有 表明PPARA激动剂和饮食补充剂，油酰乙醇酰胺（OEA）是有效的 在我们的模型中进行处理，并已进入OEA II期人类试验（正在进行）。我们有 证明了尼尔瓦丁胺（我们的抗淀粉样蛋白，抗TAU和抗炎药的铅抗AD药物 属性）和阿纳他滨（潜在的NFKB抑制剂 /抗炎剂，以前可作为 营养图）在我们的MTBI模型中显示了积极的结果，包括在 伤害后延迟的时间点（再次与人类MTBI患者人群高度相关）。我的目标 在接下来的十年中 这些研究研究了人类的AD，TBI，GWI和PTSD的临床试验。