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.

我研究的首要目标是应用分子神经科学研究来识别 更好的治疗退伍军人的条件，目前没有有效的治疗。 具体来说，我的工作集中在阿尔茨海默病（AD），创伤性脑损伤（TBI），海湾 战争病（GWI）和创伤后应激障碍（PTSD）。首先，我用老鼠模型 这些条件下，为了探索每种条件在小鼠寿命中的病理生物学， 行为、生物化学和病理水平，并在其中确定潜在的关键目标 治疗干预使用人类AD致突变创建的AD小鼠模型 （包括我发现的那些），是商业上可获得的; TBI，GWI和 PTSD是我在公司内部开发的。利用这些小鼠的脑组织和血液样本， 研究与行为和病理相关的细胞和分子水平的变化， 结果，以确定i）在大脑中，潜在的分子靶点干预 病理生物学后遗症;和ii）在血液中，潜在的诊断和治疗不确定性特征。我工作 与许多临床合作者密切合作，以告知和指导开发和表征 这些模型，并确保它们具有临床相关性，以促进转化为 临床应用。这包括获得人类血液和尸检大脑样本， 用于验证和确认我们的小鼠模型的发现。神经炎症和神经免疫 在所有这些情况下，机制正在成为关键因素，但这些总括条款 包含我们现在正在深入研究的大量细节，包括细胞特异性和时间- 具体的回答。 我的研究项目的一个独特之处是我们关注终身 在TBI、GWI或PTSD中经历的损伤/暴露的后果。这些冗长的研究 已经导致例如1）单一和 3个月大的小鼠在受伤时的重复性轻度TBI-了解至关重要的数据 神经创伤的慢性效应，并为潜在治疗方法的研究提供平台; 2） 生命早期（3个月）暴露于以下物质的终身（25个月）后果的表征 已知对GWI有贡献的药物-对于目前的患者人群非常重要， 今天遭受GWI，超过28年后，他们的有毒暴露; 3）证明， 在我们的新型PTSD小鼠模型中， 压力暴露-一个与临床前平台相关的实验，在其中模拟我们的军事和 患有持续性创伤后应激障碍的退伍军人 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 调制，减轻这些不同暴露的负面结果。在GWI， 显示PPARa激动剂和膳食补充剂油酰乙醇胺（OEA）是有效的 在我们的模型中进行治疗，并已进入OEA的II期人体试验（正在进行中）。我们有 证明了尼伐地平（我们的主要抗AD药物，具有抗淀粉样蛋白、抗tau蛋白和抗炎作用） 特性）和Anatabine（一种有效的NFkB抑制剂/抗炎剂，以前可作为 在我们的mTBI模型中，每一种都显示出积极的结果，包括当以 损伤后延迟的时间点（再次与人类mTBI患者群体高度相关）。我的目标 在未来十年内，我们的目标是推进有效的，合理的，新的治疗方法， 将这些研究纳入AD、TBI、GWI和PTSD的人体临床试验。