BLRD RESEARCH CAREER SCIENTIST AWARD APPLICATION

我研究的首要目标是应用分子神经科学研究来识别 对退伍军人目前没有有效治疗方法的情况进行更好的治疗。 具体地说，我的工作重点是阿尔茨海默病(AD)、创伤性脑损伤(TBI)、海湾 战争疾病(GWI)和创伤后压力障碍(PTSD)。首先，我使用鼠标模型 这些条件，以探索每种条件下的小鼠寿命的病理生物学 行为、生化和病理水平，并在其中确定潜在的关键目标 治疗性干预。阿尔茨海默病的小鼠模型，使用人类导致AD的突变创建 (包括我发现的那些)，是可以在商业上买到的；TBI，GWI和 创伤后应激障碍是我自己开发的。利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的变化 结果，为了确定i)在大脑中，潜在的分子靶点干预 病理生物学后遗症；以及ii)在血液中，潜在的诊断和治疗特征。我在工作 与许多临床合作者密切合作，提供信息并指导疾病的发展和特征 这些模型并确保它们具有临床意义，以便促进转换为 临床应用。这包括获取人类血液和尸检的大脑样本，这些样本可以 用来验证和验证我们的小鼠模型的发现。神经炎性和神经免疫 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 包括我们现在正在钻研的众多细节，包括特定于细胞的和时间- 具体的回应。 我的研究项目的一个独特方面是我们对终身的关注 在创伤后应激障碍、创伤后应激障碍或创伤后应激障碍中遭受侮辱/暴露的后果。这些冗长的研究 已导致例如：1)描述单身和单身的终生(27个月)后果 3个月龄小鼠在受伤时的重复性轻度脑损伤--理解至关重要的数据 神经创伤的慢性影响，并为潜在治疗方法的研究提供平台；2) 早期生活(3个月大)暴露于以下疾病的终生(25个月大)后果的特征 已知对GWI有贡献的代理-对于当前的患者群体非常重要，他们是 在接触有毒物质28年后的今天，他们遭受了GWI的痛苦；3)展示了 我们的新型创伤后应激障碍小鼠模型6个月后的行为、生化和病理结果 压力暴露-一个与翻译相关的临床前平台，在其中模拟我们的军队和 患有持续性创伤后应激障碍的退伍军人群体。 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 经过调整，减轻这些不同暴露的负面后果。在GWI，我们有 研究表明，PPARa激动剂和膳食补充剂、烯丙基乙醇胺(OEA)是一种有效的 在我们的模型中进行了治疗，并已进入OEA的第二阶段人体试验(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和抗炎作用 特性)和Anatabine(一种有效的NFkB抑制剂/抗炎剂，以前可用 营养品)在我们的mTBI模型中都显示出积极的结果，包括在 损伤后延迟的时间点(同样与人类mTBI患者群体高度相关)。我的目标 在接下来的十年里，是推进经过验证的、合理的、新的治疗方法，源于 这些研究包括AD、脑损伤、GWI和创伤后应激障碍的人体临床试验。

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.