Identification of the Molecular Mechanisms Linking Alzheimer's Disease, PERK, and Mild Repetitive Head Injury

本研究将建立轻度重复性脑外伤（mrTBI）的分子机制 以及与阿尔茨海默病（AD）相关的tau病理学的发作。我们的初步数据显示， 内质网应激是由损伤激活的显著且持久的级联反应。ER应激活性 vates一种叫做PERK的蛋白质，它负责启动保护途径，帮助恢复ER功能， 是的。然而，PERK的长期激活导致细胞死亡。脑细胞特别容易受到 PERK介导的细胞死亡。事实上，TBI和AD之间的共同标志是PERK活动过度。 我们最近确定了TBI和AD的另一个共同的病理标志，异常聚集蛋白， tau蛋白的激活是由PERK的慢性激活驱动的。PERK诱导tau采取有毒构象 与疾病相关的基因因此，本项目的总体假设是TBI诱导长- PERK的持久激活，这反过来又催化病理性tau种类的形成。这最终 导致AD风险增加。 我们将在两个目标中使用小鼠模型来测试我们的假设。在目标1中，我们将确定条件 mrTBI引起PERK激活的条件下。为了实现这一目标，小鼠将在24小时内经受mrTBI。 不同的强度和不同的时间点，并且将测量活性PERK的水平。此外，本发明还提供了一种方法， 我们将确定显示PERK活性的组织的范围。 在目标2中，我们将在患有mrTBI的tau蛋白病小鼠模型中操纵PERK活性。我们 预计PERK激活将导致更多的tau病理学并诱导对脑功能的损伤。相反地， PERK抑制将恢复大脑功能并防止tau病理。 目的3将确定使用PERK作为TBI生物标志物的有效性。我们的初步数据显示 在一生中遭受过一次或多次TBI的人， 他们的血这些数据支持了我们将研究扩展到更大人群的热情。 如果成功的话，这项资助不仅将确定损伤和AD之间联系的分子机制， 还强调了一个充满治疗靶点的关键病理途径。这些研究的逻辑延伸 包括测试PERK通路的抑制剂的潜在治疗价值。它还将缓解1.7 美国每年有100万人遭受TBI。 我们在ER应力，PERK，tau，AD和TBI方面的专业知识使我们非常适合完成亲， 工作姿势此外，我的实验室可利用的独特资源，如小动物MR成像，ADC共- 霍特样本和临床病史，以及COBRE病毒生产核心加强了影响 我们的工作，使我们更接近了解tau介导的神经毒性事件的机制干- 急诊室的明我目前与列克星敦VAMC的合作关系，包括从退伍军人那里获得血清 独特的成像和蛋白质组学仪器，使我们的实验室非常适合完成拟议的 在这个应用程序中工作。此外，尽管我的研究计划的简短发展，我们一直在 非常富有成效（自2010年以来出版了27篇出版物，自2013年以来共获得310万美元的资助）。这些成就 增加安全性，我将顺利完成拟议的工作。 !

This study will establish the molecular mechanism linking mild repetitive traumatic brain injury (mrTBI) and onset of tau pathology that is associated with Alzheimer's disease (AD). Our preliminary data suggest that endoplasmic reticulum stress is a notable and long-lasting cascade that is activated by injury. ER stress acti- vates a protein called PERK, which is responsible for initiating protective pathways that help restore ER func- tion. However, long-term activation of PERK leads to cell death. Brain cells are particularly susceptible to PERK-mediated cell death. Indeed, a common sign between TBI and AD is PERK hyperactivity. We recently established that another common pathological hallmark of TBI and AD, abnormal aggrega- tion of the protein tau, is driven by chronic activation of PERK. PERK induces tau to adopt toxic conformations that are associated with disease. Therefore, the overall hypothesis of this project is that TBI induces long- lasting activation of PERK, which in turn catalyzes the formation of pathological tau species. This ultimately leads to increased risk for AD. We will test our hypotheses using mouse models in two aims. In Aim 1, we will determine the conditions under which mrTBI causes activation of PERK. To accomplish this objective, mice will be subjected to mrTBI at different intensities and for different time points, and the levels of active PERK will be measured. In addition, we will determine the extent of tissue that shows PERK activity. In Aim 2, we will manipulate PERK activity in mouse models of tauopathy that have suffered mrTBI. We expect that PERK activation will cause more tau pathology and induce damage to brain function. Conversely, PERK inhibition will restore brain function and prevent tau pathology. Aim 3 will determine the validity of using PERK as a biomarker of TBI. Our preliminary data suggest that individuals who suffered one or more TBIs in their lifetime have two times more active/total PERK ratio in their blood. These data support our enthusiasm to expand our studies into a much larger cohort. If successful, this grant will not only identify a molecular mechanism that links injury and AD, but it will also highlight a key pathological pathway replete with therapeutic targets. Logical extensions of these studies involve testing inhibitors of the PERK pathway for potential therapeutic value. It will also offer relief to the 1.7 million people in the United States who suffer a TBI annually. Our expertise in ER stress, PERK, tau, AD, and TBI makes us uniquely suited to accomplish the pro- posed work. In addition, the unique resources available to my lab, such as small animal MR imaging, ADC co- hort biospecimens and clinical histories, and the COBRE Viral Production Core have strengthened the impact of our work and brought us closer to understanding the mechanisms of tau-mediated neurotoxic events stem- ming from the ER. My current partnership with the Lexington VAMC, including access to serum from veterans and unique instruments for imaging and proteomics, makes our lab ideally suited to accomplish the proposed work in this application. Furthermore, despite the brief development of my research program, we have been extremely productive (27 publications since 2010 and $3.1M total funding since 2013). These achievements increase the security that I will successfully complete the proposed work. !