The molecular intersection of tau, TBI, and PERK

本研究将建立轻度重复创伤性脑损伤(MrTBI)与发病的分子机制 与阿尔茨海默病(AD)相关的tau病理。我们的初步数据显示内质网 网状应激是一种显著的、持久的级联反应，由伤害激活。内质网应激激活一种蛋白质 PERK负责启动保护通路，帮助恢复ER功能。然而，龙- PERK的长期激活导致细胞死亡。脑细胞特别容易受到PERK介导的细胞死亡的影响。 事实上，脑外伤和阿尔茨海默病之间的一个共同迹象是过度活跃。我们最近证实了另一个COM- 脑损伤和阿尔茨海默病的病理特征是tau蛋白的异常聚集，是由慢性激活驱动的 当然是福利。PERK诱导tau采用与疾病相关的有毒构象。因此，总体来说， 该项目的假设是，脑损伤诱导PERK的持久激活，进而催化形成PERK 病态牛群的种类。这最终会增加AD的风险。我们将使用以下工具来测试我们的假设 小鼠模型有两个目的。在目标1中，我们将确定mrTBI引起激活的条件 额外津贴。为了实现这一目标，小鼠将受到不同强度和不同时间的mrtbi。 积分，并将测量积极津贴的水平。此外，我们将确定组织的范围 显示额外的活动。在目标2中，我们将在已经遭受牵张症的小鼠模型中操纵PERK活动 先生。我们预计，PERK的激活将导致更多的tau病理，并导致脑功能损害。 相反，抑制PERK将恢复大脑功能，防止tau病理。目标3将决定- PERK作为脑损伤生物标志物的强度。我们的初步数据表明，患有一种或多种疾病的人 在他们的一生中，更多的TBI在他们的血液中有两倍的活跃/总津贴比率。这些数据支持我们的 将我们的研究扩展到一个更大的队列的热情。如果成功，这笔赠款不仅将确定一个 将损伤和AD联系在一起的分子机制，但它也将突出一个关键的病理途径，其中充满了 治疗靶点。这些研究的合乎逻辑的扩展包括测试PERK通路的抑制剂对PO. 潜在的治疗价值。它还将为美国170万患有脑外伤的人提供救济 每年一次。我们在ER Stress、PERK、TAU、AD和TBI方面的专业知识使我们独一无二地适合实现 摆好姿势的作品。此外，我的实验室可利用的独特资源，如小动物磁共振成像，队列 生物制品和临床病史，以及UF病毒生产核心加强了我们工作的影响 并使我们更接近理解tau介导的神经毒性事件的机制，这些事件源于 呃。

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 activates a protein called PERK, which is responsible for initiating protective pathways that help restore ER function. 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 com- mon pathological hallmark of TBI and AD, abnormal aggregation 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 va- lidity 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 po- tential 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, cohort biospecimens and clinical histories, and the UF Viral Production Core have strengthened the impact of our work and brought us closer to understanding the mechanisms of tau-mediated neurotoxic events stemming from the ER.