Tau Kinetics in the human CNS in vivo and in vitro

项目摘要/摘要 本研究的总体目标是了解tau蛋白在人类中枢神经系统中的病理生理机制。 神经系统(CNS)。具体地说，我将测试tau蛋白动力学改变的假设。 阿尔茨海默病(AD)等神经官能症。 脑组织中tau的聚集和脑脊液中tau的改变是AD和 其他疾病，如进行性核上性麻痹(PSP)和皮质基底膜变性(CBD)。 以前的研究表明，随着年龄和认知能力的下降，脑脊液tau不断增加，脑脊液 总tau、脑脊液磷酸化tau和脑脊液淀粉样β蛋白(Ab)目前被用作AD的生物标志物。 然而，最近的研究表明，这并不是线性的，症状出现后，脑脊液tau会降低。 因此，更全面地了解和评价tau代谢对于它的应用是至关重要的。 作为一个真正的生物标志物，可以准确地预测疾病的发病年龄和进展。目前， 脑脊液tau改变的机制，特别是在人类中，仍不清楚。脑脊液tau升高是否由于 牛磺酸产量增加还是清除减少？像Ab值升高这样的病理情况 负担改变了牛磺酸的动力学？ 为了测量人类中枢神经系统(CNS)中的tau动力学，我开发了稳定同位素 牛磺酸的标记动力学(丝)法。在目标1中，30名AD患者，40名认知正常年龄匹配的患者 参与者，30名年轻对照组，以及多达35名非AD患者，包括PSP、CBD和MAPT 突变家族将用tau Silk方法进行分析，以检验tau动力学是 在变态中改变的。在目标2中，我将在神经细胞培养中使用tau Silk方法，包括 诱导多能干细胞(IPSCs)来源的神经元，以检验tau产生是 AD时升高，淀粉样蛋白增多。这项建议将有助于设计未来的临床研究和 最终开发针对tau的新治疗策略。 成功资助这个辅导式职业发展奖将给我带来非凡的 有机会提升我在临床成果研究、领导力和IPSC技术方面的培训。这 培训将使我掌握作为独立翻译出类拔萃所需的独特工具和技能 科学调查员。

Project Abstract/Summary The overall goal of this research is to understand the pathophysiology of tau protein in the human central nervous system (CNS). Specifically, I will test the hypothesis that tau protein kinetics are altered in tauopathies such as Alzheimer’s disease (AD). Tau aggregation in the brain and alterations in cerebrospinal fluid (CSF) tau are hallmarks of AD and other tauopathies such as Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Previous studies suggest that CSF tau continuously increases with age and cognitive decline, and CSF total tau, CSF phosphorylated tau, and CSF amyloid beta (Ab) are currently used as AD biomarkers. However, recent study indicates that this is not linear, and CSF tau decreases after symptom onset. Therefore, it is critical to understand and evaluate tau metabolism more comprehensively in order to use it as a true biomarker that would precisely predict age of onset and progress of the disease. Currently the mechanism of CSF tau alterations, especially in humans, remains unclear. Is the increased CSF tau due to increased tau production or decreased clearance? Does pathological condition such as increasing Ab burden alter tau kinetics? To measure the tau kinetics in the human central nervous system (CNS), I developed stable isotope labeling kinetics (SILK) method for tau. In Aim 1, 30 AD patients, 40 cognitively normal age-matched participants, 30 younger controls, and up to 35 non-AD tauopathies including PSP, CBD, and MAPT mutation families will be analyzed with the tau SILK methods to test the hypothesis that tau kinetics are altered in tauopathies. In Aim 2, I will use in vitro tau SILK method in neuronal cell cultures including induced pluripotent stem cell (iPSCs)-derived neurons to test the hypothesis that tau production is increased in AD, with increasing amyloid. This proposal will help design future clinical studies and ultimately develop novel therapeutic strategies targeting tau. Successful funding of this mentored career development award will afford me an extraordinary opportunity to advance my training in clinical outcome research, leadership, and iPSC technologies. This training will equip me with the unique tools and skill sets required to excel as an independent translational scientific investigator.