Tau Kinetics in the human CNS in vivo and in vitro

体内和体外人类 CNS 中的 Tau 动力学

• 批准号: 9916684
• 负责人: Chihiro Sato
• 金额: $ 11.93万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916684
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloidosis; Apolipoprotein E; Biological Markers; Brain; Cell Culture Techniques; Cerebrospinal Fluid; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Cognitive; Correlation Studies; Dactinomycin; Dementia; Disease; Drug Targeting; Etiology; Extracellular Protein; FRAP1 gene; Family; Frontotemporal Dementia; Functional disorder; Funding; Future; Genetic Transcription; Genotype; Goals; Half-Life; Human; Image; Impaired cognition; In Vitro; K-Series Research Career Programs; Kinetics; Leadership; Link; Magnetic Resonance Imaging; Measures; Mediator of activation protein; Mentors; Mentorship; Messenger RNA; Metabolic Clearance Rate; Metabolism; Methods; Modeling; Molecular Weight; Monitor; Mutation; Nerve Degeneration; Nervous system structure; Neuraxis; Neurofibrillary Tangles; Neurons; Observational Study; Other Genetics; Outcomes Research; Participant; Pathologic; Pathway interactions; Patients; Peptides; Pharmacodynamics; Phosphorylation; Physicians; Physiologic pulse; Physiological; Positron; Post-Translational Protein Processing; Production; Progressive Supranuclear Palsy; Protein Biosynthesis; Protein Isoforms; Proteins; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal Protein S6 Kinase; Ribosomes; Senile Plaques; Sirolimus; Stable Isotope Labeling; Statistical Data Interpretation; Symptoms; Tauopathies; Testing; Time; Training; Translations; Ventricular; Work; abeta oligomer; cognitive testing; cohort; corticobasal degeneration; design; extracellular; human subject; imaging genetics; in vivo; in vivo monitoring; induced pluripotent stem cell; inhibitor/antagonist; insight; monomer; mutation carrier; nerve stem cell; neuron loss; novel therapeutics; pancreatic secretory trypsin inhibitor I; sex; skills; stable isotope; stem cell technology; targeted treatment; tau Proteins; tau aggregation; tau-1; tool; true biomarker; β-amyloid burden

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.

项目摘要/摘要 这项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学。 神经系统（CNS）。具体来说，我将测试的假设，tau蛋白动力学改变， tau蛋白病如阿尔茨海默病（AD）。 大脑中的Tau聚集和脑脊液（CSF）Tau的改变是AD的标志， 其他tau蛋白病，如进行性核上性麻痹（PSP）和皮质基底节变性（CBD）。 先前的研究表明，CSF tau蛋白随着年龄和认知能力的下降而不断增加，并且CSF tau蛋白的表达也随着年龄的增加而增加。 总tau、CSF磷酸化tau和CSF淀粉样蛋白β（Ab）目前用作AD生物标志物。 然而，最近的研究表明，这不是线性的，并且CSF tau在症状发作后降低。 因此，为了利用tau代谢，更全面地了解和评估tau代谢至关重要 作为一个真正的生物标志物，可以精确预测发病年龄和疾病进展。目前 CSF tau改变的机制，特别是在人类中，仍然不清楚。CSF tau蛋白增加是否由于 增加tau蛋白的产生还是减少清除？是否有病理状态，如Ab增加 负荷改变tau动力学？ 为了测量人类中枢神经系统（CNS）中的tau动力学，我开发了稳定的同位素 标记动力学（SILK）方法。在目标1中，30名AD患者，40名认知正常的年龄匹配的 参与者，30名年轻对照，以及多达35名非AD tau蛋白病，包括PSP，CBD和MAPT 将用tau SILK方法分析突变家族，以检验tau动力学是 在tau蛋白病中改变。在目标2中，我将在神经元细胞培养物中使用体外tau SILK方法，包括 诱导多能干细胞（iPSC）衍生的神经元，以测试tau蛋白的产生是 随着淀粉样蛋白的增加，AD患者的发病率增加。该提案将有助于设计未来的临床研究， 最终开发针对tau的新的治疗策略。 成功资助这个指导职业发展奖将给我一个非凡的 有机会提升我在临床结果研究，领导力和iPSC技术方面的培训。这 培训将使我具备作为独立翻译人员所需的独特工具和技能 科学调查员。