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

基本信息

批准号：
10380106
负责人：
Chihiro Sato
金额：
$ 11.93万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10380106
关键词：
70-kDa Ribosomal Protein S6 Kinases Age Age of Onset Alzheimer&apos s Disease Alzheimer&apos 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 Induced pluripotent stem cell derived neurons 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 efficacy evaluation extracellular human subject imaging genetics in vivo in vivo monitoring induced pluripotent stem cell induced pluripotent stem cell technology inhibitor insight monomer mutation carrier nerve stem cell neuron loss novel therapeutic intervention pancreatic secretory trypsin inhibitor I sex skills stable isotope targeted treatment tau Proteins tau aggregation tau-1 tool β-amyloid burden

项目摘要

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/总结本研究的总体目标是了解人类中枢神经系统中 tau 蛋白的病理生理学具体来说，我将测试 tau 蛋白动力学发生改变的假设。 tau蛋白病，例如阿尔茨海默病（AD）。大脑中 tau 蛋白的聚集和脑脊液 (CSF) tau 蛋白的改变是 AD 和其他 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持续增加，并且CSF 总 tau、CSF 磷酸化 tau 和 CSF 淀粉样蛋白 (Ab) 目前被用作 AD 生物标志物。然而，最近的研究表明，这不是线性的，并且脑脊液 tau 在症状出现后下降。因此，更全面地了解和评估 tau 代谢以利用它至关重要作为一种真正的生物标志物，可以精确预测疾病的发病年龄和进展。脑脊液 tau 蛋白改变的机制，特别是在人类中，目前尚不清楚脑脊液 tau 蛋白的增加是否是由于。 tau 蛋白产生增加或清除率降低是否导致 Ab 增加等病理状况？负担改变tau动力学？为了测量人类中枢神经系统 (CNS) 中的 tau 动力学，我开发了稳定同位素 tau 标记动力学 (SILK) 方法在目标 1 中，30 名 AD 患者，40 名年龄匹配的认知正常患者。参与者、30 名年轻对照者以及最多 35 名非 AD tau蛋白病，包括 PSP、CBD 和 MAPT 将使用 tau SILK 方法分析突变家族，以检验 tau 动力学的假设在目标 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) 衍生的神经元来检验 tau 蛋白产生的假设随着淀粉样蛋白的增加，AD 的发病率也随之增加。该提案将有助于设计未来的临床研究和研究。最终开发出针对 tau 的新型治疗策略。这个指导性职业发展奖的成功资助将为我提供非凡的机会有机会推进我在临床结果研究、领导力和 iPSC 技术方面的培训。培训将为我提供成为独立翻译人员所需的独特工具和技能科学调查员。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction.

DOI：
10.1172/jci.insight.152012
发表时间：
2022-01-11
期刊：
JCI insight
影响因子：
8
作者：
Ezerskiy LA;Schoch KM;Sato C;Beltcheva M;Horie K;Rigo F;Martynowicz R;Karch CM;Bateman RJ;Miller TM
通讯作者：
Miller TM