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：
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
项目类别：
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&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 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

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/摘要这项研究的总体目的是了解人类中央tau蛋白的病理生理学神经系统（CNS）。特别是，我将检验以下假设：tau蛋白动力学发生了改变诸如阿尔茨海默氏病（AD）之类的tauopathies。大脑中的tau聚集以及脑脊液（CSF）TAU的改变是AD和其他tauopathies，例如进行性闭核性麻痹（PSP）和皮质型变性（CBD）。先前的研究表明，CSF TAU随着年龄和认知能力下降而不断增加，CSF 目前将TAU，CSF磷酸化的TAU和CSF淀粉样蛋白β（AB）用作AD生物标志物。但是，最近的研究表明，这不是线性的，而CSF TAU在符号发作后减少。因此，至关重要的是，更全面地理解和评估TAU代谢作为一种真正的生物标志物，可以精确预测疾病的发作和进步的年龄。目前 CSF TAU改变的机制，尤其是在人类中，尚不清楚。是由于增加的CSF TAU而导致的提高tau的产量或减少清除率？病理状况（例如增加AB）负担Alter Alter 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 Tau的标记动力学（丝）方法。在AIM 1中，有30名AD患者，40个认知正常匹配的患者参与者，30个年轻对照，最多35个非AD tauopathies，包括PSP，CBD和MAPT 将使用Tau丝绸方法分析突变家族，以检验Tau动力学的假设扭曲的改变。在AIM 2中，我将在神经元细胞培养物中使用体外Tau丝绸方法诱导多能干细胞（IPSC）衍生的神经元，以检验Tau产生的假设 AD的增加，淀粉样蛋白增加。该建议将有助于设计未来的临床研究和最终制定针对TAU的新型治疗策略。成功的Mendored职业发展奖的成功基础将为我提供非凡的基础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。这培训将使我为作为独立翻译所需的独特工具和技能设备科学研究者。