Identifying genes and Pathways that impact Tau Toxicity in FTD

识别影响 FTD 中 Tau 毒性的基因和通路

基本信息

批准号：
9562146
负责人：
LEONARD PETRUCELLI
金额：
$ 121.61万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9562146
关键词：
Advisory Committees Affect Antibodies Autophagocytosis Behavioral Symptoms Biological Assay Biological Markers Brain Cell Differentiation process Cell Survival Characteristics Clinic Clinical Cloning Collaborations Complementary DNA Data Data Set Databases Deposition Development Diagnostic Disease Disease Resistance Disease susceptibility Education Enrollment Ensure Exhibits Funding Gene Expression Profile Gene Mutation Genes Genetic Genetic Variation Genomics Goals Government Human Human Biology Inbred Strain Individual Institutes Intervention Laboratories Link Maps Measures Metabolism Methods Modeling Mouse Strains Mus Nerve Degeneration Neurobehavioral Manifestations Neurodegenerative Disorders Neurons Nucleotides Pathologic Pathology Pathway interactions Patients Pennsylvania Pharmacology Plasma Populations at Risk Production Progress Reports Progressive Supranuclear Palsy Quality Control Research Personnel Research Project Grants Resistance Reverse Transcription Risk Role Sampling Structure Systems Analysis Tauopathies Therapeutic Tissues Toxic effect United States National Institutes of Health Universities Validation Variant Viral Virus Washington base blood-based biomarker cell type cohort cooking corticobasal degeneration disorder risk gene therapy genetic risk factor genetic signature genetic variant genome sequencing in vivo innovation insight meetings motor symptom mouse model multidisciplinary mutation carrier nervous system disorder new therapeutic target novel novel therapeutics patient population proteostasis responsible research conduct specific biomarkers structural genomics tau Proteins tau aggregation tau mutation therapeutic target tool web site

项目摘要

PROJECT SUMMARY/ABSTRACT In this highly-integrated and multi-disciplinary Center without Walls entitled “Identifying genes and pathways that modulate tau toxicity in FTD”, we seek to discover novel genetic modifiers of tauopathy to provide unique insight into disease mechanisms, as well as support the development and validation of an innovative approach to measure tau burden in patients using plasma samples. Taking advantage of the genome sequencing data available from PSP patients, Project 1 will identify genetic variants that influence disease risk, and in collaboration with the Human Biology Validation Core determine how key variants are associated with tau burden. As a complementary but alternative approach to identify genetic modifiers, Project 2 will utilize the Collaborative Cross and Diversity Outbred mouse strains developed at Jax Labs to uncover genetic variants that determine sensitivity or resistance to AAV-induced tauopathy. Project 3 will investigate the hypothesis that assessment of plasma tau levels following the administration of anti-tau antibodies provides a sensitive and specific biomarker for tau aggregation in the brain, employing samples from both murine models of tauopathy as well as patients enrolled in ARTFL and LEFFTDS. Project 4 will construct a disease signature for FTD-tau and mine public databases and systems analyses to predict pharmacologic and/or genetic interventions to reverse the signature, as well as elucidate how genetic modifiers identified in Projects 1 and 2 impact tau metabolism and secretion. The four research projects will be supported by the Administrative Core (Core A), the Viral Production and Cloning Core (Core B), the Human Biology Validation Core (Core C), and the Data Coordination Core (Core D). We envision that at the conclusion of the funding period, we will have: (i) identified key genes that determine either sensitivity or resistance to tau-mediated neurodegeneration; (ii) developed a sensitive and specific blood-based biomarker for tau deposition in the brain; (iii) discovered novel therapeutic targets predicted to reverse the transcriptional signature that defines tau mutation carriers; and (iv) determined how tau mutations and genetic modifiers of tauopathy impact tau metabolism, protein homeostasis and cell viability. Therefore, our Center is uniquely poised to enable the identification of patient populations at risk, while simultaneously enhancing diagnostic capabilities and expanding therapeutic possibilities.

项目概要/摘要在这个高度一体化、多学科的无围墙中心，题为“识别基因和途径” 调节 FTD 中的 tau 毒性”，我们寻求发现 tau 病的新型遗传修饰剂，以提供对疾病机制的独特见解，并支持创新药物的开发和验证利用血浆样本测量患者 tau 负荷的方法。 PSP 患者的测序数据，项目 1 将识别影响疾病风险的遗传变异，并与人类生物学验证核心合作确定关键变异如何与作为识别遗传修饰物的补充但替代方法，项目 2 将利用 Jax 实验室开发的协作杂交和多样性远交小鼠品系以发现遗传变异项目 3 将研究以下假设：施用抗 tau 抗体后对血浆 tau 水平的评估提供了敏感且可靠的方法大脑中 tau 蛋白聚集的特异性生物标志物，采用两种 tau 蛋白病小鼠模型的样本以及参加 ARTFL 和 LEFFTDS 项目 4 的患者将为 FTD-tau 构建疾病特征。并挖掘公共数据库和系统分析来预测药理学和/或遗传干预措施逆转签名，并阐明项目 1 和 2 中识别的基因修饰剂如何影响 tau 这四个研究项目将得到行政核心（核心A）的支持，病毒生产和克隆核心（核心 B）、人类生物学验证核心（核心 C）和数据协调核心（核心 D）我们预计在资助期结束时，我们将： (i) 确定决定对 tau 介导的神经变性的敏感性或抵抗力的关键基因；大脑中 tau 沉积的敏感且特异的血液生物标志物；(iii) 发现了新的治疗方法；预测可逆转 tau 突变携带者转录特征的目标；以及 (iv) 已确定 tau 突变和 tau 蛋白病的遗传修饰如何影响 tau 代谢、蛋白质稳态和细胞因此，我们的中心具有独特的优势，能够识别处于危险中的患者群体，同时增强诊断能力并扩大治疗可能性。