Identifying genes and Pathways that impact Tau Toxicity in FTD

项目摘要/摘要 在这个高度整合、多学科、无围墙的中心，题为《鉴定基因和途径 调节FTD中的tau毒性“，我们试图发现tau病的新的遗传修饰物来提供 对疾病机制的独特见解，以及支持开发和验证创新的 用血浆样本测量患者tau负荷的方法。利用基因组 对来自PSP患者的数据进行测序，项目1将识别影响疾病风险的基因变异， 并与人类生物学验证核心合作，确定关键变异如何与 陶氏负担。作为识别遗传修饰物的补充但可选的方法，项目2将利用 Jax实验室开发的协作性杂交和多样性远交种小鼠品系发现遗传变异 它们决定了对AAV诱导的紧张症的敏感性或抵抗力。项目3将调查假设 在应用抗tau抗体后对血浆tau水平的评估提供了一种敏感和 Tau在大脑中聚集的特定生物标记物，使用来自两种tau病小鼠模型的样本 以及参加ARTFL和LEFFTDS的患者。项目4将构建FTD-tau的疾病特征 并挖掘公共数据库和系统分析以预测药理学和/或遗传干预 反转签名，以及阐明项目1和2中确定的遗传修饰物如何影响tau 新陈代谢和分泌。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)。我们设想，在供资期间结束时，我们将：(1)确定 决定对tau介导的神经变性敏感或抵抗的关键基因；(Ii)形成了一种 脑部tau沉积的敏感和特异的血液生物标记物；(Iii)发现新的治疗方法 预测将逆转定义tau突变携带者的转录签名的目标；以及(Iv)确定 Tau突变和tau病的遗传修饰物如何影响tau代谢、蛋白质动态平衡和细胞 生存能力。因此，我们的中心是独一无二的，能够识别处于危险中的患者群体， 同时提高诊断能力和扩大治疗可能性。

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.