Identifying genes and Pathways that impact Tau Toxicity in FTD

项目总结/摘要 在这个高度综合和多学科的中心，没有围墙，题为“识别基因和途径， 调节FTD中的tau毒性”，我们寻求发现tau蛋白病的新型遗传修饰剂， 对疾病机制的独特见解，以及支持开发和验证创新的 使用血浆样品测量患者中tau负荷的方法。利用基因组 PSP患者的测序数据，项目1将确定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 Tau负担。作为一种补充但替代的方法来确定遗传修饰剂，项目2将利用 协作杂交和多样性在Jax实验室开发的远交小鼠品系，以发现遗传变异 其决定对AAV诱导的tau蛋白病的敏感性或抗性。项目3将研究假设， 在施用抗-tau抗体后血浆tau水平的评估提供了一种灵敏的 脑中tau聚集的特异性生物标志物，采用来自两种tau蛋白病鼠模型的样品 以及入组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， 逆转签名，并阐明项目1和2中确定的遗传修饰剂如何影响tau蛋白 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）。我们预计，在资助期结束时，我们将： 决定对tau介导的神经变性敏感性或抗性的关键基因;（ii）开发了一种 针对脑中tau沉积的敏感且特异的基于血液的生物标志物;（iii）发现了新的治疗方法 预测逆转定义tau突变携带者的转录特征的靶标;和（iv）确定 tau蛋白突变和tau蛋白病遗传修饰剂如何影响tau蛋白代谢、蛋白质稳态和细胞 生存能力因此，我们的中心是独一无二的，能够识别有风险的患者群体， 同时增强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.