Project 2: Identifying genes and Pathways that impact Tau Toxicity in FTD

项目总结/摘要 为了发现影响tau毒性的新的遗传变异，并概括遗传多样性， 项目2的目的是利用观察到的严重性， 在转基因小鼠模型中，tau蛋白病受到改变遗传背景的显著影响。虽然大多数 已经在标准遗传背景上创建了转基因品系，单个近交系不 纳入人类群体中表型变异的主要来源之一：遗传多样性。缺乏 遗传多样性的缺乏也限制了标准小鼠模型的转化效用，因为它严重地 低估了将在人群中看到的反应的变化。因此基因上- 在目前的研究中，将使用AAV驱动突变的tau蛋白， 在一组协作杂交（CC）重组近交系小鼠以及多样性远交（DO）小鼠中表达 由CC品系的随机重复异交产生的小鼠。总的来说，CC和DO鼠标 群体提供高的作图分辨率和广泛的等位基因多样性，携带4500万个SNP和结构 变体，从而提供了发现体内调节tau毒性的新基因的独特机会。 虽然目前还没有遗传多样性的tau蛋白病模型， 存在于人类群体中，这样一个模型的发展将使研究人员能够测试 疗效和毒性的新的治疗策略，提高翻译的相关性， 传统模型中缺少的遗传变异。在这里，根据令人信服的证据， 项目3证明抗体诱导的血浆tau蛋白升高随疾病进展而波动，我们 将评估遗传背景和疾病严重程度在多大程度上影响血浆tau蛋白水平， AAV注射的CC和DO小鼠。这些发现不仅将提供对潜在意义的关键见解， 血浆tau蛋白浓度的变化与tau蛋白病的进展有关，但也提供了tau蛋白病的 在人群中可以预期的变异程度。总的来说，这些研究提出 这不仅将增加我们对潜在致病机制和途径的理解， 用于治疗tau蛋白病的新治疗靶点的鉴定。

PROJECT SUMMARY/ABSTRACT In order to uncover novel genetic variants that influence tau toxicity, and also recapitulate the genetic diversity characteristic of the human population, Project 2 aims to take advantage of the observation that severity of tauopathy in transgenic mouse models is significantly impacted by altering genetic background. While most transgenic lines have been created on a standard genetic background, a single inbred strain does not incorporate one of the major sources of phenotypic variation in human populations: genetic diversity. The lack of genetic diversity also limits the translational utility of standard mouse models because it grossly underestimates the variation of responses that will be seen in the human population. Therefore a genetically- diverse mouse model of tauopathy will be created in the current study, using AAV to drive mutant tau expression in a panel of Collaborative Cross (CC) recombinant inbred mice, as well as Diversity Outbred (DO) mice produced from random repeated outcrossing of CC strains. Collectively, the CC and DO mouse populations offer high mapping resolution and broad allelic diversity, carrying 45 million SNPs and structural variants and thus providing a unique opportunity to discover new genes that regulate tau toxicity in vivo. Although there are currently no genetically diverse models of tauopathy that are representative of the diversity present within the human population, the development of such a model would enable researchers to test the efficacy and toxicity of new therapeutic strategies, improving translational relevance by incorporating the genetic variation missing from traditional models. Here, based on the compelling evidence presented in Project 3 demonstrating that antibody-induced elevation of plasma tau fluctuates with disease progression, we will evaluate the extent to which genetic background and disease severity influence plasma tau levels in our AAV-injected, CC and DO mice. These findings will not only provide key insight into the potential significance of changes in plasma tau concentrations to progression of tauopathy, but also offer an indication of the magnitude of variability that could be anticipated in the human population. Collectively, the studies proposed will not only increase our understanding of underlying pathogenic mechanisms and pathways, but also drive the identification of new therapeutic targets for the treatment of tauopathy.