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

项目摘要/摘要 为了发现影响tau毒性的新的遗传变异，并概述遗传多样性 作为人类人口的特征，项目2旨在利用观察到的严重程度 转基因小鼠模型中的互变受到遗传背景改变的显著影响。虽然大多数人 转基因品系已经在标准的遗传背景下被创造出来，而单一的近交系却没有 纳入人类群体表型变异的主要来源之一：遗传多样性。匮乏 遗传多样性也限制了标准小鼠模型的翻译效用，因为它严重地 低估了将在人类群体中看到的反应的变化。因此，从基因上讲- 在目前的研究中，将建立不同类型的tau病小鼠模型，使用AAV来驱动突变的tau 协同杂交(CC)重组近交系小鼠及差异性近交系(DO)小鼠的表达 CC品系随机重复异交产生的小鼠。总的来说，CC和DO鼠标 群体具有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 这为发现在体内调节tau毒性的新基因提供了一个独特的机会。 尽管目前还没有遗传上不同的互动症模型来代表这种多样性 在人类群体中，这种模型的开发将使研究人员能够测试 新的治疗策略的有效性和毒性，通过整合 传统模型中缺失的遗传变异。在这里，基于在 项目3表明，抗体诱导的血浆tau升高随着疾病的进展而波动，我们 将评估遗传背景和疾病严重性对血浆tau水平的影响程度 AAV组、CC组和DO组。这些发现不仅将提供对潜在意义的关键洞察 血浆tau浓度的变化与肌萎缩侧索硬化症的进展之间的关系，但也提供了 在人类群体中可以预见到的变异性的大小。总而言之，这些研究建议 不仅会增加我们对潜在致病机制和途径的了解，而且还会推动 寻找治疗颈椎病的新靶点。

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.