UC Irvine AD Translational Center for Disease Model Resources

项目摘要 阿尔茨海默病（AD）是目前影响超过3500万人的不可治愈的神经退行性疾病 全世界有540万人，其中包括美国的540万人，每分钟诊断出一个新病例。超过 在过去的二十年里，AD研究领域最重要的发展之一是 AD小鼠模型的产生。虽然这些研究为AD的发病机制提供了重要的见解， 这些发现还没有转化为任何新的疾病修饰疗法的发展。 人类的状况此外，人们担心在人与小鼠中治疗AD的不一致性， 这可能是由于在小鼠中对该疾病的建模不完全。沿着这些路线，目前所有的 现有的模型是基于罕见的常染色体显性形式的疾病，而大多数AD 病例是散发的，其发病可能仍受显示出低遗传率的遗传学影响 与常染色体显性遗传病例相比。因此，迫切需要开发下一代 小鼠模型具有高的面部、结构和翻译有效性，这意味着这些模型应该 与散发性AD（sAD）更接近。在过去的几年里，GWAS的设施生产了 与sAD相关的风险因子基因列表迅速扩展。这里我们建议使用一个 跨学科/团队的方法来开发下一代的小鼠模型，模型sAD，使他们 可用于临床前治疗试验。我们的策略是利用我们最近开发的人性化野生- 型APPKI小鼠作为引入人tau的平台，随后是其他GWAS确定的风险 增加sAD风险的多态性。我们建议开发下一代AD 使用基因编辑技术（CRISPR/Cas9技术）的最新创新的临床前小鼠模型， 产生新的小鼠模型，更准确地代表sAD。我们将用- 最先进的定量方法，与人类状况进行直接比较并利用小说 已在UCI开发的试剂，包括独特的构象特异性抗体， 多种不同的病理形式我们将通过RNA-seq和表观遗传学来确定基因表达变化， 通过全细胞膜片钳技术结合 激光扫描光刺激，以及LTP，行为和认知，以及纵向功能 显像我们还将通过进行血浆脂质组学和代谢组学研究来开发生物标志物。 分析。我们将以快速和可访问的形式分发所有数据，并将提供 用于现场模型表征的详细协议。最后，我们建立了一个令人兴奋的 与杰克逊实验室合作，对观察到的表型进行第二次现场验证， 衍生、冷冻保存和分发所有新的动物模型，以便它们可以广泛分发给 调查员在外地。实现这些目标将是AD研究领域的变革。

Project Abstract Alzheimer's disease (AD) is currently an incurable neurodegenerative disease that affects over 35 million people worldwide, including 5.4 million individuals in the USA with a new case diagnosed every minute. Over the past two decades, one of the most significant developments in the AD research field has been the generation of mouse models of AD. Although these have provided significant insight into the mechanism of AD, the findings have not yet translated into the development of any new disease-modifying therapies for the human condition. Moreover, there is concern about the discordance of treating AD in people versus mice, which may be due the incomplete modeling of the disease in mice. Along these lines, all of the currently available models are based on the rarer autosomal dominant form of the disease, whereas the majority of AD cases are sporadic, whose onset may still be influenced by genetics that display reduced penetrance compared to the autosomal dominant cases. Hence, there is an urgent need to develop the next generation of mouse models that have high face, construct, and translational validity, which means these models should be more closely aligned with sporadic AD (sAD). Over the past several years, the facility of GWAS has produced a rapid expansion in the list of risk factor genes that are associated with sAD. Here we propose to use a transdisciplinary/team approach to develop the next generation of mouse models that model sAD so that they can be used for preclinical therapeutic testing. Our strategy is to use our recently developed humanized wild- type APPKI mouse as the platform for introducing human tau, followed by other GWAS-identified risk polymorphisms that enhance the risk of developing sAD. We propose to develop the next generation of AD preclinical mouse models using the latest innovations in gene editing technology (CRISPR/Cas9 technology) to produce new mouse models that more accurately represent sAD. We will phenotype the mice using state-of- the-art quantitative methodology and make direct comparisons to the human condition and capitalize on novel reagents that have been developed at UCI, including unique conformation specific antibodies that identify multiple distinct forms of pathology. We will determine gene expression changes via RNA-seq and epigenetic disruptions, alterations in neuronal connectivity in hippocampal circuits via whole-cell patch clamping combined with laser scanning photostimulation, as well as LTP, behavior and cognition, and longitudinal functional imaging. We will also conduct biomarker development by performing plasma lipidomic and metabolomic analyses. We will distribute all data in an expeditious and accessible form for dissemination and will provide detailed protocols for characterization of the models for the field. Lastly, we have established an exciting partnership with The Jackson Laboratory to conduct second site validation of observed phenotypes and to re- derive, cryopreserve and distribute all new animal models so that they can be widely distributed to investigators in the field. Achieving these goals will be transformative for the AD research field.