The Development of a High Throughput Whole Brain Alzheimer's Disease Drug Screening Pipeline

项目摘要 阿尔茨海默病(AD)是一种衰弱的神经退行性疾病，影响大约1/4 10个65岁以上的人。2017年，美国AD的总成本为 估计为2590亿美元，预计到2050年将攀升至1.1万亿美元。尽管 在寻找治愈方法上投入了巨大的努力，但事实证明，开发它极其困难 治疗阿尔茨海默病。造成这一困难的原因是AD是一个复杂的， 多因素疾病，发生了几十年，作为中枢神经系统疾病，很难研究 直接在诊所里。 为了应对这一挑战，2015年AD研究峰会设定了一个目标，即创造和 描述新一代改进的研究模型，它将更忠实地 在人类身上反映阿尔茨海默病。这些新车型带来了巨大的希望，但不幸的是 当代的工具充其量也是不完整的。表型全脑方法学，而 提供AD时间和空间进展的关键概述，几乎没有 相应的分子信息。与此同时，深入的分子方法仍然存在 由于时间或成本的限制，仅限于研究大脑的一小部分。这种缺乏 阿尔茨海默病在大脑中传播的分子机制概述 人类阿尔茨海默病的中心方面--在我们对病因的理解上留下了一个重要的空白 导致阿尔茨海默病的发展，阻碍了有效治疗方法的发展。架桥 这一缺口，这一建议将搭建一个灵活的成像和组织处理平台，以 快速确定AD啮齿动物模型的特征，该模型在 同时扩展对深入分子信息的访问，以促进关键临床 可译性。 该提案结合了TIseVision和NIA资助的模型-AD中心的团队 在杰克逊实验室，他们是神经科学、光学显微镜、成像方面的专家 他们拥有成功的商业化历史。共同努力，我们将在 一组令人印象深刻的初步结果描绘了整个大脑数据集和 制作药物开发流水线，以提供自动化的大脑区域映射和 阿尔茨海默病病理的组合标志物。我们相信，仪器和仪器之间的协同作用， 生物检测的发展，下一代AD研究模型代表着 开发下一代工具的理想合作伙伴，这些工具有望最终 开发治疗AD的有效方法。

Project Summary Alzheimer’s disease (AD) is a debilitating neurodegenerative disease affecting roughly 1 in 10 people over the age of 65. In 2017, the total cost of AD in the United States was estimated at $259 billion and is predicted to climb to $1.1 trillion by the year 2050. Despite enormous efforts invested in finding a cure, it has proven extremely difficult to develop treatments for AD. Contributing factors behind this difficulty is that AD is a complex, multifactorial disease, occurring over decades, and as CNS disease, is very difficult to study directly in the clinic. To address this challenge, the 2015 AD research summit set a goal to create and characterize a new generation of improved research models that would more faithfully reflect AD in humans. These new models hold enormous promise, but unfortunately contemporary tools are incomplete at best. Phenotypic whole brain methodologies, while providing a critical overview of the temporal and spatial progression of AD, have little corresponding molecular information. Meanwhile, in depth molecular methods remain confined to studying small portions of the brain due to time or cost limitations. This lack of an overview of the molecular mechanisms driving the spread of AD across the brain – a central aspect of AD in humans – leaves a crucial gap in our understanding of the etiology of the progression of AD and hinders the development of effective treatments. To bridge this gap, this proposal will build a flexible imaging and tissue processing platform to rapidly characterize AD rodent models that provides whole brain information while at the same time extends access to in-depth molecular information to facilitate crucial clinical translatability. This proposal combines teams from TissueVision and the NIA-funded MODEL-AD Center at The Jackson Laboratory who are experts in neuroscience, optical microscopy, imaging assays, and who have a successful commercialization history. Together, we will build on a set of impressive preliminary results mapping AD progression in whole brain datasets and produce a drug development pipeline to provide automated brain region mapping and combinatorial markers of AD pathology. We believe the synergy between instrumentation, biological assay development, and the next generation of AD research models represents an ideal partnership to develop next generation tools that hold the promise of finally developing effective treatments for AD.