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

高通量全脑阿尔茨海默病药物筛选流程的开发

• 批准号: 10161681
• 负责人: Timothy M. Ragan
• 金额: $ 81.45万
• 依托单位: TISSUEVISION, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161681
• 关键词: 3-Dimensional; Address; Affect; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid beta-Protein; Amyloid deposition; Animal Model; Atlases; Automobile Driving; Back; Biological Assay; Biological Markers; Biotechnology; Brain; Brain Mapping; Brain imaging; Brain region; Central Nervous System Diseases; Clinic; Collaborations; Complex; Contracts; Data Set; Development; Disease; Disease Progression; Drug Screening; Etiology; Evaluation; Funding; Generations; Goals; Growth; Human; Image; Institutes; Kinetics; Label; Late Onset Alzheimer Disease; Measures; Methodology; Methods; Microscopic; Modeling; Molecular; Molecular Analysis; Neurodegenerative Disorders; Neurosciences; Optics; Pharmacologic Substance; Phase; Phenotype; Positioning Attribute; Preclinical Testing; Production; Proteins; Protocols documentation; Rapid screening; Recording of previous events; Research; Research Contracts; Research Personnel; Rodent; Rodent Model; Sampling; Senile Plaques; Services; Slide; Stains; Standardization; The Jackson Laboratory; Therapeutic; Therapeutic Intervention; Thiazines; Time; Tissues; United States; Validation; analysis pipeline; assay development; base; brain research; clinically translatable; combinatorial; commercialization; cost; density; drug development; effective therapy; experience; flexibility; human old age (65+); image processing; imaging platform; improved; instrumentation; interest; member; microscopic imaging; next generation; novel; secondary analysis; symposium; synergism; tissue processing; tomography; tool; two-photon

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.

项目摘要 阿尔茨海默氏病（AD）是一种使人衰弱的神经退行性疾病，大约影响1 65岁以上的10人。2017年，美国的广告总成本为 估计为2590亿美元，预计到2050年将攀升至1.1万亿美元。 事实证明，为寻找治疗而投入了巨大的努力 广告的治疗方法。这一困难背后的贡献因素是广告是一个复杂的， 数十年来发生的多因素疾病，作为中枢神经系统疾病，很难研究 直接在诊所。 为了应对这一挑战，2015年广告研究峰会设定了创建和 描述了新一代改进的研究模型，这些模型将更忠实 在人类中反映广告。这些新模型具有巨大的希望，但不幸的是 现代工具充其量是不完整的。表型全脑方法，而 提供广告的临时和空间进展的批判性概述，几乎没有 相应的分子信息。平均而深度分子方法仍然存在 由于时间或成本限制，仅限于研究大脑的一小部分。这种缺乏 概述了推动AD传播整个大脑传播的分子机制 - a 人类广告的主要方面 - 在我们对病因的理解中留下了一个关键的差距 AD的进展并阻碍有效治疗的发展。桥接 该差距，该建议将建立一个灵活的成像和组织处理平台 快速表征AD啮齿动物模型，该模型在 同一时间扩展了对深度分子信息的访问，以促进至关重要的临床 翻译性。 该提案结合了Tissuevision和NIA资助的Model-AD中心的团队 在杰克逊实验室，是神经科学，光学显微镜，成像的专家 测定法，谁有成功的商业化历史。一起，我们将建立 一组令人印象深刻的初步结果绘制了整个大脑数据集中的广告进展 生产药物开发管道以提供自动大脑区域映射和 AD病理学的组合标记。我们相信仪器之间的协同作用， 生物评估开发，下一代AD研究模型代表 建立下一代工具的理想合作伙伴关系，该工具有望最终 为AD开发有效的治疗方法。