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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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

项目摘要

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.

项目概要阿尔茨海默病 (AD) 是一种使人衰弱的神经退行性疾病，影响大约 1% 的人 65岁以上10人。2017年美国AD总费用为估计为 2590 亿美元，预计到 2050 年将攀升至 1.1 万亿美元。为寻找治疗方法投入了大量资金，但事实证明开发起来极其困难 AD 治疗出现这一困难的原因是 AD 是一种复杂的、发生数十年的多因素疾病，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 AD 研究峰会设定了一个目标，即创建和描述新一代改进的研究模型，该模型将更忠实地这些新模型具有巨大的前景，但不幸的是。现代工具充其量是不完整的表型全脑方法。提供了 AD 时间和空间进展的重要概述，但几乎没有同时，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。驱动 AD 在大脑中传播的分子机制概述 – 人类AD的核心方面——在我们对其病因的理解上留下了一个重要的空白 AD 的进展并阻碍有效治疗方法的开发。为了弥补这一差距，该提案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，提供全脑信息同时扩展了对深入分子信息的访问，以促进关键的临床可译性。该提案结合了 TissueVision 和 NIA 资助的 MODEL-AD 中心的团队杰克逊实验室的神经科学、光学显微镜、成像专家化验，以及拥有成功商业化历史的人，我们将共同建立一个基础。一组令人印象深刻的初步结果，绘制了全脑数据集中的 AD 进展情况，建立药物开发流程以提供自动化的大脑区域映射和我们相信仪器之间的协同作用，生物测定的发展，以及下一代AD研究模型代表开发下一代工具的理想合作伙伴，最终实现这一目标开发 AD 的有效治疗方法。