Generation, Characterization, and Validation of Marmoset Models of Alzheimer's Disease

阿尔茨海默病狨猴模型的生成、表征和验证

基本信息

批准号：
10819807
负责人：
Gregory W Carter
金额：
$ 77.75万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10819807
关键词：
Acceleration Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk American Behavioral Bioinformatics Biological Assay Biology of Aging Callithrix Clinical Protocols Cognitive Communities Dedications Disease Disease Progression Early Onset Alzheimer Disease Event Future Generations Genes Genetic Genetic Diseases Genetic Engineering Genetic Risk Genomics Goals Human Intervention Investigation Knowledge Late Onset Alzheimer Disease Life Modeling Molecular Mutation Neurodegenerative Disorders Onset of illness Pathogenesis Pathologic Patients Phenotype Population Primates Process Protocols documentation Research Research Project Grants Resource Sharing Study models Technology Therapeutic Validation animal care animal model development comparative data dissemination data resource genomic signature in vivo multidisciplinary multimodality neurodevelopment neuroimaging neuropathology novel open data presenilin-1 prevent risk variant translational study

项目摘要

PROJECT SUMMARY OVERALL Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting nearly 6 million Americans and is expected to increase over the next several years. Our limited understanding of the mechanisms that trigger the emergence of AD has contributed to the lack of interventions that stop, prevent, or fully treat this disease. We propose to establish the marmoset as the first primate-specific model to reveal the earliest cellular and molecular events of AD processes and allow charting AD progression from its inception. To do so, we will draw from a self-sufficient and large colony of research marmosets with dedicated veterinary and husbandry teams, state-of-the-art in vivo neuroimaging and molecular assays, and a multidisciplinary team of experts in aging biology, AD genetics and genomics, animal model development and characterization, behavioral and cognitive phenotyping, and marmoset gene-editing technologies. Our proposal’s overarching goals are to develop marmoset models of early-onset AD (EOAD) and late-onset AD (LOAD) to enable the investigation of the underlying cellular and molecular root causes of the pathogenesis and progression of AD and support future translational studies. We believe that the simultaneous assessment of genetic, molecular, functional, behavioral, and pathological phenotypes in marmosets will provide translatable knowledge of the origins and progression of AD in human populations. Furthermore, we posit that the comprehensive study of gene-edited marmoset models of AD from neurodevelopment through aging will identify emerging phenotypes that precede frank neuropathology. Our proposal consists of 3 integrated Research Projects that aim to: (1) Conduct characterization and validation of PSEN1 mutations in marmosets as a model for the study of EOAD, and investigate early life molecular determinants of AD disease pathogenesis associated with genetic risk for EOAD; (2) Identify and enhance LOAD-related signatures in outbred and genetically-engineered marmosets; and (3) Conduct a comparative multimodal phenotypic characterization of marmoset models of AD. These projects will be supported by 5 Research Cores focused on project administration, bioinformatics, genetic engineering, multimodal disease characterization, and veterinary and colony management. These supporting cores will integrate marmoset and human genomic signatures and provide data dissemination and resources to the greater research community as part of our commitment to open science, generate novel gene-edited marmoset models of AD, develop optimized protocols for studying disease onset and trajectory in line with clinical protocols, evaluate therapeutic strategies, and provide specialized animal care and support, respectively, allowing complete characterization of the marmoset models. At the conclusion of this project, we will have genetically engineered three AD risk variants into marmoset models, established a disease characterization pipeline for comprehensive phenotyping, and shared these resources with the greater research community.

总体项目摘要阿尔茨海默氏病（AD）是一种毁灭性的神经退行性疾病，影响了近600万美国人和预计未来几年将增加。我们对触发机制的有限理解 AD的出现导致缺乏停止，预防或完全治疗这种疾病的干预措施。我们建议建立马莫斯特作为第一个揭示最早细胞和最早的私人特异性模型广告过程的分子事件，并允许从其成立开始绘制AD的进展。为此，我们会画从拥有专门的兽医和畜牧团队的自给自足和大型的研究摩尔群落中，最先进的体内神经影像学和分子测定法，以及衰老专家的多学科团队生物学，AD遗传学和基因组学，动物模型的发展和表征，行为和认知表型和Marmoset基因编辑技术。我们的提议的总体目标是发展早发广告（EOAD）和晚期AD（负载）的Marmoset模型，以实现研究 AD的发病机理和进展的潜在细胞和分子根本原因并支持未来翻译研究。我们认为，遗传，分子，功能，行为，同时评估和摩尔马斯群岛中的病理表型将提供有关起源和进展的可翻译知识人口中的广告。此外，我们认为基因编辑的Marmoset模型的全面研究从神经发育到衰老的广告将识别坦率之前的新兴表型神经病理学。我们的建议由3个综合研究项目组成，目的是：（1）行为在Marmosets中对PSEN1突变的表征和验证，作为研究EOAD的模型，并研究与EOAD遗传风险相关的AD疾病发病机理的早期生命分子决定剂；（2）识别和增强与载荷相关的杂种和遗传工程摩尔果中的签名；（3）进行AD的Marmoset模型的比较多模式表型表征。这些项目将由5个研究核心支持，这些研究核心专注于项目管理，生物信息学，基因工程，多模式疾病表征以及兽医和菌落管理。这些辅助核心将综合的摩尔马斯和人类基因组特征，并为更大的数据提供数据传播和资源研究社区是我们致力于开放科学的承诺的一部分，生成新颖的基因编辑的摩尔马斯模型 AD，开发优化的方案，以研究疾病发作和轨迹与临床方案一致，评估治疗策略，分别提供专业的动物护理和支持，允许 Marmoset模型的完整表征。在该项目的结论中，我们将一般将三个AD风险变体设计为Marmoset模型，建立了一个疾病表征管道全面的表型，并与更大的研究社区共享这些资源。