Project 3: Multi-modal phenotypic Characterization of marmoset models of Late Onset Alzheimer's Disease

项目3：晚发性阿尔茨海默病狨猴模型的多模式表型表征

• 批准号: 10494777
• 负责人: Afonso C Silva
• 金额: $ 23.72万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494777
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; American; Animal Model; Animals; Appearance; Behavior; Behavioral; Binding; Bioinformatics; Biological Markers; Callithrix; Callithrix jacchus jacchus; Clinical; Cognitive; Communities; Dementia; Disease; Disease Progression; Early Onset Alzheimer Disease; Engineering; Evaluation; Family; Future; Generations; Genes; Genetic; Genetic Engineering; Genetic Risk; Human; Intervention; Investigation; Knowledge; Knowledge Portal; Late Onset Alzheimer Disease; Longevity; Longitudinal Studies; Measures; Modeling; Molecular; Mutation; Neurodegenerative Disorders; Odds Ratio; Onset of illness; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Phenotype; Plant Roots; Play; Population; Primates; Research; Resources; Staging; Testing; Therapeutic; Universities; Validation; Variant; Work; age related; aged; analytical method; comparative; data integration; early detection biomarkers; effective therapy; genetic variant; genome wide association study; healthy aging; human model; member; multimodality; neuropathology; new therapeutic target; novel; presenilin-1; prevent; risk variant; social; therapeutic development

PROJECT SUMMARY PROJECT 3 Project 3: Comparative Multimodal Phenotypic Characterization of Marmoset Models of AD Alzheimer’s Disease (AD), the most common cause of dementia, is a multifactorial neurodegenerative disorder affecting ~6 million Americans. Currently, there are no interventions capable of preventing, stopping, or treating AD. The scarcity of adequate animal models that enable a comprehensive investigation of the pathogenic mechanisms at play in AD has limited our progress towards discovering effective treatments. There is a critical need for enhanced animal models that incorporate genetic variability, optimal lifespan to support age-related research, superior compatibility as a model of human social and cognitive behavior, and the presentation of AD- related pathology. The central premise of our Consortium “Generation, Characterization, and Validation of Marmoset Models of Alzheimer’s Disease” (MARMO-AD) is that the marmoset will reveal the earliest primate- specific cellular and molecular root causes of AD pathogenesis and progression. We postulate that marmosets engineered to harbor genetic risk variants for early- (EOAD) and late-onset AD (LOAD) will reveal clinical disease trajectories that model those of human AD patients and display primate-specific disease pathogenesis that can be detected with a comprehensive phenotypic characterization pipeline. We hypothesize that: (1) the comprehensive 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; and (2) the comparative, longitudinal study of the marmoset LOAD model against the EOAD models and healthy controls will identify emerging phenotypes that precede frank neuropathology and prioritize tractable targets for future therapeutic discovery. The ATP-binding cassette, sub-family A, member 7 (ABCA7) gene was identified by genome-wide association studies (GWAS) as having one of the highest odds ratios for developing LOAD in humans. In this project, we will create a novel genetically engineered marmoset LOAD model incorporating an ABCA7 LOAD variant. Once these animals are born, we will follow them longitudinally to identify emerging phenotypes that deviate from healthy aging ahead of the appearance of frank neuropathology. We will evaluate non-carrier healthy control marmosets to characterize the typical healthy aging trajectory across the lifespan and establish a baseline against which we can contrast our marmoset models of LOAD and EOAD. We will then evaluate the disease trajectory of the ABCA7 marmoset LOAD model relative to the PSEN1 EOAD models via longitudinal, multimodal phenotypic characterization in line with the clinical staging of AD patients. By contrasting our marmoset models of EOAD and LOAD, we hope to identify differential biomarkers of LOAD that can be measured ahead of the emergence of frank neuropathology and prioritize novel targets for therapeutic development. Upon validation of these unique primate AD models, we plan to expand the colony and share this precious resource with the greater AD research community to help accelerate the pace of bringing novel and effective treatments to patients.

项目摘要项目3 项目3：AD的Marmoset模型的比较多模式表型表征 阿尔茨海默氏病（AD）是痴呆的最常见原因，是多因素神经退行性疾病 影响约600万美国人。目前，没有任何干预措施能够预防，停止或治疗 广告。足够的动物模型的稀缺性，可以全面研究致病 广告中发挥作用的机制限制了我们在发现有效治疗方面的进步。有关键 需要增强的动物模型，这些模型结合了遗传变异性，最佳寿命以支持与年龄有关的 研究，作为人类社会和认知行为模型的卓越兼容性，以及表现 相关病理。我们财团的中心前提是“产生，表征和验证 阿尔茨海默氏病的摩尔马群岛模型”（Marmo-AD）是，Marmoset将揭示最早的灵长类动物 - AD发病机理和进展的特定细胞和分子根本原因。我们假设那只果果会 设计为早期（EOAD）和晚期AD（负载）的遗传风险变异型（负载）将揭示临床疾病 对人类AD患者进行建模并显示出特异性疾病发病机理的轨迹 可以通过全面的表型表征管道检测。我们假设：（1） 全面评估遗传，分子，功能，行为和病理表型 马尔莫斯人将提供有关人类种群中AD的起源和发展的可翻译知识。和 （2）与EOAD模型和健康的Marmoset负载模型的比较，纵向研究 控件将确定在坦率的神经病理学之前的新兴表型，并确定可进行的可进行的目标。 未来的治疗发现。鉴定了ATP结合盒，亚族A，成员7（ABCA7）基因 通过全基因组关联研究（GWAS），其产生负载的优势比是 人类。在这个项目中，我们将创建一个新颖的基因工程摩尔摩斯特负载模型，编码一个 ABCA7负载变体。这些动物出生后，我们将纵向跟随它们以识别新兴 在坦率的神经病理学出现之前偏离健康衰老的表型。我们将评估 非携带者健康对照摩尔果会表征整个生命周期中典型的健康衰老轨迹和 建立一个基线，我们可以对比负载和EOAD模型进行对比。然后我们会 通过通过PSEN1 EOAD模型来评估ABCA7 Marmoset负载模型的疾病轨迹 纵向，多模式表型表征与AD患者的临床分期一致。相比之下 我们的EOAD和负载模型，我们希望确定可以是负载的差异化生物标志物 在坦率的神经病理学出现之前测量并确定治疗的新目标 发展。在验证这些独特的主要广告模型后，我们计划扩大殖民地并分享 与更大的广告研究社区一起的宝贵资源，以帮助加速带来小说的步伐 有效治疗患者。