Modeling Frontotemporal Dementia in Rhesus Macaques

恒河猴额颞叶痴呆模型

• 批准号: 9894456
• 负责人: RUI CHEN
• 金额: $ 48.8万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894456
• 关键词: 17q21; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Animal Model; Animals; Atrophic; Axon; Behavior; Behavioral; Belgium; Brain; Breeding; Brothers; Caring; Cell Line; Cells; Chromosomes; Cognitive; Collaborations; Communities; Data; Dementia; Denmark; Discipline; Disease; Disease model; Family; Family member; Female; Fibroblasts; Foundations; Frontotemporal Dementia; Gene Proteins; Generations; Genes; Genetic; Genetic Models; Genotype; Gliosis; Goals; Human; Image; In Vitro; Iran; Japan; Language Disorders; Lead; Link; Macaca mulatta; Magnetic Resonance Imaging; Medicine; Memory Loss; Microtubule Stabilization; Microtubule-Associated Proteins; Midwestern United States; Missense Mutation; Modeling; Monkeys; Moods; Motor; Mutate; Mutation; Nerve Degeneration; Netherlands; Neuroanatomy; Neurodegenerative Disorders; Neurons; Outcome Measure; Parkinsonian Disorders; Pathologic; Patients; Peripheral Nervous System; Personality; Phase; Phenotype; Point Mutation; Positron-Emission Tomography; Primates; Protein Family; Records; Reporting; Research; Research Personnel; Resources; Role; Stem cells; Sweden; Symptoms; System; Tauopathies; United States; Wisconsin; base; behavior test; biomarker development; biomarker identification; college; genetic pedigree; genome sequencing; human model; in vivo; induced pluripotent stem cell; member; mutation carrier; neurobehavioral; neuron loss; nonhuman primate; offspring; programs; relating to nervous system; sex; tau Proteins; tau aggregation; tau-1; therapeutic target; therapy development; translational neuroscience; whole genome

ABSTRACT Frontotemporal dementia (FTD) with or without parkinsonism, is an Alzheimer’s disease related dementia (ADRD) that has been linked to sporadic and familial mutations in the MAPT gene, including the autosomal dominant R406W missense point mutation. Patients with FTD MAPT R406W present progressive memory loss, and late-onset of parkinsonism, personality changes, and/or language deficits. Typical pathological findings include abnormal intraneuronal accumulation of phosphorylated tau filaments (tauopathy), frontotemporal atrophy, neuronal loss, and gliosis. At the Wisconsin National Primate Research Center (WNPRC) in collaboration with Baylor College of Medicine, a rhesus monkey was identified as a carrier of the MAPT R406W mutation, identical to human patients. Progress in the development of biomarkers and treatments for FTD and other dementias has been hampered by the lack of faithful animal models of the disorder. Nonhuman primates (NHPs), in particular rhesus macaques, are an ideal species to study dementias and related neurodegeneration, due to the complexity of their behavior and neuroanatomy. In the R61 phase of this application we propose to phenotype the MAPT R406 carriers of this family and to identify additional MAPT R406W mutation carriers. The rhesus will be evaluated with a battery of age-appropriate behavioral tests (cognitive, mood and motor), MRI (for neuroanatomical and volumetric analysis) and F18-MK6240 PET (to visualize tau accumulation) and compared to age- and sex- matched controls. These animals will be the founders of a breeding colony of MAPT R406W carriers. During the R33 phase we will aim to create a MAPT R406W rhesus colony resource, by breeding the mutated rhesus and generating induced pluripotent stem cells (iPSCs) from the carriers’ fibroblasts. The offspring will be genotyped and neurobehaviorally evaluated. The iPSCs will be a platform to study the effects of ADRD alleles on in vitro neural differentiation. The overarching goal of this project is to generate an NHP resource for the ADRD research community. A well characterized NHP model of genetic FTD, supported by in vivo behavioral and imaging outcome measures and associated iPSC lines, will help understand the pathological mechanisms of the disease, which could lead to the identification of biomarkers and therapeutic targets. We have assembled a strong team of investigators across different disciplines focused on translational neuroscience and neurodegenerative diseases, human and nonhuman primate genetics, stem cells, and, most importantly, experts devoted to nonhuman primate breeding and care.

抽象的 有或没有帕金森氏症的额颞痴呆（FTD）是阿尔茨海默氏病有关的痴呆症 （ADRD）与MAPT基因中的零星和家庭突变有关，包括常染色体 主要的R406W错义点突变。 FTD MAPT R406W的患者目前的记忆力丧失， 帕金森氏症，人格变化和/或语言定义的晚期发作。典型的病理发现 包括磷酸化tau丝（tauopathy），额颞的异常神经内神经元积累 萎缩，神经元丧失和神经病。在威斯康星州国家灵长类动物研究中心（WNPRC） 与贝勒医学院的合作，恒河猴被确定为MAPT R406W的载体 突变，与人类患者相同。 FTD生物标志物和治疗的发展进展 缺乏这种疾病的忠实动物模型阻碍了其他痴呆症。非人类灵长类动物 （NHP），尤其是恒河猕猴，是研究痴呆症和相关神经变性的理想物种， 由于其行为和神经解剖学的复杂性。在此应用程序的R61阶段，我们提出了 表型，该家族的MAPT R406载体并识别额外的MAPT R406W突变 载体。将通过一系列适合年龄的行为测试（认知，情绪和情绪和 电动机），MRI（用于神经解剖学和体积分析）和F18-MK6240 PET（可视化TAU积累） 并与年龄和性别匹配的对照组相比。这些动物将是一个繁殖菌落的创始人 MAPT R406W载体。在R33阶段，我们将旨在创建MAPT R406W恒河所资源， 通过繁殖突变的恒河猴并从载体的诱导多能干细胞（IPSC）产生诱导的多能干细胞（IPSC） 成纤维细胞。后代将进行基因分型和神经行为评估。 IPSC将是一个平台 研究ADRD等位基因对体外神经分化的影响。这个项目的总体目标是 为ADRD研究社区生成NHP资源。一个良好的遗传FTD的NHP模型， 由体内行为和成像结果指标和相关IPSC线的支持，将有助于理解 该疾病的病理机制，可能导致生物标志物和治疗的鉴定 目标。我们已经组建了一个强大的调查员团队，这些研究人员的不同学科集中于翻译 神经科学和神经退行性疾病，人类和非人类灵长类动物遗传学，干细胞以及大多数 重要的是，专门致力于非人类灵长类动物的繁殖和护理。