Modeling Frontotemporal Dementia in Rhesus Macaques

恒河猴额颞叶痴呆模型

• 批准号: 10626978
• 负责人: RUI CHEN
• 金额: $ 60.49万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626978
• 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; Central Nervous System; Chromosomes; Cognitive; Collaborations; Communities; Data; Dementia; Denmark; Discipline; Disease; Disease model; Family; Family member; Female; Fibroblasts; Foundations; Frontotemporal Dementia; Generations; Genes; Genetic; Genetic Models; Genotype; Gliosis; Goals; Human; Image; In Vitro; Iran; Japan; Language Disorders; Link; MAPT gene; Macaca mulatta; Magnetic Resonance Imaging; Medicine; Memory Loss; Microtubule-Associated Proteins; Microtubules; Midwestern United States; Missense Mutation; Modeling; 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; Primates; Protein Family; Proteins; Records; Reporting; Research; Research Personnel; Resources; Rhesus; Role; Sweden; Symptoms; System; Tauopathies; United States; Visualization; Wisconsin; autosome; behavior test; biomarker development; biomarker identification; college; genetic pedigree; genome sequencing; human model; in vivo; induced pluripotent stem cell; member; mutation carrier; neural; neurobehavioral; neuron loss; nonhuman primate; offspring; programs; sex; stem cells; 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.

摘要 额颞叶痴呆(FTD)伴或不伴帕金森综合征，是一种与阿尔茨海默病相关的痴呆 (ADRD)与MAPT基因的零星和家族性突变有关，包括常染色体 显性R406W错义点突变。FTD MAPT R406W患者表现为进行性记忆丧失， 迟发性帕金森症、人格改变和/或语言缺陷。典型病理表现 包括异常的磷酸化tau丝在神经元内的聚集(tau病)，额颞部 萎缩、神经元丢失和神经胶质细胞增多症。在威斯康星州国家灵长类研究中心(WNPRC) 与贝勒医学院合作，一只恒河猴被确认为MAPT R406W的携带者 突变，与人类病人完全相同。FTD和FTD的生物标志物和治疗研究进展 其他痴呆症由于缺乏忠实的动物模型而受到阻碍。非人灵长类 (NHP)，特别是恒河猴，是研究痴呆症和相关神经变性的理想物种， 由于它们行为和神经解剖学的复杂性。在本应用程序的R61阶段中，我们建议 对该家族的MAPT R406携带者进行表型分析，并鉴定额外的MAPT R406W突变 承运人。猕猴将通过一系列与年龄相适应的行为测试(认知、情绪和 运动)、MRI(用于神经解剖和容量分析)和F18-MK6240 PET(用于可视化tau蓄积) 并与年龄和性别匹配的对照组进行比较。这些动物将成为一个繁育群体的创始人 MAPT R406W载体。在R33阶段，我们的目标是创建一个MAPT R406W恒河猴群体资源， 通过培育突变的恒河猴并从携带者体内产生诱导多能干细胞(IPSCs) 成纤维细胞。后代将接受基因分型和神经行为评估。IPSC将成为一个平台， 研究ADRD等位基因对体外神经分化的影响。这个项目的首要目标是 为ADRD研究社区生成NHP资源。一个很好描述遗传FTD的NHP模型， 由体内行为和成像结果测量以及相关的IPSC系列支持，将有助于理解 疾病的病理机制，这可能导致生物标志物的识别和治疗 目标。我们已经组建了一支由不同学科的调查人员组成的强大团队，专注于翻译 神经科学和神经退行性疾病，人类和非人类灵长类遗传学，干细胞，以及 重要的是，致力于非人类灵长类繁殖和护理的专家。