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.

抽象的 额颞叶痴呆 (FTD) 伴或不伴帕金森症，是一种阿尔茨海默病相关痴呆 (ADRD) 与 MAPT 基因的散发性和家族性突变有关，包括常染色体突变 显性 R406W 错义点突变。 FTD MAPT R406W 患者出现进行性记忆丧失， 迟发性帕金森病、性格改变和/或语言缺陷。典型病理结果 包括磷酸化 tau 丝的神经元内异常积聚（tau 病）、额颞叶 萎缩、神经元损失和神经胶质增生。位于威斯康星州国家灵长类动物研究中心 (WNPRC) 与贝勒医学院合作，恒河猴被鉴定为 MAPT R406W 的携带者 突变，与人类患者相同。 FTD 和 FTD 生物标志物和治疗方法的开发进展 由于缺乏忠实的动物模型，其他痴呆症的研究受到阻碍。非人类灵长类动物 （NHP），特别是恒河猴，是研究痴呆症和相关神经退行性疾病的理想物种， 由于他们的行为和神经解剖学的复杂性。在此应用的 R61 阶段，我们建议 对该家族的 MAPT R406 携带者进行表型分析并鉴定其他 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 运动）、MRI（用于神经解剖和体积分析）和 F18-MK6240 PET（可视化 tau 积累） 并与年龄和性别匹配的对照组进行比较。这些动物将成为繁殖群体的创始人 MAPT R406W 载体。在 R33 阶段，我们的目标是创建 MAPT R406W 恒河猴群体资源， 通过培育突变恒河猴并从携带者的基因中产生诱导多能干细胞（iPSC） 成纤维细胞。将对后代进行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。该项目的总体目标是 为 ADRD 研究社区生成 NHP 资源。一个充分表征的 NHP 遗传 FTD 模型， 得到体内行为和成像结果测量以及相关 iPSC 系的支持，将有助于了解 该疾病的病理机制，这可能导致生物标志物和治疗方法的鉴定 目标。我们组建了一支强大的跨学科研究人员团队，专注于转化 神经科学和神经退行性疾病、人类和非人类灵长类遗传学、干细胞以及大多数 重要的是，专家致力于非人类灵长类动物的繁殖和护理。