Humanized MAPT knockin mouse models for frontotemporal dementia

额颞叶痴呆人源化 MAPT 敲入小鼠模型

• 批准号: 10303887
• 负责人: Jongkyun Kang
• 金额: $ 46.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-11-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303887
• 关键词: 17q21; 5' Flanking Region; Address; Adult; Affect; Age; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease brain; Animal Model; Bacterial Artificial Chromosomes; Behavior; Behavioral; Binding; Biochemical; Brain; Brain region; Chromosomes; Clinical; Clone Cells; Code; Cognitive; Complementary DNA; Disease; Elderly; Engineering; Exons; FTD with parkinsonism; Family; Financial compensation; Frontotemporal Dementia; Functional disorder; Generations; Genes; Genetic Recombination; Genomic DNA; Genomic Segment; Genomics; Goals; Human; Hydrophobicity; Impaired cognition; Knock-in; Knock-in Mouse; Learning; Link; MAPT gene; Mediating; Memory; Memory impairment; Messenger RNA; Microtubule Stabilization; Microtubules; Missense Mutation; Modeling; Molecular; Molecular Conformation; Molecular Disease; Mus; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nucleic Acid Regulatory Sequences; Orthologous Gene; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Physiological; Pick Disease of the Brain; Population; Progressive Supranuclear Palsy; Protein Isoforms; Reagent; Recording of previous events; Study models; Techniques; Testing; Transgenic Mice; Variant; arm; blastocyst; causal variant; conditioned fear; corticobasal degeneration; embryonic stem cell; functional disability; homologous recombination; mRNA Expression; morris water maze; mouse genome; mouse model; neurodegenerative dementia; neurofibrillary tangle formation; neuronal survival; novel; overexpression; pre-clinical; promoter; protein aggregation; protein expression; tau Proteins; tau aggregation; tau expression; tau function; tau mutation; tool; vector

PROJECT SUMMARY/ABSTRACT Frontotemporal dementia (FTD) is a common neurodegenerative disorder characterized by progressive cognitive impairment and functional disability in the elderly group. MAPT (microtubule-associated protein tau) has been highlighted by its pathogenic mutations in familial FTD patients. In addition, insoluble aggregates of the tau protein in neurofibrillary tangles are a key pathological hall marker in the brains of Alzheimer’s Disease (AD) and FTD patients. In order to understand the tau mediated molecular pathogenic mechanisms of neurodegenerative diseases and dementias, animal models have been generated and characterized. However, these animal models do not recapitulate the full spectrum and complexity of molecular, cellular, pathological, behavior, and cognitive features observed in AD and FTD patients, in part because the transgenic mice which overexpress cDNA or BAC fragments of human MAPT do not represent all molecular features of the human MAPT in the mouse brain. In this application, we will generate and characterize humanized knockin (KI) mice with a pathogenic variant of MAPT (P301L) seen in FTD to recapitulate the respective pathophysiology of human patients in the mouse brain. To achieve this goal, first, we will generate novel humanized KI mice in which the wild-type human genomic region of MAPT or with P301L mutation is inserted as a replacement of an orthologous gene in the mouse genome of Mapt locus. This KI replacement of the mouse genomic region with the human genomic region will express all alternative mRNA and protein isoforms of human wild-type mutant tau under the endogenous mouse Mapt promoters. Second, we will conduct molecular characterization of hMAPT-P301L KI mice to examine the spatial and temporal expression profile of human tau in the brains. We will also perform neuropathological analyses of neuronal survival, tau pathology, and behavioral analyses in hMAPT-P301L KI mice. The completion of these studies will provide an invaluable tool to investigate the molecular disease mechanism of MAPT in AD and FTD.

项目摘要/摘要 额颞叶痴呆(FTD)是一种常见的神经退行性疾病，以进行性为特征 老年组认知功能障碍与功能障碍的关系微管相关蛋白tau 其在家族性FTD患者中的致病突变是突出的。此外，不可溶的聚集体 神经原纤维缠结中的tau蛋白是阿尔茨海默病大脑中一个关键的病理霍尔标志 (AD)和FTD患者。为了了解tau介导的分子致病机制。 已经建立了神经退行性疾病和痴呆的动物模型并进行了表征。然而， 这些动物模型不能概括分子、细胞、病理、 在AD和FTD患者中观察到的行为和认知特征，部分原因是转基因小鼠 过表达的人MAPT的cDNA或BAC片段并不能代表人类的全部分子特征 小鼠大脑中的MAPT。在本应用程序中，我们将生成人源化敲击(KI)小鼠并对其进行表征 以FTD中发现的MAPT致病变异(P301L)概括人类各自的病理生理学 老鼠大脑中的病人。为了实现这一目标，首先，我们将产生新的人源化KI小鼠，在其中 插入野生型MAPT或带有P301L突变的人类基因组区域作为直系同源基因的替代 小鼠基因组中的MAPT基因。小鼠基因组区域的这种KI替换为人类 基因组区域将表达人野生型突变体tau的所有可供选择的mRNA和蛋白质亚型 内源性小鼠MAPT启动子。其次，我们将对hMAPT-P301L KI进行分子表征 以检测人类tau在大脑中的时空表达谱。我们还将表演 HMAPT-P301L KI神经元存活的神经病理学分析、tau病理和行为分析 老鼠。这些研究的完成将为研究分子疾病提供宝贵的工具。 MAPT在AD和FTD中的作用机制。