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 额颞痴呆（FTD）是一种常见的神经退行性疾病，其特征是进行性疾病 老年组的认知障碍和功能障碍。 MAPT（微切管相关蛋白TAU） 它在家庭FTD患者中的致病突变强调了。另外，不溶性的聚集 神经原纤维缠结中的tau蛋白是阿尔茨海默氏病大脑中的关键病理大厅标记 （AD）和FTD患者。为了了解tau介导的分子致病机制 神经退行性疾病和痴呆症，动物模型已经产生和表征。然而， 这些动物模型没有概括分子，细胞，病理， 在AD和FTD患者中观察到的行为以及认知特征，部分原因是转基因小鼠 过表达人类MAPT的cDNA或BAC片段并不代表人类的所有分子特征 在小鼠大脑中移动。在此应用中，我们将生成和表征人源化敲击蛋白（Ki）小鼠 在FTD中看到的MAPT（P301L）的致病变异，以概括人类的相对病理生理学 小鼠大脑中的患者。为了实现这一目标，首先，我们将生成新颖的人源化ki小鼠 MAPT的野生型人基因组区域或P301L突变被插入直系同源 地图基因座的小鼠基因组中的基因。用人来替代小鼠基因组区域的Ki 基因组区将表达人类野生型突变体Tau的所有替代mRNA和蛋白质同工型 内源性小鼠地图启动子。其次，我们将进行HMAPT-P301L Ki的分子表征 小鼠检查人tau在大脑中的空间和临时表达谱。我们也会表演 神经元生存，TAU病理学和行为分析的神经病理学分析 老鼠。这些研究的完成将为研究分子疾病提供宝贵的工具 AD和FTD中MAPT的机理。