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Humanized MAPT knockin mouse models for frontotemporal dementia

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
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-08-01 至 2023-11-17

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中文摘要
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英文摘要
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.
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晚期妊娠维持和抑制早产中cAMP信号活化PR的作用机制研究
  • 批准号:
    81300507
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    22.0万元
  • 批准年份:
    2013
  • 负责人:
    陈黎
  • 依托单位: