Novel Stem Cell and Mouse Models to Study Frontotemporal Dementia

研究额颞叶痴呆的新型干细胞和小鼠模型

基本信息

批准号：
7697113
负责人：
Miranda Ethel Orr
金额：
$ 2.68万
依托单位：
MC LAUGHLIN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-19 至 2011-09-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7697113
关键词：
Affect Aging Alzheimer&apos s Disease American Appearance Behavioral Biochemical Biological Assay Brain Diseases Breeding Cell Culture System Cell Differentiation process Cell Line Dementia Detection Disease Epitopes Event Exhibits Frontotemporal Dementia Gene Combinations Genes Genetic Genetic Processes Goals Human Immunofluorescence Immunologic In Vitro Methods Modeling Molecular Monitor Mouse Strains Mus Mutation Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Parents Pathogenesis Pathology Patients Phenotype Prion Diseases Proteins Research Speed Stem cells System Testing Time Transgenes biochemical model disease mechanisms study disease phenotype in vitro Model in vivo mouse model mutant neuron loss novel overexpression protein aggregation protein misprocessing research study small molecule tau Proteins tau aggregation tau mutation tau phosphorylation tool transgene expression

项目摘要

DESCRIPTION (provided by applicant): Several brain diseases arise from protein aggregation; fronto-temporal dementia (FTD) and Alzheimer's disease alone affect nearly 5 million Americans. Though mice model aspects of disease, they may not become ill for months or even years. Instead, cell culture systems derived from these mice may provide information about disease mechanisms in days or weeks thereby speeding discovery of disease treatment. The overall hypothesis is that generating stem cell lines carrying mutations or combinations of genes leading to diseases will provide valuable research tools to study pathogenesis. Specifically, central nervous system stem cell containing neurospheres will be investigated for their efficacy in recapitulating parent mouse strain phenotypes in vitro. Mice with mutations in the microtubule associated protein tau gene accurately model biochemical, histological, and behavioral aspects of human FTD. Prominent cellular phenotypes of disease, hyperphosphorylation and aggregation of the tau protein, can be tracked with conventional protein detection methods and will be used as markers to assess the utility of neurospheres and their differentiated progeny as models. The focus of Aim 1 is to determine if neurospheres exhibit the same mutation-specific temporal sequence of tau pathology observed in their parental strains, and investigate how proliferation, survival, and differentiation are affected by transgene expression. Results will be compared to neurospheres and mice expressing the human encoded wild type tau gene. One pitfall to mouse modeled diseases arising from tau phosphorylation events is that endogenous mouse tau may inhibit human encoded tau phosphorylation. Therefore the focus of Aim 2 is to test the hypothesis that expression of endogenous mouse tau alters human transgene-encoded tau phosphorylation and aggregation in vivo and in vitro. Both mutant and wild type human tau transgenes will be transferred to a mouse tau null background. Mice and neurospheres will be characterized and compared to corresponding mouse tau wild type lines. If neurospheres recapitulate in vivo phenotypes of their parent mouse strains, they may serve as high through-put assay systems to investigate other genes and small molecules involved in disease pathogenesis.

描述（由申请人提供）：几种脑部疾病由蛋白质聚集引起；仅额颞痴呆（FTD）和阿尔茨海默氏病就会影响近500万美国人。尽管小鼠模型的疾病方面，但它们可能不会生病数月甚至数年。取而代之的是，从这些小鼠中得出的细胞培养系统可能会在几天或几周内提供有关疾病机制的信息，从而超速发现疾病治疗。总体假设是，产生带有突变或导致疾病的基因组合的干细胞系将为研究发病机理提供宝贵的研究工具。具体而言，将研究含有神经球的中枢神经系统干细胞，以便在体外概括母小鼠应变表型中的功效。与微管相关蛋白tau基因的突变的小鼠精确地模拟了人FTD的生化，组织学和行为方面。可以使用常规的蛋白质检测方法跟踪疾病，高磷酸化和tau蛋白的聚集的突出细胞表型，并将用作评估神经球及其分化后代作为模型的效用的标志物。目标1的重点是确定神经球是否在其亲本菌株中观察到的Tau病理学的突变特异性时间序列，并研究了转基因表达的增殖，生存和分化如何影响。结果将与表达人类编码的野生型Tau基因的神经球和小鼠进行比较。由Tau磷酸化事件引起的小鼠建模疾病的一个陷阱是内源性小鼠Tau可能抑制人类编码的TAU磷酸化。因此，目标2的重点是检验以下假设：内源性小鼠tau的表达改变了人类转基因编码的tau磷酸化和在体内和体外的聚集。突变体和野生型人tau转基因将被转移到小鼠tau null背景中。小鼠和神经球将被表征并与相应的小鼠tau野生型系进行比较。如果神经球概括其母小鼠菌株的体内表型，它们可以用作高的贯穿测定系统，以研究其他基因和涉及疾病发病机理的小分子。