UC Irvine MODEL-AD

加州大学欧文分校模型-AD

基本信息

批准号：
10592219
负责人：
Kim Green
金额：
$ 906.77万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592219
关键词：
ATAC-seq Academia Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Amyloid Beta A4 Precursor Protein Amyloid beta-Protein Animal Model Animals Apolipoprotein E Award Behavioral Biochemical Biochemistry Bioinformatics Biological Markers Brain Brain imaging California Cell Nucleus Cells Clustered Regularly Interspaced Short Palindromic Repeats Communities Data Data Set Databases Deposition Development Diet Disease Disease Progression Disease model Electrophysiology (science)Ensure Evaluation Funding Gene Expression Generations Genes Genetic Genetic Risk Genome Goals Histology Human Image Individual Industry Infrastructure International Investigation Knowledge Portal Late Onset Alzheimer Disease Liquid substance Longevity Medical Methods Modeling Mouse Strains Mus Mutation Names Nomenclature Outcome Pathology Pathway interactions Persons Phase Phenocopy Phenotype Physiology Plasma Population Proteomics Protocols documentation Reproducibility Research Research Personnel Resolution Resources Rodent Sampling Series Societies Synapses Technology Testing The Jackson Laboratory Therapeutic Intervention Time Tissues United States National Institutes of Health Universities Validation Variant Vision Work base biomarker validation cognitive testing combat data management data modeling design disorder subtype effective therapy efficacious treatment environmental stressor gene replacement genome wide association study human disease human model imaging modality improved insight lipidomics member metabolome metabolomics microbiome mouse model neuroimaging neurovascular novel open source programs response risk variant screening single-cell RNA sequencing socioeconomics tau Proteins therapeutic evaluation therapeutically effective transcriptome sequencing transcriptomics web site

项目摘要

ABSTRACT The goal of the University of California, Irvine MODEL-AD U54 Center is to develop novel mouse models of late- onset Alzheimer’s disease (LOAD), to deeply phenotype these and to make all data and mouse strains available to enable researchers to select the optimal mouse model and timepoints for therapeutic and intervention testing, as well as testing of hypotheses concerning mechanisms of LOAD. During the past five years, we have generated and deeply phenotyped mice with one component of our base genetic platform in which the Aß region of the App gene was converted from the rodent to the human sequence, and we have recently introduced the second component, a humanized MAPT (TAU) locus produced via gene-replacement. We have also used CRISPR and genome replacement to model and validate nine GWAS identified LOAD risk loci and have characterized mice with each of these both on a wild-type and 5xFAD background to determine their effects on plaque generation and damage exerted on the brain in response to pathology. In this continuation, we will use the results of these analyses to identify the combinations of LOAD risk variants most likely to phenocopy LOAD and introduce them on two complementary hAb-KI, hTAU, hAPOE4 platform lines, designed to mimic sub-types of AD that have been recently defined. To ensure translationability, we have an expanded focus on biomarkers and alignment with human phenotypes. To that end we have established a new Core – the Neuroimaging and neurovascular core (NIVC), which will provide brain imaging modalities currently employed in human AD subjects to align phenotypes in our mice with human disease progression. We have also expanded our fluid biomarker analysis efforts to include CSF, as well as plasma lipidomics and metabolomics to be compared to human AD plasma signatures. Similarly, our bioinformatics and data management efforts have been expanded to include single cell and nucleus RNA-seq and ATAC-seq, as well as spatial transcriptomics to enable alignment of data from our models with human AD signatures, but also to understand the mechanisms underlying disease progression in our mice. We are utilizing a comprehensive approach to evaluate our mice across their lifespans, which includes behavioral/cognitive assessment, electrophysiological analysis, super-resolution synaptic imaging, neuroimaging, bulk and single-cell RNA-seq, single cell level spatial transcriptomic analysis, unbiased proteomics, and microbiome and metabolome investigations. The UCI MODEL-AD Center will leverage the resources of our NIA-funded Alzheimer’s Disease Research Center combined with AMP-AD and other human AD datasets to facilitate comparisons to the human condition to identify the best mouse models to evaluate further. All data and models will be made available without restrictions, via The Jackson Labs, and data will be explorable via the modeladexplorer.org website, and raw data freely available for download via the AD Knowledge Portal.

抽象的加利福尼亚大学的目标是欧文型AD U54中心的目标是开发新颖的鼠标模型阿尔茨海默氏病（负载），深层表型，并使所有数据和小鼠菌株可用为了使研究人员能够选择最佳的鼠标模型和时间点进行治疗和干预测试，以及关于负载机制的假设的测试。在过去的五年中，我们产生了并深入表型小鼠，其基本遗传平台的一个成分在该平台中aß区域基因从啮齿动物转换为人类序列，我们最近引入了第二个成分，通过基因替代产生的人源化MAPT（TAU）基因座。我们还使用了CRISPR和基因组替换为模型并验证9个GWAS确定了负载风险基因座，并表征了小鼠每一种都在野生型和5xFAD背景上，以确定它们对斑块产生的影响并响应病理学对大脑造成的损害。在此延续中，我们将使用这些结果分析以识别最有可能在表观负载的负载风险变体的组合并引入它们在两个完整的HAB-KI，HTAU，HAPOE4平台线路上，旨在模仿AD的子类型最近被定义了。为了确保翻译性，我们对生物标志物和对齐方式有扩展的关注与人类表型。为此，我们建立了一个新的核心 - 神经影像学和神经血管核心（NIVC），它将提供当前在人类AD受试者中使用的大脑成像方式我们小鼠的表型随着人类疾病的进展。我们还扩展了流体生物标志物分析努力将CSF以及血浆脂质组学和代谢组学与人类AD等离子体进行比较签名。同样，我们的生物信息学和数据管理工作已经扩展到包括单个单元格和核RNA-seq和atac-seq，以及空间转录组学，以使我们的数据对准我们具有人类广告特征的模型，但也了解疾病进展的机制我们的老鼠。我们正在利用一种全面的方法来评估我们的老鼠在他们的救生程序中，其中包括行为/认知评估，电生理分析，超分辨率突触成像，神经影像学，散装和单细胞RNA-seq，单细胞水平的空间转录组分析，无偏见蛋白质组学以及微生物组和代谢组研究。 UCI Model-AD中心将利用我们NIA资助的阿尔茨海默氏病研究中心的资源以及AMP-AD和其他人类的资源广告数据集以促进与人类条件进行比较，以识别评估的最佳鼠标模型更远。所有数据和模型都将通过杰克逊实验室无限制地提供，并且数据将是可通过modeladexplorer.org网站进行探索，并免费下载原始数据知识门户。