Disease Model Development and Phenotyping Project

疾病模型开发和表型分析项目

• 批准号: 10006153
• 负责人: Gareth R Howell
• 金额: $ 288.59万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006153
• 关键词: Achievement; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein Precursor; Amyloid deposition; Amyloidosis; Animal Model; Behavioral Assay; Bioinformatics; Biological Assay; Biological Process; Biology; Blood; Blood Vessels; Brain region; CRISPR/Cas technology; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Communities; Complex; Computer Models; Data; Disease; Disease model; Ensure; Functional disorder; Funding; Future; Genes; Genetic; Genome engineering; Genomic approach; Genomics; Goals; Heterogeneity; Histology; Human; Human Genetics; Indiana; Late Onset Alzheimer Disease; Lead; MAPT gene; Modeling; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Outcome Measure; Pathology; Pathway interactions; Phenotype; Pre-Clinical Model; Preclinical Testing; Presenile Alzheimer Dementia; Recommendation; Reproducibility of Results; Research; Resources; Risk; Risk Factors; Staging; The Jackson Laboratory; Time; Translating; Translations; Universities; Variant; age related; amyloid precursor protein processing; apolipoprotein E-4; base; behavior test; causal variant; cholesterol trafficking; clinically relevant; clinically translatable; cost; data management; data portal; effective therapy; experience; gene interaction; genetic risk factor; genetic variant; genome editing; genome wide association study; human tissue; humanized mouse; improved; in vivo; in vivo imaging; insight; model development; mouse genetics; mouse model; neuroimaging; neuroinflammation; neuron loss; new therapeutic target; news; next generation; novel; preclinical study; presenilin-1; risk variant; screening; tau Proteins; tissue biomarkers

PROJECT SUMMARY DISEASE MODELING PROJECT (DMP) The overall goal of the Indiana University/The Jackson Laboratory Alzheimer's Disease Precision Models Center (IU/JAX ADPMC) is to develop, characterize and distribute more precise preclinical models for Alzheimer's disease (AD). The IU/JAX ADPMC Disease Modeling Development and Phenotyping Project will use CRISPR genome editing to generate mouse models that carry different combinations of human risk alleles for late-onset AD (LOAD). In addition, some of the most widely used existing models for AD will be fully characterized to develop more clinically relevant phenotyping platforms. We have assembled a team of experts in human and mouse genetics, mouse models of AD, genome editing, genomic approaches to understand complex diseases (including sequencing and computational modeling) and various biological processes implicated in AD (including APP processing, cholesterol trafficking, neuroinflammation and vascular biology). We have three specific aims. Aim 1 is to fully characterize APP/PS1, 5xFAD and hTau, three of the most widely used mouse models of AD. APP/PS1 and 5xFAD carry a combination of mutations in amyloid precursor protein (APP) and presenilin 1 (PSEN1) that cause early-onset AD (EOAD) in humans. APP/PS1 and 5xFAD have been widely used to study amyloidosis and neuroinflammation. hTau carries human wild type microtubule associated protein Tau (MAPT) in the absence of mouse Mapt and develops age-related MAPT hyperphosphorylation, aggregation, and some neurodegeneration. We will also extensively characterize a new model of LOAD that we have created that carries the two greatest genetic risk factors for LOAD, APOEε4 and TREM2R47H. We will prioritize clinically relevant endpoints including in vivo imaging, blood and tissue biomarkers and genomics, and compare these to more traditionally used endpoints such as behavioral assays that have not proven reliable when translated to the clinic. In Aim 2, we will generate mice carrying 40 new allelic variants identified through the Bioinformatics and Data Management Core and use an efficient in vivo screening strategy to determine the promising models to pass through to deep phenotyping. In the early years of the center we will prioritize understanding GWAS variants (ABCA7, BIN1 and CR1) as well as variations in two genes identified by us from analyses of the AD Sequencing Project (NANOS1) and AD Neuroimaging Initiative (IL1RAP). All models created will be made available at the earliest opportunity through the JAX AD Mouse Mutant Resource (ADMMR). In Aim 3, we will fully characterize models that show important AD- relevant phenotypes including amyloid deposition, tau pathology and neurodegeneration using the deep phenotyping strategy described in Aim 1. All new findings will be validated in human tissues. Throughout this funding period, we anticipate 40 new models will be generated and distributed, and up to 8 new and 4 existing models will be extensively characterized. Our strategy closely integrates human and mouse data, so these new AD models will show a high degree of clinical translatability for preclinical testing of new therapeutic targets.

项目概要疾病模型项目（二） 印第安纳州大学/杰克逊实验室阿尔茨海默病精确模型的总体目标 中心（IU/JAX ADPMC）是开发，表征和分发更精确的临床前模型， 阿尔茨海默病（AD）。IU/JAX ADPMC疾病建模开发和表型项目将 使用CRISPR基因组编辑生成携带人类风险等位基因不同组合的小鼠模型 迟发性AD（LOAD）。此外，一些最广泛使用的AD现有模型将完全 其特征在于开发更多临床相关的表型分析平台。我们召集了一个专家小组 在人类和小鼠遗传学，AD的小鼠模型，基因组编辑，基因组方法来了解 复杂疾病（包括测序和计算建模）和各种生物过程 参与AD（包括APP加工、胆固醇运输、神经炎症和血管生物学）。 我们有三个具体目标。目的1是充分表征APP/PS1、5xFAD和hTau，这三种最重要的生物学特性。 广泛使用的AD小鼠模型。APP/PS1和5xFAD携带淀粉样蛋白前体突变的组合 蛋白（APP）和早老素1（PSEN 1），导致人类早发性AD（EOAD）。APP/PS1和5xFAD 已被广泛用于研究淀粉样变性和神经炎症。hTau携带人野生型微管 在没有小鼠Mapt的情况下，与Tau相关的蛋白（MAPT）的表达增加，并发展出与年龄相关的MAPT。 过度磷酸化、聚集和一些神经变性。我们还将广泛描述一个新的 我们创建的LOAD模型携带LOAD的两个最大遗传风险因素，APOEε4和 TREM2R47H。我们将优先考虑临床相关终点，包括体内成像、血液和组织 生物标志物和基因组学，并将其与更传统使用的终点（如行为测定）进行比较 在临床上并不可靠。在目标2中，我们将产生携带40个新的 通过生物信息学和数据管理核心识别等位基因变体，并使用有效的体内 筛选策略，以确定有前途的模型，通过深入的表型。早些年 我们将优先了解GWAS变体（ABCA 7，BIN 1和CR 1）以及 我们从AD测序项目（NANOS 1）和AD神经影像学分析中发现了两个基因， 倡议（IL 1 RAP）。创建的所有模型都将通过JAX AD尽早提供 小鼠突变资源（ADMMR）。在目标3中，我们将充分描述显示重要AD的模型， 相关表型包括淀粉样蛋白沉积、tau病理学和神经变性， 表型分型策略描述于目的1中。所有新发现都将在人体组织中得到验证。贯穿本 在融资期间，我们预计将产生和分发40个新模型，最多8个新模型和4个现有模型 模型将被广泛描述。我们的策略紧密结合了人类和小鼠的数据，因此这些新的 AD模型将显示高度的临床可转化性，用于新治疗靶点的临床前测试。