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.

项目摘要疾病建模项目 (DMP) 印第安纳大学/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) 旨在开发、表征和分发更精确的临床前模型 阿尔茨海默病 (AD)。 IU/JAX ADPMC 疾病模型开发和表型分析项目将。 使用 CRISPR 基因组编辑生成携带不同人类风险等位基因组合的小鼠模型 此外，一些最广泛使用的现有 AD 模型将得到充分利用。 我们组建了一个专家团队，旨在开发更多临床相关的表型平台。 人类和小鼠遗传学、AD 小鼠模型、基因组编辑、理解基因组方法 复杂疾病（包括测序和计算建模）和各种生物过程 与 AD 相关（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，目标 1 是充分表征 APP/PS1、5xFAD 和 hTau（其中三个）。 广泛使用的 AD 小鼠模型携带淀粉样蛋白前体的突变组合。 蛋白质 (APP) 和早老素 1 (PSEN1) 会导致人类早发性 AD (EOAD) APP/PS1 和 5xFAD。 已被广泛用于研究淀粉样变性和神经炎症人类携带野生型微管。 蛋白相关 Tau (MAPT) 在缺乏小鼠 Mapt 的情况下产生，并产生与年龄相关的 MAPT 我们还将概括地描述一种新的过度磷酸化、聚集和一些神经变性。 我们创建的 LOAD 模型带有 LOAD 两个最大的遗传风险因素：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（例如行为测定）进行比较 在目标 2 中，我们将生成携带 40 只新小鼠。 通过生物信息学和数据管理核心识别等位基因变异，并使用有效的体内 早期确定有希望进入深度表型分析的模型的筛选策略。 在该中心，我们将优先了解 GWAS 变异（ABCA7、BIN1 和 CR1）以及 我们通过 AD 测序项目 (NANOS1) 和 AD 神经影像分析鉴定出两个基因 倡议 (IL1RAP)。创建的所有模型将尽早通过 JAX AD 提供。 在目标 3 中，我们将充分表征显示重要 AD-的模型。 使用深部分析相关表型，包括淀粉样蛋白沉积、tau 病理学和神经退行性变 目标 1 中描述的表型分析策略。所有新发现都将在人体组织中得到验证。 在资助期间，我们预计将生成和分发 40 个新模型，以及多达 8 个新模型和 4 个现有模型 我们的策略将广泛地描述模型的特征，将人类和小鼠的数据紧密结合起来，因此这些新的模型将具有广泛的特征。 AD 模型将在新治疗靶点的临床前测试中表现出高度的临床可转化性。