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氏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 阿尔茨海默氏病（AD）。 IU/JAX ADPMC疾病建模开发和表型项目将 使用CRISPR基因组编辑来生成鼠标模型，这些模型具有不同的人类风险等位基因组合 用于迟到的广告（负载）。此外，一些最广泛使用的广告模型将完全 特征是开发更临床相关的表型平台。我们组建了一个专家团队 在人类和小鼠遗传学中，AD的小鼠模型，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）和各种生物学过程 在AD中实施（包括应用程序加工，胆固醇贩运，神经炎症和血管生物学）。 我们有三个具体的目标。 AIM 1是完全表征App/ps1，5xFad和HTAU，其中三个 广泛使用的AD的鼠标模型。 APP/PS1和5XFAD携带淀粉样前体中突变的组合 蛋白质（APP）和Presenilin 1（PSEN1）在人类中引起早发AD（EOAD）。 APP/PS1和5XFAD 已广泛用于研究淀粉样变性和神经炎症。 HTAU携带人类野生型微管 在没有小鼠图的情况下，相关的蛋白质tau（mapt）并发展了与年龄相关的MAPT 高磷酸化，聚集和一些神经退行性。我们还将广泛地描述一个新的 我们创建的负载模型具有负载最大的两个遗传风险因素，APOEε4和 TREM2R47H。我们将优先考虑临床相关的终点，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（例如行为屁股）进行比较 被转化为诊所时尚未证明可靠的。在AIM 2中，我们将产生携带40个新的小鼠 通过生物信息学和数据管理核心识别的等位基因变体，并使用有效的体内 筛选策略，以确定有望模型传递到深层表型的策略。在早期 我们将优先考虑了解GWAS变体（ABCA7，BIN1和CR1）以及变化 我们从广告测序项目（NANOS1）和AD神经影像学的分析中鉴定出的两个基因 倡议（IL1RAP）。所有创建的型号将尽早通过JAX广告提供 小鼠突变资源（ADMMR）。在AIM 3中，我们将充分表征显示重要广告的模型 相关表型，包括淀粉样蛋白沉积，tau病理学和神经退行性的使用深处 AIM 1中描述的表型策略。所有新发现将在人体组织中进行验证。通过这个 资助期，我们预计将生成和分发40个新型号，并最多8个新模型和4个现有 模型将被广泛表征。我们的策略紧密整合了人类和鼠标数据，因此这些新 广告模型将显示出高度的临床转换性，用于对新的治疗靶标进行临床前测试。