IU/JAX/PITT MODEL-AD Center

项目摘要/摘要总体组件 阿尔茨海默病(AD)是导致老年人痴呆、残疾和死亡的主要原因。尽管最近 我们对阿尔茨海默病基本生物学机制的了解进展，我们还不知道如何预防 或有经批准的疾病修改干预措施。阿尔茨海默病(AD)的动物模型 对疾病的病理生理学提供了重要的见解，并提出了潜在的治疗途径； 然而，将这些发现转化为临床在很大程度上是不成功的。模型-AD联盟 是为了产生和验证晚发性阿尔茨海默病的下一代小鼠模型而启动的 (LOAD)以及对这些模型中最有希望的治疗药物进行严格的临床前测试。 基于由遗传、分子和成像研究驱动的人类疾病特征的进展，我们 已经创造了40多个携带遗传风险变体的负载小鼠模型。这些模型已经被 使用与临床相同的分子和成像方式来表征，揭示与负荷相关的 在以前的小鼠模型中没有观察到的表型。Iu/JAX/PIT模型-AD中心现在已准备好利用 这些现有的模型、方案和数据推动了我们创造可翻译的临床前工具的使命。这个 印第安纳大学(IU)/杰克逊实验室(JAX)/匹兹堡大学(IU/JAX/PIT)将利用IU和 皮特在神经退行性研究中的优势包括30多年来作为NIA支持的阿尔茨海默病 该中心(ADRC)和相当专业的临床前药物测试与JAX的80年的专业知识 哺乳动物遗传学和疾病建模，以开发、验证和传播新的、精确的动物模型 广告。此外，IU/JAX/PITT模型-AD中心包含Sage Bionetworks，以提供数据方面的专业知识 组织和传播。IU/JAX ADPMC汇聚了一支国际、多学科的团队- 包括遗传学家和遗传技术专家、定量和计算生物学家、临床专家 在阿尔茨海默病和神经成像领域，药理学家和世界领先者开发了精确的动物模型 疾病-拥有在疾病建模需求出现时进行预测的集体能力 国际舞台。这将使IU/JAX ADPMC能够有效地为AD科学界提供服务 效率很高。最终，这将最大限度地加速动物模型进步的应用 医疗福利。IU/JAX/PIT模式-AD中心的具体目标是： 目标1：确定遗传变异的优先顺序，分析模型数据，并通过数据广泛传播结果 共享和在线分析。 目标2：创建和描述新的负荷模型 目的3：通过PTC管道筛选新化合物。 目标4：协调中心、MODEL-AD联合体以及更广泛的范围内的活动 AD/ADRD研究人员社区。

PROJECT SUMMARY/ABSTRACT OVERALL COMPONENT Alzheimer’s disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances in our understanding of basic biological mechanisms underlying AD, we do not yet know how to prevent AD or have an approved disease modifying intervention. Animal models of Alzheimer’s disease (AD) have provided important insights into the pathophysiology of disease and suggested potential avenues for therapies; however, translation of these findings to the clinic has been largely unsuccessful. The MODEL-AD Consortium was initiated to generate and validate the next generation of mouse models of late-onset Alzheimer’s disease (LOAD) as well as to perform rigorous preclinical testing of the most promising therapeutics in these models. Based on advances in human disease characterization driven by genetic, molecular, and imaging studies, we have created more than 40 LOAD mouse models carrying genetic risk variants. These models have been characterized using the same molecular and imaging modalities used in the clinic, revealing LOAD-relevant phenotypes not observed in prior mouse models. The IU/JAX/PITT MODEL-AD Center is now poised to leverage these existing models, protocols, and data to further our mission of creating translatable preclinical tools. The Indiana University (IU)/Jackson Laboratory (JAX)/University of Pittsburgh (IU/JAX/PITT) will leverage IU’s and PITT’s strengths in neurodegenerative research including 30+ years as an NIA-supported Alzheimer’s Disease Center (ADRC) and considerable expertise in preclinical drug testing with JAX’s eight decades of expertise in mammalian genetics and disease modeling to develop, validate and disseminate new, precise animal models of AD. In addition, the IU/JAX/PITT MODEL-AD Center contains Sage Bionetworks to provide expertise in data organization and dissemination. The IU/JAX ADPMC brings together an international, multi-disciplinary team— including geneticists and genetics technology experts, quantitative and computational biologists, clinical experts in AD and neuroimaging, pharmacologists and world leaders in the development of precision animal models of disease—that possesses the collective ability to foresee disease modeling needs as they emerge on the international stage. This will allow the IU/JAX ADPMC to serve the AD scientific community effectively and efficiently. Ultimately, this will accelerate the application of advances in animal models for the greatest possible medical benefit. The Specific Aims of the IU/JAX/PITT MODEL-AD Center are: Aim 1: Prioritize genetic variants, analyze model data, and broadly disseminate results through data sharing and online analytics. Aim 2: Creating and characterizing novel LOAD models Aim 3: Screening of novel compounds through the PTC pipeline. Aim 4: Coordinate activities within the center, the MODEL-AD consortium, and across the broader community of AD/ADRD researchers.