IU/JAX/PITT MODEL-AD Center

项目总结/摘要总体组成部分 阿尔茨海默病（AD）是老年人痴呆、残疾和死亡的主要原因。尽管最近 虽然我们对AD的基本生物学机制的理解有所进步，但我们还不知道如何预防 AD或有批准的疾病修饰干预。阿尔茨海默病（AD）的动物模型 为疾病的病理生理学提供了重要的见解，并提出了治疗的潜在途径; 然而，将这些发现转化到临床上基本上是不成功的。MODEL-AD联盟 是为了产生和验证下一代迟发性阿尔茨海默病小鼠模型而发起的 （LOAD）以及在这些模型中对最有前途的治疗药物进行严格的临床前测试。 基于遗传学、分子学和影像学研究推动的人类疾病表征的进展，我们 已经创建了40多个携带遗传风险变体的LOAD小鼠模型。这些模型已经 使用临床中使用的相同分子和成像模式进行表征，揭示了与负荷相关的 在先前的小鼠模型中未观察到的表型。IU/JAX/PITT模型-AD中心现在准备利用 这些现有的模型，协议和数据，以进一步我们的使命，创造可翻译的临床前工具。的 印第安纳州大学（IU）/杰克逊实验室（JAX）/匹兹堡大学（IU/JAX/PITT）将利用IU和 PITT在神经退行性疾病研究方面的优势，包括30多年的NIA支持的阿尔茨海默病 中心（ADRC）和相当的专业知识，在临床前药物测试与JAX的八十年的专业知识， 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， AD.此外，IU/JAX/PITT MODEL-AD中心包含Sage Bionetworks，可提供数据方面的专业知识 组织和传播。IU/JAX ADPMC汇集了一个国际化的多学科团队- 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AD和神经影像学方面，药理学家和世界领先的精确动物模型的发展， 疾病-具有集体能力，可以预见疾病建模需求，因为它们出现在 国际舞台这将使IU/JAX ADPMC能够有效地为AD科学界服务， 有效地最终，这将尽最大可能加速动物模型的应用进展， 医疗福利。IU/JAX/PITT模型-AD中心的具体目标是： 目标1：优先考虑遗传变异，分析模型数据，并通过数据广泛传播结果 分享和在线分析。 目标2：创建和表征新的LOAD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联盟以及更广泛的 AD/ADRD研究人员。

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.