Generation and analysis of new mouse models to determine novel therapeutic targets for Down syndrome-associated cognitive deficits

摘要 阿尔茨海默病（AD）是我们这个时代在医学领域最重要的挑战之一，因为 它对非常大的患者群体的严重临床影响以及目前缺乏有效的治疗方法。在 在美国，AD目前影响约580万人，估计每年的护理费用为 3210亿美元到2060年，AD病例数量预计将增加到1400万人，每年的费用为 护理超过一万亿美元。对于早发性AD，最常见的原因是人类21三体，存在于阿尔茨海默病患者中。 唐氏综合症（Down Syndrome，DS）患者的细胞。AD相关的病理改变具有普遍性， DS患者在40岁时出现，该人群在56岁时诊断出相关痴呆症 平均年龄为30岁，超过80%的DS患者受69岁的影响。为了便于机械化 和治疗研究AD在DS（AD-DS），主要研究者的实验室已经设计了一个实质性的 基于人类和小鼠之间的进化保守性， 基因组、生理和病理水平，通过使用Cre/loxP介导的染色体工程。这些 世界各地的实验室正在研究动物模型，其中一个是三倍于所有三个 小鼠基因组区域与人21号染色体正交。在本补充申请中，我们建议 采取下一个关键步骤，进一步优化AD-DS研究的动物模型，并开发一种 用于筛选可用于治疗靶向AD-DS的分子的新实验系统。我们将 利用我们最近的成功，包括我们拥有的独特的基因试剂， 开发我们相信，我们的目标的实现将导致前所未有的新的研究平台， 将产生对AD-DS潜在机制的新见解，这反过来将促进AD-DS的发展。 有效的预防和治疗干预措施，为AD在那些与和没有DS。

ABSTRACT Alzheimer’s disease (AD) is one of the most important challenges of our time in the field of medicine because of its severe clinical impacts on a very large patient population and the lack of effective treatments at present. In the United States, AD currently affects approximately 5.8 million people with an estimated annual cost of care of $321 billion. By 2060, the number of AD cases is predicted to rise to 14 million people with an annual cost of care exceeding one trillion dollars. For early onset AD, the most common cause is human trisomy 21 present in the cells of individuals with Down syndrome (DS). The AD-associated pathological alterations are universally present in individuals with DS by 40 years of age, and related dementia is diagnosed in this population at 56 years of age on average, with over 80% of people with DS affected by 69 years of age. To facilitate mechanistic and therapeutic studies of AD in DS (AD-DS), the principal investigator’s laboratory has engineered a substantial number of animal models of DS based on the evolutionary conservation between humans and mice at the genomic, physiological, and pathological levels, by using Cre/loxP-mediated chromosome engineering. These animal models are being studied by laboratories around the world, and one of them is triplicated for all three mouse genomic regions orthologous to human chromosome 21. In this supplement application, we propose to take the next critical step to further optimize the animal models for studies of AD-DS as well as to develop a novel experimental system for screening for molecules that can be used to target AD-DS therapeutically. We will pursue these aims by taking advantage of our recent successes, including the unique genetic reagents we have developed. We believe that attainment of our objectives will result in unprecedented new research platforms that will generate novel insights into the mechanisms underlying AD-DS, which in turn will facilitate the development of effective preventive and therapeutic interventions for AD in both those with and without DS.