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

生成并分析新的小鼠模型以确定唐氏综合症相关认知缺陷的新治疗靶点

基本信息

批准号：
10711887
负责人：
Eugene Yu
金额：
$ 43.8万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-13 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711887
关键词：
Abbreviations Achievement Affect Age Age Years Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amino Acids Amyloid beta-42 Amyloid beta-Protein Animal Model Appearance Brain Cells Chromosome 16 Chromosome 21 Chromosomes Clinical Clustered Regularly Interspaced Short Palindromic Repeats Code Cognitive deficits Color Communities Copy Number Polymorphism Country Cre-LoxP Data Dementia Development Diagnosis Disease Down Syndrome Early Onset Alzheimer Disease Engineering Future General Population Generations Genes Genetic Genomic Segment Genomics Goals Heart Abnormalities Homologous Gene Human Human Chromosomes Impairment Incidence Individual Investigation Laboratories Laboratory Study Link Longitudinal Studies Measurement Mediating Medical Medicine Modeling Molecular Mus Mutant Strains Mice Mutate Mutation Nature Pathogenesis Pathologic Peptides Persons Phenotype Physiological Population Positioning Attribute Prevention Preventive Principal Investigator Proteins Reagent Reporting Research Senile Plaques Special Population Study models Symptoms System Therapeutic Therapeutic Intervention Therapeutic Studies Time United States Work aged care costs clinical diagnosis cognitive function comparative disease phenotype effective therapy experience genome editing insight mouse genome mouse model mutant neuropathology new therapeutic target novel novel strategies patient population prevent preventive intervention screening success therapeutic target tool virtual

项目摘要

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.

抽象的阿尔茨海默病（AD）是当今医学领域最重要的挑战之一，因为其对大量患者的严重临床影响以及目前缺乏有效的治疗方法。在美国，AD 目前影响大约 580 万人，估计每年的护理费用到 2060 年，AD 病例数量预计将增至 1,400 万人，每年造成的损失为 3,210 亿美元。护理费用超过万亿美元对于早发性 AD，最常见的原因是人类 21 三体性。唐氏综合症 (DS) 患者的细胞普遍存在与 AD 相关的病理改变。 DS 患者在 40 岁之前就已经出现，并且该人群在 56 岁时被诊断出相关痴呆症平均年龄，超过 80% 的 DS 患者年龄为 69 岁。 DS 中的 AD 和治疗研究 (AD-DS)，主要研究者的实验室已经设计了大量的基于人类和小鼠之间的进化保守性的 DS 动物模型的数量通过使用 Cre/loxP 介导的染色体工程，在基因组、生理和病理水平上进行研究。世界各地的实验室正在研究动物模型，其中一个模型对所有三个模型都进行了三次重复小鼠基因组区域与人类 21 号染色体直系同源。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，并开发用于筛选可用于治疗 AD-DS 的分子的新型实验系统。利用我们最近的成功，包括我们拥有的独特遗传试剂来实现这些目标我们相信，实现我们的目标将带来前所未有的新研究平台。将产生对AD-DS底层机制的新见解，这反过来又将促进开发对患有和不患有 DS 的 AD 患者进行有效的预防和治疗干预。