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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' 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

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.

摘要 阿尔茨海默病(AD)是我们这个时代在医学领域面临的最重要的挑战之一，因为 它对非常大的患者群体造成严重的临床影响，目前缺乏有效的治疗方法。在……里面 在美国，AD目前影响着大约580万人，估计每年的护理费用为 3210亿美元。到2060年，AD病例的数量预计将上升到1400万人，每年的成本为 超过一万亿美元的护理。对于早发性AD，最常见的原因是人类21三体存在于 唐氏综合征(DS)患者的细胞。与AD相关的病理改变是普遍存在的 在40岁之前出现在DS患者中，而相关的痴呆症在56岁时在这个人群中被诊断出来 平均年龄，超过80%的DS患者受69岁的影响。为了促进机械化 和DS中AD的治疗研究(AD-DS)，首席研究员的实验室已经设计了一个实质性的 基于人类和小鼠进化保守的DS动物模型的数量 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 世界各地的实验室都在研究动物模型，其中一个模型是三个模型中的三个。 小鼠基因组区域与人类21号染色体同源。在本补充申请中，我们建议 采取下一步关键步骤，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。我们会 利用我们最近的成功，包括我们拥有的独特的遗传试剂，来实现这些目标 发展起来的。我们相信，实现我们的目标将产生前所未有的新研究平台 将对AD-DS的潜在机制产生新的见解，这反过来将促进发展 对患有和不患有DS的人进行有效的AD预防和治疗干预。