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

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

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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.

抽象的阿尔茨海默氏病（AD）是我们在医学领域中最重要的挑战之一，因为目前，其严重的临床影响对非常大的患者人群以及缺乏有效治疗。在美国，广告目前影响约580万人，估计每年的护理费用 321亿美元。到2060年，预计AD案件的数量将增加到1400万人，年费用为护理超过1万亿美元。对于早期AD，最常见的原因是人类三体第21 唐氏综合征（DS）个体的细胞。广泛的病理改变是普遍的出现在DS到40岁的人群中，并在该人群中诊断出相关的痴呆症56 平均年龄，超过80％的DS患者受69岁的影响。促进机理 DS（AD-DS）中AD的治疗研究，首席研究员的实验室已经设计了大量基于人类与小鼠之间的进化保护DS动物模型的数量通过使用CRE/LOXP介导的染色体工程，基因组，物理和病理水平。这些动物模型正在由世界各地的实验室研究，其中之一是三个小鼠基因组区域直接与人类染色体21。在这种补充应用中，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，并开发用于筛选分子的新型实验系统，可用于靶向AD-DS治疗。我们将通过利用我们最近的成功来追求这些目标，包括我们拥有的独特遗传试剂发达。我们认为，我们目标的属性将导致前所未有的新研究平台将对AD-DS的机制产生新颖的见解，而AD-DS的机制将有助于发展有效的预防和治疗干预措施在患有和没有DS的患者中。