Understanding Down Syndrome as an Interferonopathy

将唐氏综合症理解为一种干扰素病

• 批准号: 9892863
• 负责人: Joaquin M. Espinosa
• 金额: $ 283.07万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892863
• 关键词: Affect; Alzheimer' s Disease; Animal Experimentation; Area; Autoimmune Diseases; Automobile Driving; Biological; Biology; Brain; Chromosomes, Human, Pair 21; Chronic; Clinic; Clinical; Clinical Management; Cohort Studies; Comorbidity; Congenital Heart Defects; Data; Data Set; Development; Diagnostic; Disease; Down Syndrome; Epilepsy; Etiology; Gene Cluster; Gene Dosage; General Population; Genetic Diseases; Health; Human; Hyperactive behavior; Immune; Immune System Diseases; Immune system; Immunology; Individual; Interferons; Investigation; Laboratories; Literature; Longevity; Malignant Neoplasms; Measures; Medical; Mission; Mouse Strains; Nature; Neurologic; Outcome; Pathologic; Pathology; Phenotype; Population; Population Study; Proteomics; Receptor Gene; Research; Research Project Grants; Role; Sampling; Signal Transduction; Solid; Testing; Therapeutic; Therapeutic Intervention; United States National Institutes of Health; autism spectrum disorder; autoinflammation; base; cell type; defined contribution; human disease; immunomodulatory therapies; improved; innovation; leukemia; metabolomics; mouse model; nervous system disorder; novel; receptor; response; study population; targeted treatment

PROJECT SUMMARY. This transformative R01 project will test the paradigm-shifting hypothesis that Down syndrome (DS) could be understood, in large measure, as an immune disorder driven by hyperactive Interferon (IFN) signaling. This hypothesis is supported by a large body of evidence demonstrating strong and widespread immune dysregulation across the lifespan of people with DS. More specifically, this project arises from the recent discovery by this team showing that trisomy 21 (T21) causes consistent activation of the IFN response in multiple cell types, concurrent with proteomics and metabolomics changes indicative of chronic IFN hyperactivity and autoinflammation in living individuals with DS. Remarkably, these results could be explained simply by the fact that four of the six IFN receptors (IFNRs) are encoded on chromosome 21. Furthermore, the rationale for this project is strongly supported by a large body of literature demonstrating the negative impacts of dysregulated IFN signaling on human health in the general population, including key roles in the etiology of diseases that are more prevalent in people with T21. To define the role of IFN hyperactivity in DS, this team will implement a synergistic combination of human research, employing an ongoing pan-omics cohort study of the population with DS, and animal research in advanced mouse models of DS. Human research efforts will define associations between markers of IFN hyperactivity, immune dysregulation, and DS co-morbidities in 300 individuals with DS, creating a rich dataset that would also enable the testing of myriad alternative hypotheses by this team and others in the field. Animal research will use mouse models of DS along with a novel mouse strain lacking the IFNR gene cluster to determine cause-effect relationships between increased IFNR gene dosage, hyperactive IFN signaling, and development of common DS co-morbidities. The transformational nature of this project cannot be overstated. If the observed chronic activation of the IFN response and consequent immune dysregulation are indeed driving many of the developmental and clinical hallmarks of DS, research on the biology of DS would have to be redirected toward the field of immunology. If the IFNR gene cluster on chromosome 21 is indeed a major contributor to DS phenotypes and co-morbidities, our clinical understanding of DS would be reframed, justifying the development of immune-based diagnostic and therapeutic strategies to improve health outcomes in people with T21. Ultimately, this research project could not only change the way we study DS in the laboratory and how DS is managed in the clinic, but would also advance our mechanistic understanding of the role of IFN signaling and the immune system in the myriad medical conditions that are modulated, either positively or negatively, by T21, thus advancing the NIH mission on multiple fronts.

项目摘要。 这个变革性的R01项目将测试唐氏综合症（DS） 在很大程度上可以理解为由过度活跃的干扰素（IFN）驱动的免疫紊乱 发信号。这一假设得到了大量证据的支持，这些证据表明， DS患者的免疫失调。更具体地说，该项目源于最近的 该研究小组的发现表明，21三体（T21）引起多个细胞中IFN应答的一致激活， 细胞类型，同时伴有蛋白质组学和代谢组学变化，表明慢性IFN活性亢进， DS活体个体的自身炎症。值得注意的是，这些结果可以简单地解释为， 六种干扰素受体（IFNRs）中的四种在21号染色体上编码。此外，这样做的理由 该项目得到了大量文献的有力支持，这些文献证明了失调的负面影响。 IFN信号对普通人群健康的影响，包括在疾病病因学中的关键作用， 在T21患者中更为常见。 为了明确IFN活性亢进在DS中的作用，该研究小组将实施一种协同组合的人 研究，采用正在进行的DS人群的泛组学队列研究，以及 DS的高级小鼠模型。人类的研究工作将确定干扰素标志物之间的关联 300名DS患者的多动、免疫失调和DS合并症，创建了丰富的数据集 这也将使该小组和实地其他人员能够检验各种不同的假设。动物 研究将使用DS沿着的小鼠模型以及缺乏IFNR基因簇的新型小鼠品系， 确定增加的IFNR基因剂量、过度活跃的IFN信号传导和 常见DS合并症的发生。 这个项目的变革性质怎么强调都不过分。如果观察到的干扰素的慢性激活 反应和随之而来的免疫失调确实推动了许多发展和临床 由于DS的特征，DS生物学的研究必须转向免疫学领域。如果 染色体21上IFNR基因簇确实是DS表型和共病的主要贡献者， 我们对DS的临床理解将被重新构建，证明基于免疫的诊断和 治疗策略，以改善T21患者的健康状况。 最终，这个研究项目不仅可以改变我们在实验室中研究DS的方式， 管理在临床上，但也将推进我们的机制的理解IFN信号的作用， 免疫系统在无数的医疗条件下，无论是积极或消极的调节，由T21， 从而在多个方面推进NIH的使命。