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) 的范式转变假设 在很大程度上可以理解为由高活性干扰素 (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，证明了这一假设是强有力且广泛存在的 DS 患者一生中的免疫失调。更具体地说，这个项目源于最近 该团队的发现表明，21 三体 (T21) 会导致多种细胞中 IFN 反应的持续激活 细胞类型，与表明慢性干扰素过度活跃的蛋白质组学和代谢组学变化同时发生 DS 活体患者的自身炎症。值得注意的是，这些结果可以简单地用以下事实来解释： 六种干扰素受体 (IFNR) 中的四种是在 21 号染色体上编码的。此外，其基本原理 该项目得到了大量文献的大力支持，证明了失调的负面影响 IFN 信号传导对普通人群的人类健康，包括在以下疾病的病因学中的关键作用 在 T21 患者中更为常见。 为了明确 IFN 过度活跃在 DS 中的作用，该团队将实施人类 研究，采用正在进行的 DS 人群泛组学队列研究以及动物研究 DS高级鼠标型号。人类研究工作将确定 IFN 标记物之间的关联 300 名 DS 患者的多动症、免疫失调和 DS 合并症，创建了丰富的数据集 这也将使该团队和该领域的其他人能够测试无数的替代假设。动物 研究将使用 DS 小鼠模型以及缺乏 IFNR 基因簇的新型小鼠品系来 确定 IFNR 基因剂量增加、IFN 信号传导过度活跃和 常见 DS 合并症的发展。 该项目的变革性质怎么强调都不为过。如果观察到 IFN 的慢性激活 反应和随之而来的免疫失调确实驱动了许多发育和临床疾病 由于 DS 的特点，DS 的生物学研究必须转向免疫学领域。如果 21 号染色体上的 IFNR 基因簇确实是 DS 表型和合并症的主要贡献者， 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的发展是合理的。 改善 T21 患者健康结果的治疗策略。 最终，这个研究项目不仅可以改变我们在实验室研究 DS 的方式以及 DS 的研究方式 在临床上进行管理，但也将增进我们对 IFN 信号传导和作用的机制理解。 免疫系统在多种疾病中受到 T21 的积极或消极调节， 从而在多个方面推进 NIH 的使命。