Type I Interferon Dysregulation in Down Syndrome

唐氏综合症中的 I 型干扰素失调

基本信息

批准号：
10474048
负责人：
Dusan Bogunovic
金额：
$ 32.02万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474048
关键词：
Affect Antiviral Agents Antiviral Response Astrocytes Autoimmune Autoimmune Diseases of the Nervous System Autoimmunity Basal Ganglia Biological Assay Biology Blood Cardiac Cell Line Cells Child Chromosome 21 Clinical Cognitive Cognitive deficits Communicable Diseases Defect Disease Down Syndrome Fibroblasts Functional disorder Gene Dosage Genes Genetic Genetic Transcription Genotype Health Human IFNAR1 gene IFNAR2 gene Immune Immunity Immunologics Immunophenotyping In Vitro Individual Inflammation Inflammatory Intellectual functioning disability Interferon Type I Interferons Lead Measures Mediating Microglia Molecular Neurodevelopmental Problem Neurologic Neurons Pathogenesis Pathologic Pathology Pathway interactions Patients Phagocytosis Phosphotransferases Play Predisposition Regulation Series Signal Transduction Skin Specificity Synaptosomes Technology Testing Textbooks Therapeutic autosome calcification cell type cytokine gastrointestinal in vivo induced pluripotent stem cell inhibitor/antagonist innovation insight nerve stem cell peripheral blood pseudotoxoplasmosis syndrome receptor response single-cell RNA sequencing trafficking transcription factor type I interferon receptor young adult

项目摘要

Project Summary Type I interferons (IFN-Is) are potent cytokines, playing a key role in the antiviral response. However, they can also be detrimental to human health. Type I interferonpathies are disorders known to be caused by IFN-I dysregulation. Mendelian type I interferonopathies, such as Aicardi–Goutières syndrome (AGS), illustrate how the dysregulation of IFN activity can lead to neurological and autoimmune diseases. Down syndrome (DS) is the most common genetic cause of intellectual and developmental disabilities in children and young adults, affecting over 200,000 individuals in the US. In addition to cognitive problems, individuals with DS often have cardiac and gastrointestinal abnormalities. They also have various immunity- related defects, ranging from increased susceptibility to an array of infectious diseases to autoimmunity. Unfortunately, the exact molecular mechanism underlying these immune defects has yet to be elucidated. In most cases, DS is caused by the presence of an extra chromosome 21. Interestingly, the 200 or so genes present on this autosome include those encoding the type I interferon receptors (IFNAR1 and IFNAR2), suggesting a possible effect of gene dosage. Given that some type I interferonopathies are driven by minute increases in the levels of IFN-I cytokines, we decided to investigate the regulation of IFN-I in individuals with DS. This proposal is built around the hypothesis that the relative levels of IFNAR1 and IFNAR2 are the essential factors controlling the responsiveness to and duration of IFN-I responses in a cell type-specific manner in individuals with DS, thereby contributing to the disease. We plan to test this hypothesis, by studying DS patients in vitro, ex vivo, and in vivo at the molecular, immunological, neurological and clinical levels, to assess the functional effects of the increases in the dosage of these genes on the regulation of the IFN pathway in humans. A deeper understanding of the molecular regulation of IFN-I in DS will provide us with greater insight into the pathophysiology of DS and pave the way for the possible use of inhibitors to alleviate the persistent inflammatory disorders associated with DS.

项目摘要 I型干扰素（IFN-IS）是潜在的细胞因子，在抗病毒反应中起关键作用。然而，他们也可能对人类健康有害。 I型干扰素路径是已知是由 IFN-I失调。 Mendelian I型干预病，例如Aicardi -Goutières综合征（AGS），说明 IFN活性的失调如何导致神经系统和自身免疫性疾病。唐氏综合症（DS）是智力和发育障碍的最常见遗传原因儿童和年轻人影响了美国超过200,000人。除了认知问题，患有DS的个体通常患有心脏和胃肠道异常。他们也有各种免疫力 - 相关的缺陷，从增加的敏感性到一系列传染病到自身免疫性。不幸的是，这些免疫脱离物的基本分子机制尚未阐明。在大多数情况下，DS是由21个额外染色体的存在引起的。有趣的是，200左右该自染色体上存在的基因包括编码I型干扰素受体（IFNAR1和IFNAR2）的基因，提出基因剂量的可能作用。鉴于某种类型的I干涉病是由分钟驱动的随着IFN-I细胞因子水平的升高，我们决定调查患有IFN-I的调节 DS。该提议围绕以下假设：IFNAR1和IFNAR2的相对水平是控制细胞类型特异性中IFN-I响应的响应性和持续时间的基本因素 DS的个体的方式，从而导致该疾病。我们计划通过研究这一假设在分子，免疫学，神经和临床水平上，体外，体内和体内的DS患者评估这些基因剂量增加对IFN调节的功能效应人类的道路。对DS中IFN-I的分子调节的更深入了解将使我们对 DS的病理生理学和为可能使用抑制剂减轻持续的方式铺平了道路与DS相关的炎性疾病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dysregulation of the Immune System in a Natural History Study of 1299 Individuals with Down Syndrome.

对 1299 名唐氏综合症患者进行的自然历史研究显示免疫系统失调。

DOI：
10.21203/rs.3.rs-3647800/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Gansa,William;Menon,Kartikeya;Sazeides,Christos;Stewart,O'Jay;Bogunovic,Dusan
通讯作者：
Bogunovic,Dusan

Bourgeoning Scientific Research in Down Syndrome.

唐氏综合症的科学研究蓬勃发展。