Mechanisms of childhood obesity underlying the susceptibility to multisystem inflammatory syndrome in children (MIS-C)

儿童肥胖导致儿童多系统炎症综合征易感性的机制（MIS-C）

基本信息

批准号：
10641777
负责人：
Janet Chou
金额：
$ 44.25万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10641777
关键词：
12 year old 2019-nCoV Accounting Acute Adult Autoimmune Diseases Biological Biological Markers Blood Coagulation Disorders Body mass index Body measure procedure COVID-19 COVID-19 test COVID-19 vaccine Cells Child Child Care Childhood Clinic Collaborations Communities Complication Coronary Aneurysm Data Data Analyses Data Set Development Disease Education Endocrinology Europe Exanthema Exhibits Fever Functional disorder Genetic Polymorphism Genetic Risk Genetic Screening Genetic study Goals Hematological Disease Hospitalization Immune Immune response Immunity Infection Inflammation Inflammatory Inflammatory Response Interferons Lymphopenia Mediating Metabolism Multiomic Data Multisystem Inflammatory Syndrome in Children Myocardial dysfunction Obesity Only Child Overweight Patients Phase Population Predisposition Prevalence Public Health Pulmonary Heart Disease Research Personnel Risk Risk Assessment Risk Factors SARS-CoV-2 infection Sampling Severities Shock Signal Transduction Symptoms Syndrome T-Cell Activation T-Lymphocyte Testing United States Vaccine Clinical Trial Variant Viral Virus Virus Diseases Weight acute infection cohort comorbidity cytopenia disorder risk gastrointestinal symptom genetic risk factor genetic variant immune activation insight multiple omics obesity genetics obesity in children post SARS-CoV-2 infection severe COVID-19

项目摘要

PROJECT SUMMARY/ABSTRACT Unpredictability is the hallmark of Multisystem Inflammatory Syndrome in Children (MIS-C). MIS-C is a severe pediatric complication of SARS-CoV-2 infection. MIS-C is distinct from COVID-19. It is not associated with pre-existing cardiopulmonary, autoimmune, or hematologic disorders. It can occur either during acute phase with detectable SARS-CoV-2 virus, or in the post-infectious period of several weeks after acute infection. Milder symptoms of MIS-C include fevers, rashes, and gastrointestinal symptoms, but can progress to cytopenias, coagulopathy, myocardial dysfunction, coronary aneurysms, and/or shock. We and others have found that MIS- C is associated with pediatric overweight and obesity, thereby identifying over 380 million children at risk for this disease. The mechanisms by which overweight and obesity influence the development of MIS-C are unknown. Until a vaccine against SARS-CoV-2 is globally available to all children, they will remain vulnerable to MIS-C. Our preliminary studies indicate that MIS-C is a highly inflammatory disease that incites more severe immune cell activation than COVID-19, particularly in overweight and obese children. Overweight and obese children with MIS-C had more T cell lymphopenia and T cell activation than their normal weight counterparts, suggesting an increased risk for more severe disease. Deleterious genetic variants increasing IFN and inflammatory signaling were exclusively found in patients with MIS-C, rather than severe COVID-19. This is a mechanistic counterpoint to defective IFN signaling associated with severe COVID-19 in adults. Our central hypothesis is that pediatric overweight and obesity prime interferon signaling, thereby increasing T cell activation and ultimately, the risk of MIS-C Aim 1 will elucidate how pediatric overweight and obesity drive immune cell dysfunction during MIS-C. The proposed studies will test the hypotheses that pediatric overweight and obesity are associated with more severe MIS-C, characterized by excessive interferon signaling and T cell activation. Aim 2 will identify mechanistic risk factors for MIS-C. The proposed studies will test the hypothesis that, even in the absence of infection, circulating immune cells from overweight and obese children exhibit an increased interferon signature that promotes T cell activation. We will develop a strategy for stratifying MIS-C by integrating genetic screening with measures of body mass index. Building on collaborations spanning over a decade and unique cohorts of children with MIS-C and/or obesity, our investigator team brings expertise in MIS-C, host immunity, pediatric obesity and endocrinology, and multiomics. This project will generate causal insights of how overweight and obesity influence the development and severity of MIS-C, with the goal of developing strategies for a population that remains at risk for this disease.

项目概要/摘要不可预测性是儿童多系统炎症综合征 (MIS-C) 的特点。 MIS-C是一个 SARS-CoV-2 感染的严重儿科并发症。 MIS-C 与 COVID-19 不同。没有关联患有先前存在的心肺、自身免疫或血液系统疾病。它可以发生在急性期具有可检测到的 SARS-CoV-2 病毒，或在急性感染后几周的感染后时期。较温和 MIS-C 的症状包括发烧、皮疹和胃肠道症状，但可进展为血细胞减少，凝血障碍、心肌功能障碍、冠状动脉瘤和/或休克。我们和其他人发现 MIS- C 与儿童超重和肥胖有关，因此确定了超过 3.8 亿儿童面临这种风险疾病。超重和肥胖影响 MIS-C 发展的机制尚不清楚。在全球所有儿童都能获得针对 SARS-CoV-2 的疫苗之前，他们仍将容易受到 MIS-C 的影响。我们的初步研究表明，MIS-C 是一种高度炎症性疾病，会引发更严重的炎症反应。免疫细胞的激活程度高于 COVID-19，特别是在超重和肥胖儿童中。超重和肥胖患有 MIS-C 的儿童比正常体重的儿童有更多的 T 细胞淋巴细胞减少和 T 细胞活化，表明患更严重疾病的风险增加。有害的基因变异会增加干扰素和炎症信号只在 MIS-C 患者中发现，而不是在重症 COVID-19 患者中发现。这是一个与成人严重 COVID-19 相关的缺陷 IFN 信号传导的机制对应。我们的中央假设儿童超重和肥胖会引发干扰素信号传导，从而增加 T 细胞激活并最终导致 MIS-C 的风险目标 1 将阐明儿童超重和肥胖如何在 MIS-C 期间导致免疫细胞功能障碍。拟议的研究将检验儿童超重和肥胖与更多疾病相关的假设。严重的 MIS-C，其特征是干扰素信号传导过度和 T 细胞激活。目标 2 将确定 MIS-C 的机械风险因素。拟议的研究将检验以下假设：即使没有感染，超重和肥胖儿童的循环免疫细胞也表现出增加干扰素特征，促进 T 细胞活化。我们将制定 MIS-C 分层策略：将基因筛查与体重指数测量相结合。以十多年来的合作和独特的 MIS-C 和/或肥胖儿童群体为基础，我们的研究团队带来了 MIS-C、宿主免疫、儿童肥胖和内分泌学方面的专业知识，以及多组学。该项目将产生关于超重和肥胖如何影响发育的因果见解以及 MIS-C 的严重程度，目标是为仍面临这种疾病风险的人群制定策略。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic diagnosis of immune dysregulation can lead to targeted therapy for interstitial lung disease: A case series and single center approach.

免疫失调的基因诊断可以导致间质性肺疾病的靶向治疗：病例系列和单中心方法。

DOI：
发表时间：
2022-07
期刊：
影响因子：
3.1
作者：
Wobma, Holly;Perkins, Ryan;Bartnikas, Lisa;Dedeoğlu, Fatma;Chou, Janet;Vleugels, Ruth Ann;Lo, Mindy S;Janssen, Erin;Henderson, Lauren A;Whangbo, Jennifer;Vargas, Sara O;Fishman, Martha;Krone, Katie A;Casey, Alicia
通讯作者：
Casey, Alicia