Proteomics and Metabolomics Core: IDEAL shapes vaccine response, susceptibility to respiratory infectious disease and asthma

蛋白质组学和代谢组学核心：IDEAL 影响疫苗反应、呼吸道传染病和哮喘的易感性

• 批准号: 10589811
• 负责人: Hanno Steen
• 金额: $ 28.22万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589811
• 关键词: Affect; Aliquot; Antibody Response; Asthma; Biological; Biological Markers; Birth; Blood; COVID-19; COVID-19 patient; Cells; Child; Childhood; Clinical; Communicable Diseases; Complement; Consumption; Data; Development; Diagnosis; Dimensions; Disease; Early treatment; Epigenetic Process; Exhibits; Extravasation; Frequencies; Goals; Growth; Health; Hospitalization; Hour; Human; Immune; Immune system; Immunologics; Immunology; Immunophenotyping; Impairment; In Vitro; Infant; Infection; Infrastructure; Intervention; Life; Maps; Measurement; Methods; Microbe; Molecular; Molecular Profiling; Mucous body substance; Nasal cavity; Nasopharynx; National Institute of Allergy and Infectious Disease; Newborn Infant; Nose; Outcome; PRTN3 gene; Pathway interactions; Pattern; Pharyngeal structure; Phenotype; Plasma; Predisposition; Prevention; Process; Prognosis; Proteins; Proteome; Proteomics; Publishing; Research; Resolution; Respiratory System; Respiratory Tract Infections; Risk; Role; Sampling; Services; Shapes; System; Testing; Time; Tissues; Vaccination; Vaccines; biomarker identification; chemokine; clinical phenotype; clinically relevant; comorbidity; cytokine; data management; early childhood; endophenotype; high risk; immunoregulation; infancy; insight; interest; liquid chromatography mass spectrometry; metabolome; metabolomics; neonate; novel strategies; pathogen; respiratory; vaccine immunogenicity; vaccine response

Project Summary: IDEAL Proteomics and Metabolomics Core (PMC) The central premise of the overall proposal Immune Development in Early Life (IDEAL) Shapes Vaccine Response, Respiratory Infectious Disease and Asthma is that childhood immune development generates immunological endotypes with distinct biological mechanisms leading to co-morbidity among the three clinical phenotypes of interest vaccine responsiveness, respiratory infection proneness, and asthma. Our overall hypothesis is that unfavorable immune trajectories in early life result in clinical phenotypes such as low vaccine responsiveness, frequent respiratory infections and development of asthma, with significant overlap. These three clinical phenotypes are the converging clinical manifestations of various immune endotypes, i.e., distinct cellular and molecular signatures associated with the underlying mechanistic processes. The objective of the proposal is to test this hypothesis and to provide multidimensional quantitative molecular maps enabling description of the underlying immunological endotypes, with the ultimate goal to identify biomarkers to identify children at risk for unfavorable immune trajectories and to identify actionable targets for intervention. Given the importance of cytokines/chemokines, proteins and metabolites in modulating immune development, mapping their differential abundances in the context of the three different clinical phenotypes will be essential to understand the underlying immunological endotypes, which will be identified in Project 1 (PR1), further examined in vitro in PR3, and ultimately integrated with epigenetic data from PR2. To enable the proposed research, the Proteomics and Metabolomics Core (PMC) will manage, handle, and aliquot ~1900 plasma and ~600 nasopharyngeal wash samples (provided/collected by the IDEAL Clinical Core; CC) and provide the Data Management Core (DMC) the quantitative cytokine/chemokine, proteome, and metabolome maps. Specific Aim 1 will use a well-established multiplex platform (Luminex; 41-plex Milliplex system) to detect and quantify 41 cytokines and chemokines in plasma and nasopharyngeal wash samples. Specific Aim 2 describes a 2-pronged LC/MS-based plasma proteomics approach yielding ~700 proteins detected per sample, which covers the classical plasma proteome as well as a major fraction of the tissue leakage proteins in plasma. Furthermore, the nasopharyngeal wash proteomes will be mapped using LC/MS- based methods. All LC/MS analyses will be carried out in a high throughput fashion (60 to 100 samples/day) including 96-well plate-based processing. Specific Aim 3 coordinate the aliquoting and shipment of samples to Metabolon, Inc which, as leader in the field of metabolomics services, will perform the LC/MS-based metabolomic analysis of the plasma yielding >1,000 metabolites detected per sample as well as nasopharyngeal wash samples. The PMC will leverage the infrastructure and expertise of management, handling and analyzing 1000s of plasma samples as part of NIAID’s IMPACC study to identify immunophenotypes in hospitalized COVID-19 patients.

IDEAL Proteomics and Metabolomics Core（PMC） 生命早期免疫发育（IDEAL）疫苗总体提案的中心前提是 反应，呼吸道传染病和哮喘是儿童免疫发展产生的 具有不同生物学机制的免疫内型导致三种临床疾病的共病， 感兴趣的表型疫苗反应性、呼吸道感染倾向和哮喘。 我们的总体假设是，生命早期不利的免疫轨迹导致临床表型，如 疫苗反应性低、呼吸道感染频繁和发生哮喘，有很大的重叠。 这三种临床表型是各种免疫内型的会聚临床表现，即， 与潜在的机械过程相关的独特的细胞和分子特征。客观 的建议是测试这一假设，并提供多维定量分子图谱， 描述潜在的免疫学内型，最终目标是鉴定生物标志物， 儿童处于不利的免疫轨迹的风险，并确定可采取行动的干预目标。 鉴于细胞因子/趋化因子、蛋白质和代谢物在调节免疫发育中的重要性， 在三种不同临床表型的背景下绘制它们的差异丰度将是至关重要的， 了解将在项目1（PR 1）中确定的潜在免疫学内型，进一步检查 在体外PR 3中，并最终与来自PR 2的表观遗传数据整合。为了使拟议的研究能够进行， 蛋白质组学和代谢组学核心（PMC）将管理、处理和等分约1900份血浆和约600份 鼻咽洗液样本（由IDEAL临床中心提供/收集; CC）并提供数据 管理核心（DMC）定量细胞因子/趋化因子，蛋白质组和代谢组图谱。 Specific Aim 1将使用完善的多重平台（Luminex; 41-plex Milliplex系统）检测和 定量血浆和鼻咽洗液样品中的41种细胞因子和趋化因子。 具体目标2描述了一种基于LC/MS的双管齐下的血浆蛋白质组学方法，可产生约700种蛋白质 每个样本检测到的蛋白质组，涵盖了经典的血浆蛋白质组以及组织的主要部分 血浆中的渗漏蛋白。此外，将使用LC/MS对鼻咽洗液蛋白质组进行图谱分析。 基于方法。所有LC/MS分析将以高通量方式进行（60至100个样本/天） 包括基于96孔板的处理。 Specific Aim 3负责协调样品的分装和运输，以Metabolon，Inc.作为该领域的领导者 代谢组学服务，将进行基于LC/MS的血浆代谢组学分析，产生> 1000 每个样本以及鼻咽洗液样本检测到的代谢物。 PMC将利用基础设施和专业知识管理、处理和分析1000个血浆 样本作为NIAID的IMPACC研究的一部分，以确定住院COVID-19患者的免疫表型。