Project 3: In vitro modeling to define mechanisms of childhood vaccine response, susceptibility to respiratory infectious disease and asthma

项目 3：体外建模以确定儿童疫苗反应、呼吸道传染病和哮喘易感性机制

• 批准号: 10589826
• 负责人: OFER LEVY
• 金额: $ 22.79万
• 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/10589826
• 关键词: Acceleration; Address; Adjuvant; Age; Allergens; Anti-Inflammatory Agents; Antigen Presentation; Antigens; Asthma; Attenuated Vaccines; Autologous; BCG Live; Biological Assay; Biological Markers; Boston; CD8-Positive T-Lymphocytes; Cells; Child; Child Health; Childhood; Clinical; Communicable Diseases; Data; Development; Disease; Disease susceptibility; Evaluation; Exposure to; Flow Cytometry; Gene Expression Profiling; Goals; Growth; Health; Human; Immune; Immune response; Immunological Models; Immunomodulators; In Vitro; Individual; Infant; Infection; Innate Immune Response; Italy; Lead; Leukocytes; Life; MHC Class I Genes; Mediating; Memory; Modeling; Molecular; Mononuclear; Natural Immunity; Participant; Pathway interactions; Pattern recognition receptor; Pediatric Hospitals; Peptides; Phenotype; Plasma; Population; Predisposition; Prognostic Marker; Proteins; Publishing; Respiratory Disease; Respiratory Tract Infections; Risk; Rome; Sampling; Secondary to; Serum; Shapes; Signal Pathway; Small Interfering RNA; Sorting; Stimulus; System; Systems Biology; T-Cell Activation; T-Lymphocyte; Technology; Testing; Training; Translating; Translations; Vaccines; adaptive immune response; adaptive immunity; age related; antigen-specific T cells; asthmatic; biobank; clinical phenotype; cohort; cytokine; disorder subtype; human model; immune activation; immune modulating agents; in vitro Assay; in vitro Model; in vivo; insight; monocyte; neutralizing monoclonal antibodies; novel; peripheral blood; programs; prospective; protein expression; respiratory; response; small molecule; small molecule inhibitor; vaccine response

Project Summary – Project 3 (PR3) Immune development in early life (IDEAL) is dynamic and growing evidence suggests that it impacts the risk for common undesirable clinical phenotypes including low vaccine responsiveness, and proneness to respiratory infection and/or asthma. However, little is known regarding precise mechanisms nor how to redirect immune development to more favorable phenotypes. The Precision Vaccines Program (PVP) at Boston Children’s Hospital (BCH) has developed cutting-edge human in vitro assays which model age related changes in leukocyte function- i.e., immune ontogeny and population (e.g. age)-specific effects and mechanisms of action of immunomodulatory agents, including metabolites, proteins, adjuvants and vaccines. Project 3 (PR3) will leverage human in vitro modeling to gain insight into signaling pathways that are relevant to the clinical phenotypes observed. Our published and unpublished preliminary data indicate that our sample-sparing human in vitro assay platforms can model innate and adaptive immune responses of infants and young children which vary by age and disease status. Our hypothesis is that our innate and adaptive in vitro modeling platforms can meaningfully interrogate molecular signaling pathways relevant to endotypes (disease sub-types) of clinical phenotypes such as vaccine responsiveness, respiratory infection and/or asthma. Our goal is to leverage our cutting-edge human in vitro assay systems to model human immune cell responses to infant vaccines as well as to confirm, assess and translate the pathways identified in PR1 and PR 2. We will achieve this goal by pursuing the following Specific Aims (SAs): SA1. Assess mechanisms underlying IDEAL endotypes. In this aim we will pursue molecular interrogation of pathways, biomarkers, metabolites discovered in PR1 and PR2. SA2. Identify immunomodulators that re-direct trajectories from unfavorable to favorable endotypes. We will model immune activation in response to agents capable of re- shaping immune endotypes, including agents that impact the relevant endotype-associated pathways identified in PR1 and PR2 . Overall, successful completion of PR3 will provide fresh insight into IDEAL in relation to vaccine responsiveness, infection and/or asthma proneness. This effort will provide mechanistic insight into IDEAL, help confirm and probe novel prognostic biomarkers and pathways identified in PR1 and PR2, and identify agents (e.g., proteins, metabolites, adjuvants, vaccines) that can redirect human infant leukocytes away from unfavorable endotypes associated with low vaccine responsiveness, respiratory infection and/or asthma and towards favorable trajectories and endotypes thereby advancing child health.

项目摘要 – 项目 3 (PR3) 生命早期的免疫发展 (IDEAL) 是动态的，越来越多的证据表明它会影响 常见不良临床表型的风险，包括疫苗反应性低和容易出现 呼吸道感染和/或哮喘。然而，人们对精确机制以及如何重定向知之甚少。 免疫发育到更有利的表型。波士顿儿童医院的精准疫苗计划 (PVP) Hospital (BCH) 开发了尖端的人体体外检测方法，可模拟白细胞的年龄相关变化 功能 - 即免疫个体发育和群体（例如年龄）特异性效应和作用机制 免疫调节剂，包括代谢物、蛋白质、佐剂和疫苗。 项目 3 (PR3) 将利用人体体外模型来深入了解以下信号通路： 与观察到的临床表型相关。我们已发表和未发表的初步数据表明，我们 保留样本的人体体外检测平台可以模拟婴儿和婴儿的先天性和适应性免疫反应 幼儿，因年龄和疾病状况而异。我们的假设是我们的先天性和适应性在体外 建模平台可以有意义地询问与内型相关的分子信号传导途径 临床表型（疾病亚型），例如疫苗反应性、呼吸道感染和/或 哮喘。我们的目标是利用我们最先进的人体体外检测系统来模拟人体免疫细胞 对婴儿疫苗的反应以及确认、评估和翻译 PR1 和 PR 中确定的途径 2. 我们将通过追求以下具体目标 (SA) 来实现这一目标： SA1。评估机制 潜在的理想内型。为了这个目标，我们将对通路、生物标志物、 PR1 和 PR2 中发现的代谢物。 SA2。识别重新引导轨迹的免疫调节剂 对有利的内型不利。我们将模拟免疫激活，以响应能够重新 塑造免疫内型，包括影响已确定的相关内型相关途径的药物 在 PR1 和 PR2 中。 总体而言，PR3 的成功完成将为 IDEAL 与疫苗相关的领域提供新的见解 反应性、感染和/或哮喘倾向。这项工作将为 IDEAL 提供机械洞察，帮助 确认和探索 PR1 和 PR2 中发现的新的预后生物标志物和途径，并确定药物（例如， 蛋白质、代谢物、佐剂、疫苗），可以将人类婴儿白细胞从不利的地方重定向 与疫苗反应性低、呼吸道感染和/或哮喘相关的内型以及有利的 轨迹和内型从而促进儿童健康。