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: 10435043
• 负责人: OFER LEVY
• 金额: $ 19.86万
• 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/10435043
• 关键词: 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; 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; Shapes; Signal Pathway; Small Interfering RNA; Sorting - Cell Movement; 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; in vitro Assay; in vitro Model; in vivo; insight; monocyte; neutralizing monoclonal antibodies; novel; peripheral blood; programs; prospective; protein expression; protein metabolite; respiratory; response; small molecule; small molecule inhibitor; vaccine response; 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; 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; Shapes; Signal Pathway; Small Interfering RNA; Sorting - Cell Movement; 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; in vitro Assay; in vitro Model; in vivo; insight; monocyte; neutralizing monoclonal antibodies; novel; peripheral blood; programs; prospective; protein expression; protein metabolite; 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） 早期生命（理想）的免疫发展是动态的，越来越多的证据表明，它影响了 常见不良临床表型的风险，包括低疫苗反应性和对 呼吸道感染和/或哮喘。但是，关于精确机制或如何重定向知之甚少 免疫发育对更有利的表型。波士顿儿童的精密疫苗计划（PVP） 医院（BCH）开发了尖端的人体体外测定法，这些测定模型与年龄相关的白细胞变化 功能 - 即免疫本体发育和种群（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，调节剂和疫苗。 项目3（PR3）将利用人类的体外建模来深入了解信号通路 与观察到的临床表型有关。我们发表的未发表的初步数据，表明我们的 分类的人体体外测定平台可以对婴儿的先天和适应性免疫调查进行建模 年龄和疾病状况不同的幼儿。我们的假设是我们的先天和自适应体外 建模平台可能意味着完全询问与内型相关的分子信号通路 （疾病亚型）的临床表型，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尖端的人体体外测定系统来建模人类免疫细胞 对婴儿疫苗的反应以及确认，评估和翻译PR1和PR中鉴定的途径 2。我们将通过追求以下特定目标（SAS）：SA1来实现这一目标。评估机制 理想的内型基础。在此目标中，我们将追求对途径，生物标志物的分子询问， 在PR1和PR2中发现的代谢产物。 SA2。确定从 不利于有利的内型。我们将模拟免疫激活，以响应能够重复的药物 塑造免疫型，包括影响相关内型相关途径的药物 在PR1和PR2中。 总体而言，成功完成PR3将为与疫苗有关的理想提供新的见解 反应性，感染和/或哮喘蛋白质。这项努力将为理想，帮助提供机械洞察力 确认并探测PR1和PR2中鉴定的新型预后生物标志物和途径，并鉴定药物（例如， 蛋白质，代谢产物，调节剂，疫苗）可以将人类白细胞重新定向远离不利 与低疫苗反应能力，呼吸道感染和/或哮喘以及有利的疫苗反应能力相关的内型 轨迹和内型，从而推进儿童健康。