Identifying Asthma-causing RSV Strains and Elucidating the Mechanisms of RSV-mediated Asthma Development

鉴定引起哮喘的 RSV 菌株并阐明 RSV 介导的哮喘发展机制

• 批准号: 9975086
• 负责人: Tina V Hartert
• 金额: $ 32.35万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975086
• 关键词: Acute; Address; Age; Area; Asthma; Biological Specimen Banks; Birth; Child; Childhood; Childhood Asthma; Collaborations; Data; Development; Disease; Dose; Enrollment; Environment; Epithelial Cells; Event; Funding; Goals; Human; Hypersensitivity; Immune; Immune response; Immune system; In Vitro; Infant; Infrastructure; Leadership; Life; Link; Lower Respiratory Tract Infection; Mediating; Outcome; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Positioning Attribute; Prevention; Recurrence; Research; Respiration; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Risk; Risk Factors; Series; Severities; T memory cell; Testing; Time; Vaccines; Viral; Wheezing; Work; airway epithelium; cohort; design; follow-up; in vivo; infancy; infant morbidity; innovation; microbial; microbial host; modifiable risk; neonatal infection; novel; prevent; respiratory morbidity; response; vaccine development

Abstract PROJECT 1: Identifying Asthma-causing RSV Strains and Elucidating the Mechanisms of RSV- mediated Asthma Development Respiratory syncytial virus (RSV) lower respiratory tract infection during infancy represents a common risk factor that is strongly and consistently associated with asthma. It also represents an asthma risk factor with the strongest body of evidence establishing a causal relationship. In the first funding cycle we have been the first group to ever sequence and identify RSV strains associated with significantly increased risk of recurrent wheezing outcomes, as well as differential immune response and airway microbial patterns. This proposal addresses the next logical series of questions: (1) are these RSV strains associated with later childhood asthma development, and (2) can we better understand the mechanisms of RSV-mediated asthma development by assessing the host response to these strains in vivo and in vitro? To test our hypotheses that there are RSV strains associated with enhanced risk of asthma development, and they act through eliciting differential acute response to infant infection, altering airway and immune development, and early life microbial patterns, we propose to extend longitudinal follow-up of the 1900 children enrolled in the established INSPIRE birth cohort who will be four at the end of the first U19 funding period. This will enable us to confirm if the RSV strains that we have identified to cause more severe infant morbidity and early wheezing outcomes are also associated with asthma, and the pathways through which these RSV strains cause asthma. We propose the following: (1) Identify RSV strains associated with asthma inception at ages 6 to 8 years; (2) Determine how RSV strains impact the host microbial environment during primary RSV infection; (3) Assess primary airway epithelial cell (AEC) response to asthma-causing RSV strains; (4) Determine RSV induced immune responses associated with asthma inception in the INSPIRE cohort. Ultimately this information may inform the design and development of a vaccine that prevents “asthmagenic” RSV strains from predisposing to asthma development. The leadership team has worked in this area for 15 years, have an in-place infrastructure, established collaborations and ongoing cohort with detailed phenotyping and rich biospecimen repository making us well positioned to successfully carry out this novel and impactful study.

抽象的 项目 1：鉴定引起哮喘的 RSV 菌株并阐明 RSV 的机制 介导的哮喘发展 婴儿期呼吸道合胞病毒 (RSV) 下呼吸道感染是一种常见风险 与哮喘密切且一致相关的因素。它也代表了哮喘的危险因素 建立因果关系的最有力的证据。在第一个融资周期中，我们是第一个 小组对与复发风险显着增加相关的 RSV 菌株进行测序和鉴定 喘息结果，以及不同的免疫反应和气道微生物模式。这个提议 解决了接下来一系列合乎逻辑的问题：(1) 这些 RSV 菌株与儿童后期有关吗？ 哮喘的发展，以及（2）我们能否更好地了解 RSV 介导的哮喘机制 通过评估体内和体外宿主对这些菌株的反应来开发？为了检验我们的假设 有些 RSV 菌株与哮喘发生风险增加相关，它们通过以下方式发挥作用： 引起对婴儿感染的不同急性反应，改变气道和免疫发育，以及 为了了解生命早期的微生物模式，我们建议对参加该项目的 1900 名儿童进行纵向随访。 建立了 INSPIRE 出生队列，在第一个 U19 资助期结束时将有四人。这将使我们能够 确认我们已确定的 RSV 菌株是否会导致更严重的婴儿发病和早期喘息 结果也与哮喘以及这些 RSV 菌株引起哮喘的途径有关。 我们建议如下： (1) 识别与 6 至 8 岁哮喘发病相关的 RSV 菌株； (2) 确定 RSV 菌株在原发性 RSV 感染期间如何影响宿主微生物环境； (3) 评估 原代气道上皮细胞 (AEC) 对引起哮喘的 RSV 菌株的反应； (4) 确定RSV诱导的 INSPIRE 队列中与哮喘发作相关的免疫反应。最终这些信息可能 为预防“哮喘”RSV 菌株诱发的疫苗设计和开发提供信息 哮喘的发展。领导团队在该领域工作了15年，拥有一支到位的团队 基础设施、已建立的合作以及正在进行的具有详细表型分析和丰富生物样本的队列 存储库使我们能够成功地开展这项新颖且有影响力的研究。