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: 10230392
• 负责人: Tina V Hartert
• 金额: $ 155.02万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-23 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230392
• 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; 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：确定引起哮喘的RSV菌株并阐明RSV-的机制 介导的哮喘发育 婴儿期呼吸综合病毒（RSV）下呼吸道感染是普遍的风险 与哮喘密切相关的因素。它也代表了哮喘风险因素 建立因果关系的最强证据。在第一个资金周期中，我们是第一个 组以序列并识别与复发的风险显着增加相关的RSV菌株 喘息的结果以及差异免疫反应和气道微生物模式。这个建议 解决下一个逻辑系列问题：（1）这些是与童年后期相关的RSV菌株 哮喘发育，（2）我们可以更好地了解RSV介导的哮喘的机制 通过评估体内和体外菌株的宿主反应来开发？测试我们的假设 RSV菌株与增强的哮喘发育风险相关，它们通过 引起对婴儿感染的差异急性反应，改变气道和免疫发育，以及 早期生命微生物模式，我们提议扩展1900名儿童入学的纵向随访 建立的Inspire Birth Cohort将在第一个U19融资期结束时四岁。这将使我们 确认我们已经确定的RSV菌株是否会引起更严重的婴儿发病率和早期旋转 结果也与哮喘以及这些RSV菌株引起哮喘的途径有关。 我们提出以下建议：（1）确定6至8岁年龄段与哮喘成立相关的RSV菌株； （2） 确定在原发性RSV感染期间RSV菌株如何影响宿主微生物环境； （3）评估 原发性气道上皮细胞（AEC）对引起哮喘的RSV菌株的反应； （4）确定RSV诱导 与哮喘的启发队列有关的免疫反应。最终这些信息可能 告知防止“哮喘” RSV菌株的疫苗的设计和开发 哮喘发育。领导团队在该领域工作了15年，有一个就地 基础架构，建立合作和持续的队列，并具有详细的表型和丰富的生物测试 存储库使我们有好处，可以成功地进行这项小说和有影响力的研究。