The effect of early-life nasal colonization with Lactobacillus on the development of the local immune response and the later onset of recurrent wheeze, childhood asthma, and allergic rhinitis

生命早期鼻腔定植乳酸菌对局部免疫反应发展以及后期反复喘息、儿童哮喘和过敏性鼻炎的影响

• 批准号: 9806797
• 负责人: Christian Rosas-Salazar
• 金额: $ 18.49万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806797
• 关键词: Address; Age; Allergic rhinitis; Animals; Anterior nares; Asthma; Bacteria; Bioinformatics; Biological Markers; Birth; Blinded; Cesarean section; Child; Childhood; Childhood Asthma; Chronic Disease; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Collaborations; Conduct Clinical Trials; Control Groups; Data; Development; Development Plans; Disease; Enrollment; Ensure; Environment; Epidemiology; Evaluation; Fostering; Future; Gatekeeping; Goals; Hospitals; Human; Immune; Immune response; Immunology; Infant; Intervention; Knowledge; Laboratories; Lactobacillus; Leadership; Life; Logistics; Lung diseases; Measures; Mentors; Mentorship; Methods; Microbiology; Morbidity - disease rate; Mothers; Nose; Outcome; Pathway interactions; Pattern; Persons; Phase; Population; Prevention strategy; Primary Prevention; Procedures; Randomized; Randomized Controlled Trials; Recurrence; Regulatory T-Lymphocyte; Research; Research Design; Research Personnel; Risk; Role; Safety; School-Age Population; Specific qualifier value; Sterility; Swab; Testing; Time; Translating; United States National Institutes of Health; Vagina; Wheezing; Work; arm; base; career; career development; clinical implementation; cohort; cytokine; design; dysbiosis; experience; follow-up; group intervention; infancy; interest; microbiome research; mortality; multidisciplinary; nasal microbiome; novel; patient oriented; population based; prevent; primary outcome; protective effect; recruit; respiratory; respiratory microbiome; responsible research conduct; secondary outcome; skills; success; therapy design; vaginal microbiome; vaginal microbiota

PROJECT SUMMARY The aggregated evidence suggests that certain taxa of the early-life upper airway microbiome act as gatekeepers to prevent the onset of childhood respiratory diseases, which are a leading cause of morbidity and mortality in the pediatric population. In this context, the results from our prior studies in children and those from multiple animal studies allude to a potential protective effect of nasal colonization with Lactobacillus in infancy on the development of childhood asthma and other atopic diseases. However, this has not been adequately studied in humans. The mechanisms through which nasal colonization with Lactobacillus in infancy could be protective are also largely unknown. Furthermore, there are currently no available interventions to modify the nasal microbiome in infants at risk of upper airway dysbiosis, such as those born by cesarean section. To address these gaps in knowledge, we propose the following specific aims: Aim 1: To examine whether early- life nasal colonization with Lactobacillus is associated with the establishment of a distinct local immune response and the later development of recurrent wheeze, allergic rhinitis, and childhood asthma. Aim 2: To determine the feasibility of a randomized controlled trial (RCT) assessing the utility of vaginal seeding in modifying the early-life nasal microbiome of infants born by cesarean section. To achieve Aim 1, we will conduct a nested cohort study among a group of healthy infants enrolled in an ongoing large, population- based, birth cohort (n=749). To achieve Aim 2, we will conduct a single-center, parallel-arm, blinded, sham- controlled, feasibility RCT in healthy cesarean-born infants (n=40). The purpose of this NIH K23 – Independent Clinical Trial Required (PA-18-374) proposal is for the candidate to develop expertise in how to study the impact of the early-life upper airway microbiome on childhood respiratory diseases and how to translate findings to the implementation of clinical trials, so he can ultimately emerge as an independent patient-oriented investigator in the primary prevention of childhood asthma. To accomplish this, he will augment his research skills by achieving the proposed specific aims and through a combination of expert mentorship, advanced didactic coursework, hands-on experience in clinical and microbiome research, and other focused career development activities. He will work closely with a multidisciplinary team of mentors with collective expertise in pediatric asthma epidemiology, microbiome research, microbiology and immunology, and the design and conduct of clinical trials. This team also has extensive experience in fostering the development of early-stage investigators, which —in addition to a strong institutional commitment to the candidate’s research career and an exceptional academic environment— will undoubtedly ensure his continued success.

项目概要 汇总的证据表明，生命早期上呼吸道微生物组的某些​​分类单元充当 预防儿童呼吸道疾病发病的把关人，这是导致发病和死亡的主要原因 儿科人群的死亡率。在这种情况下，我们之前对儿童和来自儿童的研究结果 多项动物研究暗示婴儿期鼻腔定植乳酸菌具有潜在的保护作用 儿童哮喘和其他特应性疾病的发展。然而，这还没有得到充分 在人类身上进行研究。婴儿时期乳杆菌鼻定植的机制可能是 保护性也很大程度上未知。此外，目前没有可用的干预措施来修改 有上呼吸道失调风险的婴儿（例如剖腹产婴儿）的鼻腔微生物组。到 为了解决这些知识差距，我们提出以下具体目标： 目标 1：检查是否早期- 乳杆菌的鼻腔定植与独特的局部免疫的建立有关 反应以及随后出现反复喘息、过敏性鼻炎和儿童哮喘。目标 2： 确定评估阴道播种效用的随机对照试验（RCT）的可行性 改变剖腹产婴儿的早期鼻腔微生物组。为了实现目标1，我们将 在正在进行的大规模人口统计中登记的一组健康婴儿中进行嵌套队列研究 基于出生队列（n=749）。为了实现目标 2，我们将进行单中心、平行臂、盲法、假手术 对健康剖腹产婴儿进行的对照、可行性随机对照试验 (n=40)。 NIH K23 – 需要独立临床试验 (PA-18-374) 提案的目的是让候选人 培养如何研究生命早期上呼吸道微生物组对儿童呼吸道影响的专业知识 疾病以及如何将研究结果转化为临床试验的实施，以便他最终能够成为 儿童哮喘一级预防中以患者为中心的独立研究者。为了完成 为此，他将通过实现拟议的具体目标并通过结合以下方法来增强他的研究技能： 专家指导、高级教学课程、临床和微生物组研究的实践经验， 以及其他重点职业发展活动。他将与多学科导师团队密切合作 拥有儿科哮喘流行病学、微生物组研究、微生物学和 免疫学，以及临床试验的设计和进行。该团队在培育方面也拥有丰富的经验 早期研究人员的发展，除了对 候选人的研究生涯和卓越的学术环境——无疑将确保他 持续的成功。