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

项目摘要 综合证据表明，生命早期的上呼吸道微生物组的某些分类群作为 预防儿童呼吸道疾病的发病，这是发病的主要原因， 儿童死亡率。在这种情况下，我们先前对儿童的研究结果和 多项动物研究暗示婴儿期乳酸杆菌鼻腔定植的潜在保护作用 儿童哮喘和其他特应性疾病的发展。然而，这并不足以 在人类身上进行了研究。婴儿期鼻内乳酸杆菌定植的机制可能是 保护性也是未知的。此外，目前还没有可用的干预措施来改变 鼻微生物组在有上呼吸道生态失调风险的婴儿中的应用，例如通过剖宫产出生的婴儿。到 为了解决这些知识差距，我们提出了以下具体目标：目标1：研究早期- 乳酸杆菌的生活鼻腔定植与建立独特的局部免疫有关 过敏性鼻炎和儿童哮喘的发生。目标2： 确定一项随机对照试验（RCT）的可行性，该试验评估了阴道种植在 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 在一个正在进行的大型人群中招募的一组健康婴儿中进行嵌套队列研究， 出生队列（n=749）。为了实现目标2，我们将进行一项单中心、平行组、设盲、假手术， 健康剖腹产婴儿的对照、可行性RCT（n=40）。 本NIH K23 -独立临床试验要求（PA-18-374）提案的目的是让候选人 发展如何研究早期上呼吸道微生物组对儿童呼吸系统的影响的专业知识 疾病以及如何将发现转化为临床试验的实施，因此他最终可以成为 儿童哮喘一级预防的独立患者导向研究者。完成 为此，他将通过实现拟议的具体目标和通过以下结合来增强他的研究技能： 专家指导，先进的教学课程，临床和微生物组研究的实践经验， 和其他有重点的职业发展活动。他将与多学科的导师团队密切合作 在儿科哮喘流行病学、微生物组研究、微生物学和 免疫学以及临床试验的设计和实施。该团队还拥有丰富的培养 培养早期调查人员，除了对以下方面作出强有力的机构承诺外， 候选人的研究生涯和特殊的学术环境-无疑将确保他的 持续的成功。

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.