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: 10459426
• 负责人: Christian Rosas-Salazar
• 金额: $ 18.02万
• 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/10459426
• 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; Respiratory Disease; 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 trial 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; respiratory morbidity; 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.

项目摘要 汇总证据表明，早期生命的上呼吸道微生物组的某些​​分类群是 网守以防止儿童呼吸道疾病的发作，这是发病率和 小儿人口的死亡率。在这种情况下，我们先前对儿童研究的结果以及 多个动物研究暗示了婴儿期鼻腔化的潜在保护作用 关于童年哮喘和其他特应性疾病的发展。但是，这还不够 研究人类。在婴儿期间用乳杆菌鼻菌定殖的机制可能是 保护性也在很大程度上未知。此外，目前尚无可用干预措施来修改 鼻腔疾病的鼻微生物组患有上呼吸道营养不良的风险，例如剖宫产。到 解决知识中的这些差距，我们提出以下具体目的：目标1：检查早期是否早期 乳酸杆菌的生命鼻殖与建立独特的局部免疫有关 反应和后来的复发性轮胎，过敏性鼻炎和儿童哮喘的发展。目标2：到 确定评估阴道播种效用的随机对照试验（RCT）的可行性 修改剖宫产出生的婴儿的早期鼻微生物组。为了实现目标1，我们将 在正在进行的大型人群中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，盲目的假手术 在健康的剖宫产婴儿中受控的可行性RCT（n = 40）。 这项NIH K23的目的 - 独立临床试验（PA-18-374）提案是为了候选人 在如何研究早期生命高气道微生物组对儿童呼吸的影响方面发展专业知识 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 独立的面向患者的研究者，主要预防儿童哮喘。完成 这，他将通过实现拟议的特定目标并结合在一起来增强他的研究技能 专家精通，高级教学课程，临床和微生物研究中的动手经验， 以及其他重点的职业发展活动。他将与一个多学科的导师团队紧密合作 具有小儿哮喘流行病学，微生物组研究，微生物学和 免疫学以及临床试验的设计和行为。该团队在培养方面也有丰富的经验 早期调查人员的发展，除了对机构的强烈承诺外 候选人的研究职业和卓越的学术环境 - 无疑将确保他的 继续成功。