Patient-oriented microbiome and advanced culture approaches to identifying the microbial determinants of chronic pediatric disease

项目摘要/摘要 K24的目标是为Lucas Hoffman，医学博士，博士提供工资，行政和研究支持，以 允许他将至少25%的时间用于指导学生、研究员和初级教员以病人为导向 慢性儿科疾病的微生物决定因素研究。这项提议将使霍夫曼博士能够 扩大他的翻译研究计划，将受训人员纳入该计划，并提供其他 受保护的时间和资源，用于指导现有的和更多的受训人员，特别是在以患者为导向方面 他们致力于现有的翻译研究项目以及由此产生的新项目时进行研究 正在进行的工作。该提案还提供了时间和基础设施来帮助霍夫曼博士加强他的指导 技能，包括课堂作业、与学员互动的新机会，以及专门的监督委员会 聚焦于这一主题。三个正在进行的特色研究项目利用现有资源(项目 1)或涉及与患者的面对面互动(项目2和3)，并产生新的问题和新的 为这些和未来以患者为中心的研究提供资源，为受训人员提供最佳机会： 项目1调查婴儿胃肠道(GI)微生物群与遗传病的关系 疾病囊性纤维化(CF)与生长和其他临床结果在生命的第一年。这个项目 基于我们的初步发现，患有CF的儿童患有胃肠道失调，预计会影响 肠道健康和炎症。由于患有CF的婴儿往往不能充分发育，早期营养不良 结果与整个病程相关，确定早期CF生长障碍的机制是一种 这是一个重要而未被研究的话题。在这项研究中，我们分析了纵向粪便样本和临床数据。 收集的数据是最近完成的一项多中心儿童营养临床研究的一部分。 项目2正在进行一项对金黄色葡萄球菌变种的多中心研究，金黄色葡萄球菌是最常见的细菌 病原体最常见的培养自CF患者的呼吸道。这些变体被称为 小菌落变种(SCV)在实验室中生长缓慢，临床上不会常规检测到 实验室。我们的初步数据表明，SCV通常会感染儿童CFV，而且它们是 与没有SCV的儿童相比，肺部疾病严重得多。我们正在调查 SCV感染的患病率、临床相关性和分子机制 患有CF型肺炎的儿童。这项研究还收集了细菌分离株、相关数据和其他资源，用于未来的研究。 项目3是一项正在进行的、多中心的关于儿童和成人的痰微生物群的研究， 在接受为期一个月的妥布霉素吸入治疗期间和之后。碳纤维的微生物决定因素 肺部疾病和临床反应研究得很好，但了解得很少。在这个项目中，我们使用高- 基于吞吐量测序的微生物组方法识别与抗生素反应相关的微生物组 通过比较单一药物抗生素治疗期间肺功能的变化与微生物群的变化。

PROJECT SUMMARY/ABSTRACT The goal of this K24 is to provide salary, administrative, and research support for Lucas Hoffman, MD, PhD, to allow him to spend at least 25% of his time mentoring students, fellows, and junior faculty in patient-oriented research on the microbial determinants of chronic, pediatric diseases. This proposal will enable Dr. Hoffman to expand his translational research program, integrate trainees into the program, and provide additional protected time and resources for mentoring existing and additional trainees specifically in patient-oriented research as they work on existing translational research projects as well as new projects to emerge from this ongoing work. The proposal also provides time and infrastructure to help Dr. Hoffman enhance his mentoring skills, including classwork, new opportunities to interact with trainees, and an oversight committee specifically focused on this topic. The three ongoing, featured research projects leverage either existing resources (Project 1) or involve face-to-face interactions with patients (Projects 2 and 3) and are yielding novel questions and new resources for these and future patient-oriented studies, providing optimal opportunities for trainees: Project 1 investigates the relationship between gastrointestinal (GI) microbiomes of infants with the genetic disease cystic fibrosis (CF) with growth and other clinical outcomes during the first year of life. This project builds on our preliminary finding that young children with CF have GI dysbioses that are predicted to impact intestinal health and inflammation. As infants with CF often fail to grow adequately, and early nutritional outcomes correlate with overall disease course, identifying the mechanisms of early CF growth failure is an important and understudied topic. In this study, we are analyzing longitudinal fecal specimens and clinical data collected as part of a recently completed, multicenter clinical study of CF infant nutrition. Project 2 is an ongoing, multicenter study of variants of Staphylococcus aureus, the most common bacterial pathogen most commonly cultured from the respiratory tracts of people with CF. These variants, known as small-colony variants (SCVs), grow slowly in the laboratory and are not routinely detected by clinical laboratories. Our preliminary data indicate that SCVs commonly infect children with CF, and that they are associated with dramatically worse lung disease compared with children without SCVs. We are investigating the prevalence and clinical associations, as well as molecular mechanisms, of SCV infection in a cohort of children with CF. This study also collects bacterial isolates, linked data, and other resources for future studies. Project 3 is an ongoing, multicenter study of sputum microbiomes among children and adults with CF before, during, and after receiving a month-long treatment with inhaled tobramycin. The microbial determinants of CF lung disease and clinical responses are well-studied yet poorly understood. In this project, we are using high- throughput sequencing-based microbiome methods to identify the microbiome correlates of antibiotic response by comparing lung function changes with microbiome changes during antibiotic treatment with a single agent.