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

项目总结/摘要 这个K24的目标是为Lucas霍夫曼，医学博士，博士提供工资，行政和研究支持， 允许他花至少25%的时间指导学生，研究员和初级教师以患者为导向， 研究慢性儿科疾病的微生物决定因素。这项提案将使霍夫曼博士能够 扩大他的翻译研究计划，将受训人员纳入计划，并提供额外的 保护时间和资源，以指导现有和额外的学员，特别是在以患者为导向的 研究，因为他们对现有的转化研究项目，以及新的项目，从这个出现的工作 正在进行的工作。该提案还提供了时间和基础设施，以帮助霍夫曼博士加强他的指导 技能，包括课堂作业，与受训者互动的新机会，以及专门的监督委员会 专注于这个话题。三个正在进行的特色研究项目利用现有资源（项目 1)或涉及与患者面对面的互动（项目2和3），并产生新的问题和新的 为这些研究和今后面向病人的研究提供资源，为受训者提供最佳机会： 项目1调查了婴儿胃肠道（GI）微生物组与遗传因素之间的关系。 疾病囊性纤维化（CF）与生长和其他临床结果在第一年的生活。这个项目 基于我们的初步发现，患有CF的幼儿患有GI失调，预计会影响 肠道健康和炎症。由于患有CF的婴儿通常无法充分生长， 结果与总体病程相关，确定早期CF生长失败的机制是一个重要的研究方向。 重要的和未充分研究的主题。在这项研究中，我们正在分析纵向粪便标本和临床数据 作为最近完成的CF婴儿营养多中心临床研究的一部分收集。 项目2是一项正在进行的多中心研究，研究对象是金黄色葡萄球菌（Staphylococcus aureus）的变种， 最常从CF患者的呼吸道培养的病原体。这些变体称为 小菌落变异体（SCV）在实验室中生长缓慢，临床常规检测不到 laboratories.我们的初步数据表明，SCV通常会感染CF儿童，并且它们是 与没有SCV的儿童相比，我们正在调查 SCV感染的患病率和临床关联，以及分子机制， 儿童CF这项研究还收集了细菌分离株、相关数据和其他资源，供未来研究使用。 项目3是一项正在进行的、多中心的CF儿童和成人痰液微生物组研究， 在接受长达一个月的吸入妥布霉素治疗期间和之后。CF的微生物决定因素 肺部疾病和临床反应已得到充分研究，但了解甚少。在这个项目中，我们使用高- 基于通量测序的微生物组方法，用于鉴定抗生素反应的微生物组相关性 通过比较肺功能变化与单药抗生素治疗期间微生物组的变化。

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.