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

以患者为中心的微生物组和先进的培养方法来识别慢性儿科疾病的微生物决定因素

• 批准号: 10400043
• 负责人: Lucas R Hoffman
• 金额: $ 10.74万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-22 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400043
• 关键词: Adult; Advisory Committees; Aftercare; Antibiotic Therapy; Antibiotics; Bacteria; Basic Science; Bioinformatics; Biometry; Child; Childhood; Chronic; Chronic Disease; Clinical; Clinical Data; Clinical Microbiology; Clinical Research; Clinical Trials; Collaborations; Communicable Diseases; Complex; Core Facility; Cystic Fibrosis; Data; Discipline; Disease; Disease Outcome; Doctor of Philosophy; Environment; Exocrine pancreatic insufficiency; Exposure to; Faculty; Failure; Fatty acid glycerol esters; Fellowship; Funding; Future; Gastroenterology; Gastrointestinal Diseases; Genetic Diseases; Geography; Goals; Growth; Health; Heart; High-Throughput Nucleotide Sequencing; Infant; Infection; Inflammation; Infrastructure; Inhalation; Intestinal Obstruction; Intestines; Laboratories; Life; Link; Longevity; Longitudinal observational study; Lung diseases; Malabsorption Syndromes; Measures; Medical; Medicine; Mentors; Mentorship; Methods; Microbiology; Molecular; Morbidity - disease rate; Multi-site clinical study; Multicenter Studies; Nutrient; Nutritional; Nutritional status; Obstructive Lung Diseases; Outcome; Patients; Persons; Phenotype; Physicians; Population; Prevalence; Program Development; Proteins; Pseudomonas aeruginosa; Pulmonary Cystic Fibrosis; Pulmonology; Quality of life; Research; Research Personnel; Research Project Grants; Research Support; Resources; Respiratory System; Risk; Science; Scientist; Specimen; Sputum; Staphylococcus aureus; Staphylococcus aureus infection; Structure; Students; Testing; Therapeutic; Time; Tobramycin; Training; Translational Research; Universities; Variant; Wages; Washington; Work; aggressive therapy; base; children with cystic fibrosis; clinically significant; cohort; cystic fibrosis airway; density; doctoral student; dysbiosis; early cystic fibrosis; fecal microbiome; gastrointestinal; gut inflammation; gut microbiome; improved; infant nutrition; interest; longitudinal analysis; metabolomics; microbial; microbial community; microbiome; mortality; multidisciplinary; next generation sequencing; novel; pathogen; pathogenic bacteria; patient oriented; patient oriented research; programs; pulmonary function; pulmonary function decline; research and development; respiratory; respiratory microbiota; response; skills; student mentoring; student training; training opportunity; translational research program; translational study

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.

项目摘要/摘要 该K24的目标是为MD，博士的Lucas Hoffman提供薪水，行政和研究支持 让他至少花25％的时间指导学生，研究员和初级教师以患者为导向 关于慢性儿科疾病的微生物决定因素的研究。该建议将使霍夫曼博士能够 扩大他的翻译研究计划，将受训者整合到该计划中，并提供其他 受保护的时间和资源，用于指导现有的和其他学员，专门针对患者 研究他们从事现有的转化研究项目以及新项目的研究 正在进行的工作。该提案还提供时间和基础设施，以帮助霍夫曼博士增强他的指导 技能，包括课堂工作，与学员互动的新机会以及专门的监督委员会 专注于这个话题。这三个正在进行的特色研究项目利用了现有资源（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问题 这些和未来以患者为导向的研究的资源，为学员提供了最佳机会： 项目1研究了婴儿的胃肠道（GI）微生物与遗传的关系 疾病囊性纤维化（CF）在生命的第一年中具有生长和其他临床结果。这个项目 建立在我们的初步发现的基础上，CF患有胃肠道的幼儿会影响胃肠道 肠道健康和炎症。由于患有CF的婴儿通常无法充分生长，并且早期营养 结果与整体疾病病程相关，确定早期CF生长衰竭的机制是一种 重要而研究的话题。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婴儿营养的多中心临床研究的一部分。 项目2是对金黄色葡萄球菌变体的持续多中心研究，是最常见的细菌 病原体最常见的是Cf患者的呼吸道培养。这些变体，称为 小颜色变体（SCV），在实验室中生长缓慢，并且不会常规地检测到临床 实验室。我们的初步数据表明，SCV通常感染CF儿童，并且是 与没有SCV的儿童相比，与肺部疾病急剧恶化有关。我们正在调查 SCV感染的患病率和临床关联以及分子机制 CF的孩子这项研究还收集细菌分离株，链接的数据和其他资源，以供将来研究。 Project 3是一项对CF儿童和成人中痰微生物组的持续多中心研究， 在接受了一个月的吸入毒素治疗期间，并在接受了一个月的治疗。 CF的微生物决定因素 肺部疾病和临床反应得到了充分研究，但知之甚少。在这个项目中，我们正在使用高 基于吞吐量测序的微生物组方法，以识别抗生素反应的微生物组相关性 通过比较单个药物期间抗生素处理期间的肺功能变化与微生物组的变化。