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.

项目概要/摘要 K24 的目标是为医学博士、哲学博士卢卡斯·霍夫曼 (Lucas Hoffman) 提供薪资、行政和研究支持，以 让他花至少 25% 的时间指导学生、研究员和初级教师以患者为导向 慢性儿科疾病的微生物决定因素的研究。该提案将使霍夫曼博士能够 扩大他的转化研究计划，将受训者纳入该计划，并提供额外的 受保护的时间和资源，用于指导现有的和额外的学员，特别是在以患者为中心的方面 研究，因为他们致力于现有的转化研究项目以及由此产生的新项目 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 专注于这个话题。这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内容 这些和未来以患者为导向的研究的资源，为学员提供最佳机会： 项目 1 研究婴儿胃肠道 (GI) 微生物群与遗传基因之间的关系 疾病囊性纤维化（CF）在生命第一年伴随生长和其他临床结果。这个项目 基于我们的初步发现，患有 CF 的幼儿患有胃肠道失调，预计会影响 肠道健康和炎症。由于患有 CF 的婴儿通常无法充分生长，因此早期营养 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任务 重要且未被充分研究的主题。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 是一项针对最常见细菌金黄色葡萄球菌变种的持续多中心研究 最常从 CF 患者呼吸道中培养出来的病原体。这些变体被称​​为 小集落变异 (SCV) 在实验室中生长缓慢，临床通常无法检测到 实验室。我们的初步数据表明，SCV 通常会感染患有 CF 的儿童，并且它们是 与没有 SCV 的儿童相比，肺部疾病严重得多。我们正在调查 一组人群中 SCV 感染的患病率和临床关联以及分子机制 患有 CF 的儿童。这项研究还收集细菌分离株、关联数据和其他资源以供未来研究使用。 项目 3 是一项正在进行的多中心研究，研究之前患有 CF 的儿童和成人的痰微生物组， 在接受为期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组的变化。