Microbiome-based diagnosis of pneumonia in the acute respiratory distress syndrome

项目摘要 本申请表是关于以病人为导向的研究事业发展奖的申请书，名为 “基于微生物组的急性呼吸窘迫综合征肺炎诊断”。我是一个 匹兹堡大学的肺部和重症监护医学研究员，我需要额外的培训来 培养作为危重疾病微生物组转译研究人员的专业知识。我的中心目标是 研究是利用新兴的微生物DNA测序技术来更快、更准确地诊断 危重病人的肺炎。我的研究重点是急性呼吸窘迫综合征 (ARDS)，一种严重的炎症性肺损伤，通常由肺炎引起，占10% 美国重症监护病房入院患者死亡率为40%。在当前标准的诊断限制下- 在微生物培养的护理下，患者经常接受经验性的广谱抗生素，这些抗生素可以 不适合或不适合他们的个人需求，还会促进抗生素耐药性-主要公众 对健康的威胁。我的初步数据证明了微生物测序的可行性和概念验证 与直接从患者样本中提取DNA相比，直接从患者样本中提取DNA可以更快、更准确地诊断肺炎 文化。这项研究的目的是开发基于序列的肺炎定义，在(1)培养- 通过整合微生物组和宿主反应数据，阳性和(2)培养阴性患者，然后3)到 评估测序对抗生素选择的预期影响。我将进行一项前瞻性队列研究 ARDS患者，并使用现代培养独立的测序技术和计算生物学 方法研究肺部微生物群与宿主反应和微生物培养的关系。建议数 基于测序的方法有可能提高肺炎诊断的准确性(捕获两者 可培养的和不可培养的生物体)，并向临床医生提供信息的速度比培养快得多。 因此，我的建议解决了发展创新的感染诊断方法的高度优先问题 改善抗生素的使用，并提供独特的翻译培训机会。我提议进行一项研究- 职业生涯发展的强化阶段，包括实践和高级顺序教学培训 技术、生物信息学、计算生物学和临床试验设计与实施。这项工作将是 在匹兹堡大学肺、过敏和重症监护医学部内进行， 它在培训内科科学家方面有着出色的记录，并且拥有高度发达的基础设施 进行翻译研究。我得到了Converent公司坚定的指导伙伴关系的支持 在微生物组和重症护理研究方面的专业知识，以及一个多元化的指导咨询委员会。有了支持 从K23导师职业发展奖，我将制定一个独立的项目审查 未来五年R01提案的基于测序的肺炎诊断。

PROJECT ABSTRACT This application is for a Mentored Patient-Oriented Research Career Development Award entitled “Microbiome-based diagnosis of pneumonia in the acute respiratory distress syndrome”. I am a Pulmonary and Critical Care Medicine Fellow at the University of Pittsburgh and I require additional training to develop expertise as a translational researcher in the microbiome of critical illness. The central objective of my research is to utilize emerging microbial DNA sequencing techniques for faster and more accurate diagnosis of pneumonia in critically-ill patients. The focus of my research is the acute respiratory distress syndrome (ARDS), a serious form of inflammatory lung injury often caused by pneumonia and accounting for 10% of intensive care unit admissions in the US with 40% mortality. With diagnostic limitations of the current standard- of-care of microbial cultures, patients often receive empiric, broad-spectrum antibiotics that can be inappropriate or inadequate for their individual needs, and also promote antibiotic resistance – a major public health threat. My preliminary data demonstrate feasibility and proof-of-concept that sequencing of microbial DNA directly from patient samples can lead to faster and more accurate diagnosis of pneumonia compared to cultures. The aims of the study are to develop sequencing-based definitions for pneumonia in (1) culture- positive and (2) culture-negative patients by integrating microbiome and host response data, and then 3) to assess the anticipated impact of sequencing on antibiotic selection. I will execute a prospective cohort study in patients with ARDS and use modern culture-independent sequencing techniques and computational biology methods to study the lung microbiome in relation to host-responses and microbiologic cultures. The proposed sequencing-based approach has the potential to improve accuracy of pneumonia diagnosis (capturing both cultivable and non-cultivable organisms) and to provide information to clinicians much faster than cultures. Thus, my proposal addresses a high priority issue for development of innovative diagnostics of infections to improve antibiotic usage and provides a unique translational training opportunity. I propose a research- intensive period of career development with hands-on and didactic training in advanced sequencing techniques, bioinformatics, computational biology and clinical trial design and implementation. The work will be conducted within the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Pittsburgh, which has an outstanding record of training physician-scientists and a highly-developed infrastructure for the conduct of translational studies. I am supported by a committed mentoring partnership with convergent expertise in microbiome and critical care research, and a diverse Mentoring Advisory Committee. With support from the K23 Mentored Career Development Award, I will develop an independent project examining sequencing-based pneumonia diagnostics for an R01 proposal over the next five years.