The Role of the Microbiome in the Acute Respiratory Distress Syndrome

 描述（由申请人提供）：本K23提案将完成医学博士Robert Dickson的培训，以实现他的长期职业目标，即通过调查微生物组来提高我们对肺部疾病的理解和治疗。Dickson博士是密歇根大学的肺部和重症监护医生和科学家，在肺部微生物组研究的新兴领域取得了成功。该提案建立在Dickson博士先前在肺部病理生理学和微生物生态学方面获得的专业知识基础上，并在临床研究方法和计算生物学方面进行了新的培训。这些已建立和新获得的技能将被整合，以提高我们对微生物组在急性呼吸窘迫综合征（ARDS）发病机制中的作用的理解。本研究将在主要导师加里B的指导下进行。Huffnagle博士，共同导师西奥多J. Standiford医学博士和一个顾问委员会的成就调查人员与专业知识，在临床研究方法，计算生物学和肺免疫学以及广泛的指导成功。这个5年计划包括正式的课程，专业发展和逐步独立的研究，具有明确的里程碑，以确保生产力和成功过渡到独立。急性呼吸窘迫综合征（ARDS）是发病率、死亡率和费用的主要原因，估计每年造成74，500名美国人死亡。许多研究已经发现了细菌从胃肠道转移到肺的间接证据，但迄今为止还没有研究评估细菌从胃肠道转移到肺的可能性。 微生物组在ARDS发病机制中的作用。本提案将通过两个特定的科学目的来检验肠道细菌移位至肺部引起ARDS炎症和损伤的假设。目的1将确定肠细菌移位到肺微生物组是否先于ARDS的临床发展，目的2将确定呼吸生态失调、宿主炎症和ARDS临床发作之间的时间关系。为了实现这些高水平的目标，Dickson博士将对ARDS高危患者进行前瞻性队列研究，利用现代细菌鉴定的非培养技术来描述高危患者肺部和胃肠道中的细菌群落，并将先进的计算建模新技术应用于ARDS发病机制的复杂非线性系统。这项工作将建立在至少两个R01提案的基础上：1）确定肺部微生物组是否有助于患有ARDS的患者的疾病进展，2）确定是否可以在危重患者中对肺部微生物组进行治疗性操作，以预防或调节呼吸系统疾病。除了为了解微生物组在肺部疾病中的作用的计划性研究奠定基础外，该提案还将为Dickson博士提供适用于人类微生物组和ARDS研究其他领域的研究技能。这个K23奖项将使Dickson博士成为这个充满希望的领域的独立研究者和国际领导者。

 DESCRIPTION (provided by applicant): This K23 proposal will complete Robert Dickson, MD's training towards his long-term career goal of improving our understanding and treatment of lung disease by investigation of the microbiome. Dr. Dickson is a Pulmonary and Critical Care physician and scientist at the University of Michigan with established success in the burgeoning field of lung microbiome studies. This proposal builds on Dr. Dickson's previously acquired expertise in pulmonary pathophysiology and microbial ecology with new training in clinical research methods and computational biology. These established and newly-acquired skills will be integrated to improve our understanding of the role of the microbiome in the pathogenesis of the Acute Respiratory Distress Syndrome (ARDS). This research will be conducted under the guidance of primary mentor Gary B. Huffnagle PhD, co- mentor Theodore J. Standiford MD and an advisory board of accomplished investigators with expertise in clinical research methods, computational biology and lung immunology as well as extensive mentoring success. This 5-year plan includes formal coursework, professional development, and progressively independent research, with defined milestones to ensure productivity and a successful transition to independence. The Acute Respiratory Distress Syndrome (ARDS) is a major cause of morbidity, mortality and expense, responsible for an estimated 74,500 U.S. deaths per year. Numerous studies have identified indirect evidence of translocation of bacteria from the gastrointestinal tract to the lung in patients at risk for ARDS, but to date no study has evaluated the role of microbiome in the pathogenesis of ARDS. This proposal will test the hypothesis that translocation of gut bacteria to the lung provokes the inflammation and injury of ARDS via two specific Scientific Aims. Aim 1 will determine if translocation of enteric bacteria to the lung microbiome precedes the clinical development of ARDS, and Aim 2 will determine the temporal relationship between respiratory dysbiosis, host inflammation and the clinical onset of ARDS. Inherent to completing these high-level aims, Dr. Dickson will execute a prospective cohort study of patients at high risk for ARDS, utilize modern culture-independent techniques of bacterial identification to describe the bacterial communities in the lungs and gastrointestinal tracts of high-risk patients, and apply novel techniques of advanced computational modeling to the complex nonlinear system of ARDS pathogenesis. This work will build to at least two R01 proposals: 1) to determine if the lung microbiome contributes to disease progression among patients with established ARDS and 2) to determine if the lung microbiome can be therapeutically manipulated in critically ill patients to prevent or modulate respiratory disease. n addition to building a foundation for a programmatic line of research to understand the role of the microbiome in lung disease, this proposal will provide Dr. Dickson with research skills applicable to additional domains of human microbiome and ARDS research. This K23 award will equip Dr. Dickson to establish himself as an independent investigator and international leader in this promising field.