The Role of the Microbiome in the Acute Respiratory Distress Syndrome

 描述(由申请人提供)：这份K23计划将完成罗伯特·迪克森医学博士的培训，以实现他的长期职业目标，即通过调查微生物群来提高我们对肺部疾病的理解和治疗。迪克森博士是密歇根大学的肺部和重症监护内科医生和科学家，在新兴的肺部微生物组研究领域取得了公认的成功。这项建议建立在迪克森博士之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的基础上，并在临床研究方法和计算生物学方面进行了新的培训。这些已建立的和新获得的技能将被整合起来，以提高我们对微生物群在急性呼吸窘迫综合征(ARDS)发病机制中的作用的理解。这项研究将在主要导师Gary B.Huffnagle PhD、共同导师Theodore J.Standiford MD和一个由具有临床研究方法、计算生物学和肺部免疫学专业知识并取得广泛指导成功的杰出研究人员组成的顾问委员会的指导下进行。这一5年计划包括正规课程、专业发展和逐步独立的研究，并制定了明确的里程碑，以确保生产率和成功过渡到独立。急性呼吸窘迫综合征(ARDS)是导致发病率、死亡率和费用的主要原因，据估计，美国每年有74,500人死于ARDS。许多研究已经确定了细菌从胃肠道转移到肺部的间接证据，但到目前为止还没有研究对有ARDS风险的患者进行评估。 微生物组在ARDS发病机制中的作用这项提议将检验肠道细菌移位到肺通过两个特定的科学目标引发ARDS的炎症和损伤的假设。目的1将确定肠道细菌移位到肺微生物组是否先于ARDS的临床发展，目的2将确定呼吸失调、宿主炎症和ARDS临床发病之间的时间关系。为了完成这些高水平的目标，迪克森博士将对ARDS高危患者进行前瞻性队列研究，利用现代独立于培养的细菌鉴定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。这项工作将至少建立在两个R01建议的基础上：1)确定肺微生物组是否有助于已确定的ARDS患者的疾病进展，以及2)确定是否可以在危重患者中对肺微生物组进行治疗操作，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程序性研究路线奠定基础外，这项提案还将为Dickson博士提供适用于人类微生物组和ARDS研究的其他领域的研究技能。这项K23奖项将使迪克森博士成为这一前景广阔的领域的独立调查员和国际领导者。

 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.