ARDS Endotypes: Expanded Analysis of Clinical and Biological Phenotypes and Evolution Over Time

摘要 这是一个新的申请K24奖卡罗琳S。Calfee，MD，医学副教授 在加州大学旧金山弗朗西斯科从事麻醉学研究。Calfee医生是一名医生， 肺和重症监护医学谁是坚定地致力于以病人为导向的研究（POR）的职业生涯 并指导下一代的转化科学家。在她完成奖学金后的8年里， 她开发了一个资金充足的独立研究项目，专注于提高我们对 急性呼吸窘迫综合征（ARDS）是呼吸衰竭的常见原因， 仅在美国每年就有近20万例危重患者，死亡率为30 - 40%。这 K24奖将使Calfee博士实现两个主要目标：（1）使用分子流行病学工具， 提高我们对人类ARDS发病机制的理解，重点关注ARDS危险因素， 亚表型;（2）进一步发展她在ARDS中指导POR学员的技能，同时扩大 她把时间都花在了指导上Calfee博士正处于职业生涯中获得K24奖项的理想阶段，因为她提供了 在POR进行指导的专用受保护时间将使她能够扩展目前的研究计划， 扩大和保护她专门用于辅导的时间，并获得辅导技能方面的进一步培训。获得 在这个关键的职业生涯中期阶段，K24奖项对于支持Calfee博士在POR的职业生涯并保护她至关重要 在这种充满挑战的融资环境中继续指导学员的能力。 新的研究将由该奖项支持将建立在博士Calfee的广泛的跟踪记录， 以发病机制为导向的ARDS分子表型研究，为有前途的 她的研究新方向以及丰富的培训机会。具体而言，该奖项将 支持ARDS包含两种不同的亚表型（也称为 42 Calfee博士最近鉴定并证实了ARDS的两种不同的内型， 三项大型随机对照试验。16这些内型具有显著不同的临床特征， 生物标志物谱、临床结局和显著的内型特异性治疗反应， 在以前被认为是"阴性"的临床试验中被确定。然而，由于这些内型是 在随机对照试验的背景下，使用一组狭窄的临床和生物学数据， 目前尚不清楚扩大的一组临床特征和生物标志物是否有助于 对ARDS内型鉴定有重要意义。同样，患者是否能够过渡到 在他们的疾病过程中，ARDS内型之间的关系，以及每种内型的生物学如何演变， ARDS的最初几天。为该奖项提出的研究将直接解决这些差距， 了解ARDS内型，以提高我们设计针对患者的个性化治疗的能力。 ARDS重症患者的疾病生物学。

ABSTRACT This is a new application for a K24 award for Carolyn S. Calfee, MD, Associate Professor of Medicine and Anesthesia at the University of California, San Francisco. Dr. Calfee is a physician specializing in pulmonary and critical care medicine who is strongly committed to a career in patient-oriented research (POR) and to mentoring the next generation of translational scientists. In the 8 years since completing her fellowship, she has developed a well-funded independent research program focused on improving our understanding of the pathogenesis of the acute respiratory distress syndrome (ARDS), a common cause of respiratory failure in critically ill patients with nearly 200,000 cases per year in the US alone and mortality rates of 30-40%. This K24 award will allow Dr. Calfee to achieve two principal goals: (1) to use the tools of molecular epidemiology to improve our understanding of the pathogenesis of human ARDS, with a focus on ARDS risk factors and subphenotypes; and (2) to further develop her skills in mentoring trainees in POR in ARDS while expanding her time devoted to mentoring. Dr. Calfee is at an ideal stage in her career for a K24 award, since providing dedicated protected time for mentoring in POR would allow her to expand her current research program, expand and protect her time dedicated to mentoring, and obtain further training in mentoring skills. Obtaining a K24 award at this critical mid-career stage is vital to supporting Dr. Calfee's career in POR and protecting her ability to continue mentoring trainees in this challenging funding climate. New research to be supported by this award will build on Dr. Calfee's extensive track record in pathogenesis-oriented studies of molecular phenotypes of ARDS, providing tangible support for a promising new direction in her research as well as a wealth of opportunities for trainees. Specifically, this award will support investigation of the novel hypothesis that ARDS contains two distinct subphenotypes (also known as “endotypes”).42 Dr. Calfee recently identified and validated the presence of two distinct endotypes of ARDS in three large randomized controlled trials.16 These endotypes had strikingly different clinical characteristics, biomarker profiles, and clinical outcomes, and significant endotype-specific treatment responses were identified within a clinical trial previously thought to be “negative.” However, because these endotypes were identified in the setting of randomized controlled trials, using a narrow set of clinical and biological data, it remains unknown whether an expanded set of clinical characteristics and biomarkers would contribute significantly to ARDS endotype identification. Likewise, it remains unknown whether patients can transition between ARDS endotypes over the course of their illness and how the biology of each endotype evolves over the first several days of ARDS. The research proposed for this award will directly address these gaps in knowledge about ARDS endotypes, so as to improve our ability to design personalized therapies tailored to the biology of disease for critically ill patients with ARDS.