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

摘要 这是医学副教授卡罗琳·S·卡尔菲的K24奖项的新申请 以及加州大学旧金山分校的麻醉学。卡尔菲博士是一名内科医生，专门研究 肺部和重症监护医学，坚定致力于以患者为中心的研究(POR) 并为指导下一代翻译科学家干杯。在完成奖学金后的8年里， 她制定了一个资金充足的独立研究计划，专注于提高我们对 急性呼吸窘迫综合征(ARDS)的发病机制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奖将使卡尔菲博士实现两个主要目标：(1)利用分子流行病学的工具 提高对人类ARDS发病机制的认识，重点关注ARDS的危险因素和 亚型；以及(2)在扩展的同时，进一步发展她在ARDS中指导POR学员的技能 她的时间都用在指导上了。卡尔菲博士在她的职业生涯中处于K24奖的理想阶段，因为 在POR中专门用于指导的保护时间将使她能够扩大她目前的研究计划， 扩大和保护她在指导方面的时间，并获得进一步的指导技能培训。获得一个 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 有能力在这种充满挑战的融资环境中继续指导学员。 该奖项将支持的新研究将建立在卡尔菲博士在 以发病机制为导向的ARDS分子表型研究，为有希望的 她的研究出现了新的方向，也为学员提供了丰富的机会。具体地说，这个奖项将 支持对ARDS包含两种不同亚型(也称为 42卡尔菲博士最近发现并证实存在两种不同的ARDS内型。 三个大型随机对照试验。16这些内型具有显著不同的临床特征， 生物标记物概况、临床结果和显著的内型特异性治疗反应 在之前被认为是“阴性”的临床试验中被确认。然而，因为这些内型是 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确定，它 目前尚不清楚一组扩大的临床特征和生物标志物是否会起作用 对ARDS内型鉴定有重要意义。同样，目前尚不清楚患者是否可以过渡 ARDS病程中的内型与每种内型的生物学进化之间的关系 ARDS的头几天。为该奖项提出的研究将直接解决这些差距 了解ARDS内型，从而提高我们设计个性化治疗方案的能力 ARDS危重患者的疾病生物学。

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.