Patient-Oriented Research in Acute Lung Injury and Host Defense in the ICU

摘要：这一新申请职业生涯中期研究人员奖的总体目标是以患者为本 研究是为了使Lee博士能够在以患者为导向的急性呼吸道疾病研究中建立研究和指导计划 肺损伤和宿主防御。ICU中的急性下呼吸道牵引性感染(LRTI)仍然是一个巨大的 美国和世界各地的医疗负担。下呼吸道感染仍然是脓毒症的主要原因和急性肺的危险因素 受伤。细菌性下呼吸道感染也是急性肺损伤的常见并发症，增加了患者的发病率、长度 住院费用和医疗保健费用。李博士是一位致力于拓宽分子理解的内科科学家。 通过探测宿主-病原体的相互作用阐明生物学对急性肺损伤等危重病综合征的影响 使个体容易受到病原体诱导的伤害的宿主因素。这项裁决将为 致力于教学、培训和指导受训人员，包括初级教员、研究员、住院医生和医务人员 转化性研究的学生，关注危重病人出现的问题。具体地说，指导将 支持对常见革兰氏阴性菌急性下呼吸道感染的新研究 重症监护室里的病原体。主要的假设是宿主-病原体的不同分子决定因素相互作用 在替补席上确定的提供了对宿主防御机制的损害的独特见解，这些机制与 ICU中的不良临床结局。提出了两个目标，以利用 翻译研究中的调查员。目标1将评估使患者容易接触组织的微生物因素 革兰氏阴性杆菌呼吸道铜绿假单胞菌引起的炎症和损伤 重症监护室中的分离物。我们将测试在实验台上确定的分子通路，以探索 病原体蛋白水解酶对患者预后的作用，例如下呼吸道的微生物持久性， 无呼吸机天数、住院时间和死亡率。目标2将评估宿主体液免疫的损害 在危重疾病期间并检查与患者预后的关系，包括多器官功能障碍， 死亡率、多药耐药ICU感染的获得性和包埋革兰阴性菌的血清杀伤率 病原体肺炎克雷伯氏菌。这一K24奖项将使李博士实现两个主要目标：(1)建立联系 基础生物学与医学在ICU设置中的相互作用及改进 了解严重疾病综合症，例如急性呼吸窘迫综合症；及(2)进一步发展辅导技巧 以患者为中心的分子危重护理研究的实习生，同时增加了她用于指导的时间。 这一奖项的成功执行将提高K24调查员的生产率并增加 训练有素的临床医生研究人员，他们有能力将基础生物学转换到床边 再回来。

Abstract: The overall goal of this new application for a Midcareer Investigator Award in Patient-Oriented Research is to enable Dr. Lee to build a research and mentoring program in patient-oriented research in acute lung injury and host defense. Acute lower respiratory traction infections (LRTI) in the ICU remains an enormous healthcare burden in the US and worldwide. LRTI remains a major cause of sepsis and risk factor for acute lung injury. Bacterial LRTI is also a frequent complication of acute lung injury that increases patient morbidity, length of stay and health-care costs. Dr. Lee is a physician scientist focused on broadening molecular understanding of critical illness syndromes such as acute lung injury by probing host-pathogen interplay to elucidate the biology of host factors that predispose individuals to pathogen-induced injury. This award will allow protected time for dedicated teaching, training, and mentoring of trainees that include junior faculty, fellows, residents, and medical students in translational research focusing on problems arising in critically ill patients. Specifically, mentoring will support novel investigations into acute lower respiratory tract infections from common Gram-negative bacterial pathogens in the ICU. The major hypothesis is that distinct molecular determinants of host-pathogen interplay identified at the bench provide unique insights into impairments of host defense mechanisms that associate with adverse clinical outcomes in the ICU. Two aims are proposed that leverage the unique capabilities of the investigator in translational research. Aim 1 will evaluate microbial factors that predispose patients to tissue inflammation and injury instigated by the Gram-negative pathogen Pseudomonas aeruginosa (PA) respiratory isolates in the ICU. We will test molecular pathways identified at the bench to explore the relationship between pathogen protease function to patient outcomes such as microbial persistence in the lower respiratory tract, ventilator-free days, length of stay and mortality. Aim 2 will evaluate impairments in host humoral immunity during critical illness and examine the relationship to patient outcomes including multiple organ dysfunction, mortality, acquisition of multi-drug resistant ICU infections, and serum killing of encapsulated Gram-negative pathogen Klebsiella pneumoniae. This K24 award will allow Dr. Lee to achieve two principal goals: (1) forge links between basic biology and medicine by probing host-pathogen interplay in the ICU setting and improve understanding of critical illness syndromes such as ARDS; and (2) to further develop her skills in mentoring trainees in patient-oriented research in molecular critical care while expanding her time devoted to mentoring. The successful execution of this award will enhance the productivity of both the K24 investigator and increase the pool of well-trained clinician investigators who are equipped to translate fundamental biology to the bedside and back.