Impact of Cigarette Smoke Exposure on Acute Lung Injury

描述（由申请人提供）：这是一份K23奖的申请，申请对象是加州大学旧金山分校肺/重症医学高级博士后Carolyn Calfee。Calfee博士在急性肺损伤（ALI）的发病机制导向临床研究中开始了她的职业生涯。K23奖将使Calfee博士能够实现以下几个目标：(1)发展进行ALI前瞻性临床研究的专业知识；（二）接受环境医学和遗传流行病学方面的额外培训；(3)将先进的生物统计学方法应用于临床和生物学数据，以深入了解疾病的发病机制；(4)向独立调查员身份过渡。为了实现这些目标，Calfee博士组建了一个指导团队，其中包括她的赞助人和主要导师Michael Matthay博士（国际公认的ALI转化研究专家），以及两位重要的科学顾问Neal Benowitz博士（吸烟相关生物标志物专家）和Mark Eisner博士（ALI和二手烟流行病学研究专家）。香烟烟雾暴露（CSE）对ALI易感性的影响尚未在前瞻性、严格的临床研究中进行评估。Calfee博士的初步数据表明，CSE可能是发生ALI的主要危险因素。Calfee博士将首先在350名ALI高风险的重大创伤患者中测试主动和被动CSE增加ALI易感性的假设（目的1）。然后，她将利用正在进行的队列研究的资源，在更广泛的患者群体中验证这一假设，对ALI患者和年龄匹配的危重患者进行病例对照研究（目标2）。将测量CSE的新生物标志物，以比较病例和对照组的短期和长期暴露，控制重要的混杂因素。然后，Calfee博士将通过研究纳入病例对照研究的患者的内皮损伤、肺上皮损伤和凝血障碍的关键生物标志物来研究CSE和ALI之间的机制关系（目的3）。这些研究将为Calfee博士提供所需的数据，以准备R01申请，重点关注CSE和ALI结果之间的关系，包括基因-环境相互作用的作用。公共卫生相关性：急性呼吸衰竭仍然是危重患者急性呼吸衰竭的常见和经常致命的原因，没有具体的预防策略或治疗方法。因此，研究CSE在ALI发展中的作用可能有助于开发新的治疗方法，并将为消除主动和被动CSE的措施提供进一步的理论依据和支持。（摘要结束）

DESCRIPTION (provided by applicant): This is an application for a K23 award for Carolyn Calfee, M.D., a senior postdoctoral fellow in pulmonary/critical care medicine at the University of California San Francisco. Dr. Calfee is beginning her career as a young investigator in pathogenesis-oriented clinical research in acute lung injury (ALI). This K23 award will allow Dr. Calfee to achieve several goals: (1) to develop expertise in the conduct of prospective clinical studies in ALI; (2) to obtain additional training in environmental medicine and genetic epidemiology; (3) to apply advanced biostatistical methodology to clinical and biological data in order to obtain insight into disease pathogenesis; and (4) to transition to independent investigator status. To achieve these goals, Dr. Calfee has assembled a mentoring team that includes her sponsor and primary mentor, Dr. Michael Matthay, an internationally recognized expert in translational research on ALI, and two key scientific advisors, Dr. Neal Benowitz, an expert in smoking-related biomarkers, and Dr. Mark Eisner, an expert in epidemiologic studies of both ALI and secondhand smoking. The contribution of cigarette smoke exposure (CSE) to ALI susceptibility has not been evaluated in prospective, rigorous clinical studies. Dr. Calfee's preliminary data indicate that CSE may be a major risk factor for developing ALI. Dr. Calfee will first test the hypothesis that active and passive CSE increase susceptibility to ALI in an ongoing cohort of 350 major trauma patients at high risk for ALI (Aim 1). She will then test this hypothesis in a broader group of patients by using the resources of ongoing cohort studies to perform a case-control study of patients with ALI and age-matched, critically ill controls (Aim 2). Novel biomarkers of CSE will be measured to compare short and long-term exposure in cases and controls, controlling for important confounders. Dr. Calfee will then investigate the mechanistic relationship between CSE and ALI by studying key biomarkers of endothelial injury, lung epithelial injury, and disordered coagulation in patients enrolled in the case-control study (Aim 3). These studies will provide Dr. Calfee with the data needed to prepare an R01 application focused on the relationship between CSE and ALI outcomes, including the role of gene-environment interactions. Public Health Relevance: ALI remains a common and frequently fatal cause of acute respiratory failure in critically ill patients, with no specific preventative strategies or therapies available. Therefore, studying the role of CSE in the development of ALI may help develop new therapies and will provide further rationale and support for measures to eliminate active and passive CSE. (End of Abstract)