Molecular Epidemiology of ARDS and Septic Shock

随着拟议的指导患者为导向的研究职业发展奖，申请人打算继续她长期以来的兴趣，通过调查遗传易感性急性呼吸窘迫综合征（ARDS）和感染性休克（SS）的应用基础科学和技术的临床问题。在大卫Christiani博士的赞助下，候选人打算达到她的目标，成为一名独立的肺部和重症监护医学学术研究者。她的具体目标是：1）评估ARDS与TNF 1/2、TNFB 1/2、IL-1ra、IL-10、SP-B、PAI-1、HSP-70 - 2和TGF-β的以下候选遗传多态性之间的可能关联; 2)评估SS的发生与TNF 1/2、TNFB 1/2、IL-1ra、IL-10、PAI-1和HSP-70 - 2的以下多态性之间的可能关联：3）评估不同血清细胞因子浓度与TNF 1/2、TNFB 1/2、IL-1ra、IL-10、PAI-1和TGF-β 1的以下多态性之间的可能关联;和4）探索使用差异基因阵列来鉴定新的、尚未被怀疑的、在ARDS和SS的发展中重要的基因。为了实现这些目标，研究设计包括两项病例对照研究，这些研究来自一组因感染或其他已知的ARDS风险因素（如创伤、大量输血或误吸）而入住重症监护室的危重患者。一项研究将检查ARDS的遗传易感性，而另一项研究将重点关注SS的遗传易感性。将通过DNA提取和PCR基因分型方法确定对上述候选多态性的遗传易感性。对于目标3，将收集血清用于测量TNF-α、IL1-ra、IL-10、PAI-1和TGF-1。对于目标4，将对ARDS患者及其对照、ARDS发展前后的ARDS患者以及SS患者及其对照进行差异基因阵列分析。与各自的对照相比，在ARDS或SS中一致上调的基因可能在上述病症的发病机制中是重要的。这样一个项目具有重要的健康相关性，因为结果可以帮助澄清为什么只有一小部分有感染或其他危险因素的重症患者进展为ARDS或SS。识别急性损伤或感染后发生ARDS或SS的高风险患者可以帮助确定一组可能受益于抗细胞因子治疗等干预措施的患者。

With the proposed Mentored Patient Oriented Research Career Development award, the applicant intends to continue her long standing interest in applying basic science and technology to clinical problems by investigating genetic susceptibility to acute respiratory distress syndrome (ARDS) and septic shock (SS). Under the sponsorship of Dr. David Christiani, the candidate intends to reach her Objective of maturing into an independent academic investigator in pulmonary and critical care medicine. Specifically she aims: 1) To assess for a possible association between ARDS and the following candidate genetic polymorphisms in TNF1/2, TNFB1/2, IL-1ra, IL-10, SP-B, PAI-1, HSP-70-2, and TGF-B;. 2) To assess for a possible association between the development of SS and the following polymorphisms in TNF1/2, TNFB1/2, IL-1ra, IL-10, PAI-1, and HSP-70-2; 3) To assess for a possible association between varying serum cytokine concentration and the following polymorphisms in TNF1/2, TNFB1/2, IL-1ra, IL-10, PAI-1, and TGF-B1; and 4) To explore the use of differential gene arrays to identify novel, as yet unsuspected, genes important in the development of ARDS and SS. To address these aims, the research design consists of two case control studies derived from a prospective cohort of critically ill patients admitted to the intensive care units with infections or other known risk factors for ARDS such as trauma, massive transfusions, or aspiration. One study will examine genetic susceptibility to ARDS while the other will focus on genetic susceptibility to SS. Genetic susceptibility to the above candidate polymorphisms will be determined through the methods of DNA extraction and PCR genotyping. For Aim 3, serum will be collected for the measurement of TNF-alpha, IL1-ra, IL-10, PAI-1 and TGF-1. For Aim 4, differential gene array analysis will be performed for ARDS patients and their controls, for ARDS patients before and after the development of ARDS and for patients with SS and their controls. Genes that are consistently up regulated in ARDS or in SS compared with their respective controls are likely to be important in the pathogenesis of the above conditions. Such a project has important health relatedness in that the results can help clarify why only a fraction of critically ill patients with infections or other risk factors progress to ARDS or SS. The identification of patients with a high risk of developing ARDS or SS after an acute injury or infection can help define a group of patients that may benefit from interventions such as anti-cytokine therapy.