Molecular Epidemiology of ARDS and Septic Shock

有了拟议的以患者为导向的研究职业发展奖，申请者打算通过研究急性呼吸窘迫综合征(ARDS)和感染性休克(SS)的遗传易感性，继续她长期以来对将基础科学和技术应用于临床问题的兴趣。在大卫·克里斯汀尼博士的赞助下，这位候选人打算实现她的目标，即成熟为一名肺部和危重护理医学领域的独立学术研究员。她的目标是：1)评估ARDS与下列候选基因多态的可能关联：TNF1/2、TNFB1/2、IL-1ra、IL-10、SP-B、PAI-1、HSP-70-2和转化生长因子-B；2)评估SS的发生与TNF1/2、TNFB1/2、IL-1ra、IL-10、PAI-1和HSP-70-2基因多态性之间的可能关联；3)评估血清细胞因子浓度变化与TNF1/2、TNFB1/2、IL-1ra、IL-10、PAI-1和TGF-β1基因多态性之间的可能关联；以及4)探索使用差异基因阵列来鉴定在ARDS和SS的发生中起重要作用的新基因。为了达到这些目标，研究设计包括两项病例对照研究，来自重症监护病房的危重患者的预期队列，这些患者有感染或其他已知的ARDS危险因素，如创伤、大量输血或吸入。一项研究将检查ARDS的遗传易感性，而另一项研究将侧重于SS的遗传易感性。上述候选多态的遗传易感性将通过DNA提取和PCR基因分型的方法来确定。对于目标3，将收集血清以测定肿瘤坏死因子-α、白介素1-α、白介素10、纤溶酶原激活物-1和转化生长因子-1。对于AIM 4，将对ARDS患者及其对照组、ARDS患者发生ARDS前后以及SS患者及其对照组进行差异基因芯片分析。与各自的对照相比，在ARDS或SS中持续上调的基因可能在上述疾病的发病机制中起重要作用。这样的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危重患者进展为ARDS或SS。确定急性损伤或感染后发生ARDS或SS的高危患者有助于确定一组可能从抗细胞因子治疗等干预措施中受益的患者。

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.