Molecular Epidemiology of ARDS and Septic Shock

申请人拟获“以病人为导向的研究事业发展奖”，继续研究急性呼吸窘迫症候群（ARDS）及感染性休克（SS）的遗传易感性，并将基础科学技术应用于临床问题。在Dr. David Christiani的赞助下，候选人打算实现她的目标，成为一名独立的肺和重症医学学术研究者。具体而言，她的目标是：1)评估ARDS与以下候选遗传多态性TNF1/2、TNFB1/2、IL-1ra、IL-10、SP-B、PAI-1、HSP-70-2和TGF-B之间的可能关联；2)评估SS的发生与以下TNF1/2、TNFB1/2、IL-1ra、IL-10、PAI-1和HSP-70-2多态性之间的可能关联；3)评估不同血清细胞因子浓度与以下TNF1/2、TNFB1/2、IL-1ra、IL-10、PAI-1和TGF-B1多态性之间的可能关联；4)探索差异基因阵列的使用，以识别在ARDS和SS发展中尚未被怀疑的重要基因。为了实现这些目标，研究设计包括两个病例对照研究，这些研究来自于重症监护病房的危重患者，这些患者患有感染或其他已知的ARDS危险因素，如创伤、大量输血或误吸。一项研究将检测ARDS的遗传易感性，另一项研究将关注SS的遗传易感性。对上述候选多态性的遗传易感性将通过DNA提取和PCR基因分型方法确定。对于Aim 3，将收集血清用于测量tnf - α， il -1 -ra, IL-10， PAI-1和TGF-1。在Aim 4中，将对ARDS患者及其对照、ARDS发生前后的患者、SS患者及其对照进行差异基因阵列分析。与相应的对照相比，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，因为结果可以帮助阐明为什么只有一小部分感染或其他危险因素的危重患者进展为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可能从抗细胞因子治疗等干预措施中受益的患者群体。

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.