Molecular Epidemiology of ARDS and Septic Shock

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.