The long-term objective of the proposed program is to develop an independent career in patient-oriented clinical research. The training goal of the program is to develop the skills required to carry out translational studies, including clinical trials, and molecular epidemiological investigations into the genetic determinants of outcomes in critical illnesses. The scientific objective of the proposed award is to develop a research program in the field of genomics as applied to acute lung injury (ALI). Background: Adverse clinical outcomes in patients with ALI are associated with decreased plasma levels of protein C, and increased plasma levels of thrombomodulin, and plasminogen activator inhibitor-1 (PAI-1). Several polymorphisms in the genes that regulate coagulation and fibrinolysis are associated with variation in the plasma levels of respective proteins and disordered coagulation. New preliminary data suggest that these polymorphisms may also be associated with the development and clinical outcomes of ALI, and the response to treatment with activated protein C (ARC) in patients with sepsis. Our primary hypothesis is that polymorphisms in genes of protein C and fibrinolysis pathways are an important determinant of clinical outcomes and severity of ALI in adults and children.
In Specific Aim 1 we will test this hypothesis in 500 patients enrolled in the recently completed ARDS Network Fluid and Catheter Treatment Trial.
In Specific Aim 2 we will prospectively enroll children with ALI in order to test this hypothesis in critically ill children. We will enroll 315 patients over the next 5 years at University of California San Francisco and Children's Hospital, Oakland.
In Specific Aim 3 we will determine if these polymorphisms will predict the response to treatment with ARC in an ongoing phase II clinical trial of ARC in patients with ALI. Experimental Design: DNA samples will be analyzed using high throughput DNA sequencing technology to identify common polymorphisms in the genes of interest. Plasma samples will be used to measure the relevant plasma protein concentrations. Polymorphisms and protein concentrations will be analyzed for relationship to clinical severity and outcome utilizing the ARDS network clinical database (Aim 1) and the prospectively collected data (Aim 2 and Aim 3). Significance: The studies will capitalize on the valuable resources of the NHLBI ARDS network clinical trials to produce a comprehensive analysis of the effects of common genetic variations in genes regulating coagulation and fibrinolysis on clinical outcomes and their interaction with APC treatment in ALI. Positive findings would support roles for these genes in pathophysiology of ALI in adults and children. Public Health Relevance: This study will provide new genetic markers for risk stratification. It may also lead to development of novel targeted therapies and identify genetic markers that predict response to APC therapy in patients with ALI, which is an initial step towards tailoring therapy to the needs of the individual patient.
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