The over-arching goal of this career development award proposal is to equip the applicant with sufficient resources, training, and time to transition into an independent clinical and translational investigator in critical illness with a specific focus on the acute respiratory distress syndrome (ARDS). ARDS is a devastating complication of a broad range of common serious medical conditions, including sepsis and trauma, which results in respiratory failure. Despite advances in the care of this common syndrome, its mortality rate remains unacceptably high and survivors are often left with high rates of physical, cognitive and psychological deficits. The underlying molecular causes of ARDS are incompletely understood, highlighted by the observation that only a fraction of patients with clinical risk factors for ARDS go on to develop it. Recent studies have identified several genetic polymorphisms which are associated with the development and severity of ARDS including polymorphisms in the surfactant protein B (SFTPB) and vascular endothelial growth factor A (VEGF A) genes. However, little is known about how post-transcriptional modification of gene expression may influence the development and course of ARDS. Micro RNAs (miRNAs) are small segments of non-coding RNA that negatively regulate gene expression by binding to messenger RNA and inhibiting its translation. It has recently been shown that miRNAs can exist extracellularly inside of exosomes or bound to protein and serve as a mechanism of cell-to-cell communication. Our preliminary data demonstrate that specific extracellular miRNAs are differentially expressed in septic patients who develop ARDS compared to septic patients who do not. Two of these differentially expressed miRNAs (miR-887 and miR-15a) are of particular relevance as they are known to target and inhibit the expression of SFTPB and VEGF A as well as other genes with known associations with ARDS. The proposed research plan will examine the role of these miRNAs in ARDS. This will be accomplished in Aim 1 by examining their plasma expression in a larger cohort of patients with and without sepsis-related ARDS and correlating their expression with that of their known secreted targets as well as targets newly discovered by the applicant's preliminary experiments. In addition, associations between these miRNAs and clinical outcomes including in-hospital morality and worsening or resolution of ARDS will be examined.
Aim 2 will explore how sepsis-related stimuli alter exosomal release of these miRNAs. In addition, it will explore how these miRNAs impact gene expression and cell function in both endothelial and epithelial cells. The proposed training plan capitalizes on an expert and successful mentoring team, a collaborative research environment, and carefully selected didactic learning experiences. Thus, this career development award will lead to a novel understanding of the role that miRNAs play in ARDS as well as a well-trained researcher poised to conduct multi-disciplinary clinical and translational research on critical illness.
The Acute Respiratory Distress Syndrome (ARDS) is a major cause of mortality and morbidity in critically ill patients. There are no proven effective pharmacologic therapies for the syndrome in part because the current understanding of the causes of ARDS is limited. The aims of this grant are to examine the role that extracellular micro RNA play in the endothelial and epithelial dysfunction which occurs in ARDS.
