This proposal represents a five-year curriculum and research plan that is designed to transition the candidate from his current mentored-bench research focus to one of independent investigator driven clinical research. The plan is five years in duration to facilitate the appropriate class work as well as the execution of the specific research objectives. Broadly, the main objectives are to confirm current in vitro hypotheses in humans with clinical signs of sepsis and complete coursework in clinical research sciences. The candidate's current research has centered on the role of inflammatory cell recruitment in lung disease. Sepsis has a very high associated mortality and its incidence may be rising. Lung injury is one of the more common organ dysfunctions present in severe sepsis. Transforming Growth Factor Beta (TGFb) is known to be present in early lung injury and may be serving to repair the initial pulmonary insult. Vascular events known to be important in sepsis include inflammation and initiation of the coagulation cascade. The balance between inflammation and repair caused by these cascades may be critical to resolution of lung injury. As a result, the end products of these cascades may have a potential role in affecting the course of organ dysfunction in severe sepsis. Thrombospondin-1 (TSP-1) is increased in human sepsis, but its implications are not fully understood. Because TSP-1 is known to interact with and activate latent TGF-beta, its presence may serve to initiate the TGF-beta response necessary to repair acute lung injury in severe sepsis.
Specific Aim : To investigate whether TSP-1 is important in modulating the course of sepsis-induced acute lung injury. Hypothesis 1.1: In human sepsis, increased TSP-1 levels will be associated with subsequent increases in TGFbeta1. Hypothesis 1.2: In human sepsis, increased TSP-1 levels will be associated with a lower incidence and shorter course of lung-injury. Hypothesis 1.3: Patients with the Asn682Ser polymorphism in the TSP-1 gene will have a higher incidence of and a more severe course of lung injury. Through these studies, the importance, clinical relevance and potential implications of TSP-1 and TGF-beta interactions on the development of ARDS in septic patients can be determined. The development portion of this grant is designed to facilitate the applicant's career goals of becoming an independently funded clinical researcher in the area ARDS and sepsis. The combined resources of this institution (tertiary care hospital, GCRC and College of Medicine and Public Health) will be available to the candidate to achieve these goals.
