) The adult respiratory distress syndrome (ARDS) is still a major cause of morbidity and mortality among trauma and critically ill patients. ARDS is believed to be the result of local pulmonary activation of the inflammatory cascade after local or systemic injury, leading to lung tissue damage. After trauma or gram negative sepsis, LPS from the bacterial cell wall binds to CD14 receptors on mononuclear cells causing the release of inflammatory mediators such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), Tumor Necrosis Factor-a (TNF-a), platelet activating factor and nitric oxide. These mediators are believed to be responsible for the physiologic changes seen in ARDS after trauma or sepsis. Lipopolysaccharide binding protein (LBP), found in serum and produced locally, enhances the binding of LPS to CD14 receptor. The applicant has previously found elevated LBP production in pulmonary tissue after distant injury. LBP may therefore contribute to over amplification of the lung inflammatory response in the presence of minute amounts of LPS. The mechanism by which lung LBP production is controlled and its role in the pathophysiology of ARDS in traumatized patients remains unknown. The current proposal seeks to investigate and understand the role of locally produced LBP in lung tissue after trauma. The applicant hypothesizes that elevated local pulmonary production of LBP as a result of local or systemic injury may predispose the lung to an overwhelming activation of the inflammatory system leading to greater tissue destruction. He therefore aims to define the factors regulating LBP production by pulmonary cells in vitro as well as in vivo and to determine the functional role of locally produced pulmonary LBP on host responses to LPS in ARDS. This grant proposal is composed of two phases. The first phase will consist of a training plan. Through the completion of a core curriculum of courses and frequent didactic sessions with both primary and secondary mentors, the candidate will acquire a strong knowledge base as well as obtain technical expertise in the fields of molecular biology, cell biology and genetics. The candidate will gain critical knowledge of advanced and complex techniques under the tutelage of the primary mentor, Dr. Stewart C. Wang, while working on the research proposal. The second phase will focus on completing the specific aims of the application and allow the candidate to gain a broader range of scientific knowledge. The goal is for the candidate to develop independent areas of research.
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