Gram-Negative Pneumonia and Lipopolysaccharide Binding Protein

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DESCRIPTION (provided by applicant): This proposal is designed as a training program for the development of an academic career in Trauma Surgery and Surgical Critical Care. The program builds on prior research experiences and ultimately leads to a career of independent medical research. The applicant will be exposed to new experimental techniques, apply them to a new area of basic science research, and interact with two experienced co-mentors. The research project will focus on the pathogenesis of Gram-negative bacterial pneumonia, specifically with respect to the role of lipopolysaccharide binding protein (LBP). LBP is an acute phase protein that recognizes the lipid A moiety of LPS. LBP can be expressed by lung tissue and has been shown to play a unique role in the recognition and clearance of Gram-negative bacteria. We hypothesize that LBP is a key element in the pathogenesis of Gram-negative pneumonia. The specific aims of the proposed research include: 1) Elucidating the role of endogenous LBP in the pathogenesis of Gram-negative bacterial pneumonia. 2) Evaluate the effect of over-expression of LBP on altering the pathogenesis of Gram-negative pneumonia. 3) Block the normal pathogenesis of Gram-negative pneumonia by inhibiting the systemic recognition of LPS with LBP like peptides. The experiments proposed will utilize classic immunology, molecular biology, and gene therapy. In addition the research will focus on proteomics with use of a novel protein microarray immunoassay and development of LBP-like peptides. The long-term goal is to further our understanding of the role of LBP at the local and systemic level in responding to bacterial infection within the lung. The Surgery Department of the University of Michigan provides an optimal setting for training the next generation of surgeon-scientists. This program incorporates the expertise of many different advisors, outlines didactic coursework in research fundamentals, and draws on the vast resources of the Medical School to provide a customized teaching experience. The University of Michigan Department of Surgery has a long history of nurturing successful surgeon-investigators and the co-mentors will maximize the opportunity for the principal investigator to succeed in establishing a sound foundation for a long and successful research career as an independent investigator. Relevance: Bacterial pneumonia can lead to severe morbidity and mortality in trauma, burn and post- surgical patients. It is the sixth most common cause of hospital death within the United States and results in health care costs of greater than $20 billion per year. The insights gained from the experiments proposed may lead to new therapeutic interventions for treatment and prevention of bacterial pneumonia.