Lung infections account for a tremendous burden of disease worldwide, representing the most frequent cause of infection-related deaths and a common cause of acute lung injury. The long term goal of both the candidate and his laboratory is to elucidate intra- and extra-pulmonary signaling pathways required for host defense and the prevention of lung injury. The candidate has focused on pulmonary host defense since initiating his research career, and has through his accomplishments demonstrated a strong commitment to academic research. He is conducting research in a successful environment, Harvard School of Public Health, which is wholly suited to maximize his career development during the mentored phase and, ultimately, his transition toward independence. Prevention of lung infections requires a local inflammatory response that is facilitated by early response cytokines (TNF-a and IL-1) and IL-6. These cytokines signal in large part through NF-kappaB RelA and STATS, respectively. Local pulmonary immune responses occur in tandem with a systemic acute phase response (APR). Although the APR has long been recognized as a useful biomarker of disease progression during pneumonia, mechanisms mediating the APR and the collective impact of acute phase proteins (APPs) on inflammation and host defense during pneumonia are unknown. The central hypothesis of the proposed research plan is that during pneumonia, acute phase responses are induced by STATS and RelA activation in the liver and are necessary for host defense in the lung. To address this, the candidate aims to test the specific hypotheses that, during pneumonia, (1) the activation of STATS and RelA and the expression of APPs in hepatocytes require TNF-a, IL-1, and IL-6, (2) STATS and RelA in hepatocytes are required for APP expression, and (3) STATS and RelA in hepatocytes contribute to inflammation and host defense in the lungs. These studies will employ innovative approaches, including the use of mice with hepatocyte-targeted (Cre-LoxP-mediated) gene deletions of RelA, STATS or both RelA and STATS. Preliminary data support the central hypothesis and the feasibility of the proposed experimental approaches. Completion of these studies will demonstrate whether mechanisms regulating APP expression in the liver may be novel therapeutic targets for patients with pneumonia or other severe infections.
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