Hypoxia-induced Responses and Innate Immunity

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Macrophage and neutrophils are essential for an immediate response to infection as components of the innate immune system, and these cells often function in a hypoxic micro-environment during microbial, and especially bacterial, infection. Our goal is to determine the mechanisms of hypoxic response in myeloid cells during bacterial challenge, through studying the role of the hypoxia-induced transcription factor HIF-1a during that process. The specific aims of this proposal are: Specific aim 1: Determine the role of HIF-1a in regulating the microbial killing functions of myeloid cells; 1a. Analyze the role of HIF-1a in neutrophil and macrophage bacterial killing under normoxic, hypoxic and anoxic conditions; 1b. Determine the role of HIF-1a in neutrophil and macrophage production of the oxidative burst and reactive nitrogen species; 1c. Determine the role of HIF-1a in neutrophil protease activity and the production and activation of cathelicidin antimicrobial peptides; Specific aim 2: Determine the role of HIF-1a in the migratory, survival and immune-activating functions of myeloid cells; 2a. Analyze the role of HIF-1a in neutrophil chemotaxis and endothelial transcytosis under normoxic, hypoxic and anoxic conditions; 2b. Determine the role of HIF-1a in protection of neutrophils and macrophages against bacterial-induced cytotoxicity and apoptosis; 2c. Determine the role of HIF-1a in the pattern of proinflammatory cytokine gene activation in neutrophils and macrophages responding to a bacterial stimulus; Specific aim 3: Determine the function of HIF-1a in innate immune defense against bacterial infection in vivo; 3a. Determine the role of HIF-1a in localized neutrophil migration and killing using a murine subcutaneous tissue cage model; 3b. Determine the role of HIF-1a in restricting systemic spread of infection from a hypoxic focus using a murine subcutaneous infection mode!; 3c. Determine the role of HIF-1a in development and control of bacterial septicemia using a murine intravenous infection model.