The strong inter-related research themes, common investigative interests, and collaborative ties of the scientists who comprise this renewal application have served as key underpins for over 20 years of continued research productivity under the auspices of this Program Project. The joint interactions of the scientific sections continue to promote a unified, hypothesis-driven objective of this application: To understand the mechanisms whereby various inflammatory mediators contribute to the initiation, maintenance, and resolution of acute and chronic lung inflammation and injury. This global objective will be addressed by the various sections using well establish experimental models to comprehend: 1) the role of C5a and C5a receptors, as they interact with specific cytokines and chemokines during acute lung injury (Project I, Peter A. Ward, M.D); 2) the mechanism of chemokine receptor (CCR4) and its ligands (TARC and MDC) in the initiation, maintenance, and progression/fibrosis of chronic granulomatous lung inflammation defined by specific cytokine phenotypes (project II, Steven L. Kunkel, Ph.D.); 3) to assess the mechanism(s) whereby FIZZ1 (Found in Inflammatory Zone 1), a novel protein induced by type 2 cytokines, participates in driving myofibroblasts to differentiate and participate in lung fibrosis (Project III, Sem H. Phan, M.D., Ph.D.); and 4) to determine the mechanistic role for a specific chemokine receptor (CCR6) and its ligand (MIP-3 alpha) in the development of dendritic and T-cell dependent, allergen-driven airway hyper-reactivity (Project IV, Nick Lukacs, Ph.D.). The scientific sections will be supported by an Administrative Core (Core A, Steven L. Kunkel, Ph.D.) and a Morphology Core (Core B, Kent J. Johnson, M.D) to aid in coordinating personnel and Financial matters and assist in the morphology and morphometric analyses, respectively. The overall rationale of this Program Project is to foster and focus the combined experience of investigators with established collaborative ties and proven expertise in specific areas of lung inflammation on the mechanistic contribution of C5a and its receptors, cytokines, chemokines, and growth and differentiation factors during the evolution of lung inflammation and injury. Data from the proposed experiments in this Program Project will provide novel insight into the mechanisms that dictate the pathology of acute and chronic lung inflammation and aid in developing strategies for new therapeutic targets.
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