Stanniocalcin-1, a novel anti-inflammatory protein

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DESCRIPTION (provided by applicant): Project Summary/Abstract Macrophages are important mediators of inflammation. Our data show stanniocalcin-1 (STC1) decreases macrophage response to chemoattractants and migration across an endothelial monolayer. STC1 also diminishes superoxide generation in macrophages, possibly by inducing uncoupling protein-2 (UCP2), and inhibits the NF-:B pathway. In cultured endothelial cells, STC1 inhibits cytokine-induced changes in permeability and tight junction protein expression. STC1 transgenic mice, which exhibit elevated serum levels and preferential expression of STC1 in macrophages and endothelium, display less inflammatory macrophages in the glomeruli during anti-glomerular basement membrane (GBM) disease, resulting in kidney protection. Overall hypothesis: STC1 suppresses inflammation through inhibition of macrophage recruitment and function, and cytokine-induced increase in endothelial permeability. In Objective I, we will determine the role of superoxide in STC1-mediated inhibition of NF-:B in murine macrophages. In Objective II, we will determine the effect of STC1 on cytokine- induced changes in expression and assembly of tight junction proteins in cultured primary kidney endothelial cells. In Objective III, in the context of anti-GBM disease, we will examine endothelial permeability of native kidney vessels, as well as kidney inflammation and function, after kidney endothelium-specific or macrophage-specific overexpression or deletion of STC1. Potential Impact on Veterans Health Care: Outcomes from these studies may lead to the development of new therapeutic targets for inflammatory diseases of the kidney, and expand work on understanding and treating chronic diseases and their complications in such areas as kidney disorders, heart diseases and stroke, which are prevalent in veterans. PUBLIC HEALTH RELEVANCE: Our preliminary results show stanniocalcin-1 inhibits macrophages, stabilizes blood vessels and decreases kidney inflammation from glomerulonephritis. We plan to study how stanniocalcin-1 inhibits macrophages and how it stabilizes blood vessels during inflammation. Available conventional therapies for inflammation are frequently associated with significant side effects, and our proposed experiments could lead to new therapeutic targets for suppressing inflammation.