Stanniocalcin-1, a novel anti-inflammatory protein

描述（由申请人提供）：巨噬细胞是炎症的重要介质。我们的数据显示斯钙素-1（STC 1）降低巨噬细胞对化学引诱物的反应和跨内皮单层的迁移。STC 1也减少超氧化物生成的巨噬细胞，诱导解偶联蛋白-2（UCP 2），并抑制NF-？B途径。在培养的内皮细胞中，STC 1抑制了精氨酸诱导的通透性和紧密连接蛋白表达的变化。STC 1转基因小鼠表现出升高的血清水平和STC 1在巨噬细胞和内皮细胞中的优先表达，在抗肾小球基底膜（GBM）疾病期间在肾小球中表现出较少的炎性巨噬细胞，从而导致肾脏保护。总体假设：STC 1通过抑制巨噬细胞的募集和功能以及姜黄素诱导的内皮通透性增加来抑制炎症。在具体目标我，我们将确定UCP 2上调STC 1和STC 1介导的抑制NF-？巨噬细胞中的B。在特定目标II中，我们将确定STC 1对在培养的原代肾内皮细胞中的紧密连接蛋白的表达和组装中的精氨酸诱导的变化的影响。在具体目标III中，在抗GBM疾病的背景下，我们将检查在STC 1的肾内皮特异性或巨噬细胞特异性过表达或缺失后天然肾血管的内皮通透性以及肾脏炎症和功能。公共卫生相关性：我们的初步结果表明斯钙素-1蛋白抑制巨噬细胞，稳定血管，减少肾脏炎症。我们计划研究斯钙素-1如何抑制巨噬细胞，以及它如何在炎症期间稳定血管。这一点很重要，因为现有的炎症常规疗法通常与显著的副作用有关，我们提出的实验可能会导致识别治疗炎症的新药。

DESCRIPTION (provided by applicant): 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, 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 Specific Aim I, we will determine mechanisms of UCP2 upregulation by STC1 and the role of superoxide in STC1-mediated inhibition of NF-?B in macrophages. In Specific Aim 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 Specific Aim 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. PUBLIC HEALTH RELEVANCE: Our preliminary results show stanniocalcin-1 protein inhibits macrophages, stabilizes blood vessels and decreases kidney inflammation. We plan to study how stanniocalcin-1 inhibits macrophages and how it stabilizes blood vessels during inflammation. This is important because available conventional therapies for inflammation are frequently associated with significant side effects, and our proposed experiments could lead to identification of new medications to treat inflammation.