Stanniocalcin-1, a novel anti-inflammatory protein

描述（申请人提供）：巨噬细胞是炎症的重要介质。我们的数据显示STC1降低巨噬细胞对化学引诱剂的反应和跨内皮单层的迁移。STC1还通过诱导解偶联蛋白2 （UCP2）减少巨噬细胞中超氧化物的产生，并抑制NF-？B通路。在培养的内皮细胞中，STC1抑制细胞因子诱导的通透性和紧密连接蛋白表达的变化。STC1转基因小鼠在抗肾小球基底膜（anti-glomerular basal membrane， GBM）疾病期间，肾小球内炎症性巨噬细胞减少，从而起到保护肾脏的作用，其血清水平升高，STC1在巨噬细胞和内皮中优先表达。总体假设：STC1通过抑制巨噬细胞募集和功能，以及细胞因子诱导的内皮通透性增加来抑制炎症。在Specific Aim I中，我们将确定STC1上调UCP2的机制以及超氧化物在STC1介导的NF-抑制中的作用。巨噬细胞中的B。在Specific Aim II中，我们将确定STC1对细胞因子诱导的培养的原代肾内皮细胞中紧密连接蛋白表达和组装变化的影响。在特异性目的III中，在抗gbm疾病的背景下，我们将检查肾脏内皮特异性或巨噬细胞特异性STC1过表达或缺失后天然肾脏血管的内皮通透性，以及肾脏炎症和功能。公共卫生相关性：我们的初步结果显示，斯坦钙素-1蛋白抑制巨噬细胞，稳定血管，减少肾脏炎症。我们计划研究斯坦钙素-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经常伴有明显的副作用，而我们提出的实验可能会导致发现治疗炎症的新药物。

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.