Stanniocalcin-1, a novel anti-inflammatory protein

描述（由申请人提供）： 项目摘要/摘要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还可能通过诱导解偶联蛋白-2（UCP 2）减少巨噬细胞中超氧化物的产生，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。在目的I中，我们将确定超氧化物在STC 1介导的小鼠巨噬细胞NF-：B抑制中的作用。在目的II中，我们将确定STC 1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的表达和组装变化的影响。在目的III中，在抗GBM疾病的背景下，我们将在肾内皮特异性或巨噬细胞特异性过表达或缺失STC 1后检查天然肾血管的内皮通透性以及肾脏炎症和功能。对退伍军人医疗保健的潜在影响：这些研究的结果可能会导致肾脏炎症性疾病的新治疗靶点的开发，并扩大对肾脏疾病，心脏病和中风等领域慢性疾病及其并发症的理解和治疗工作，这些疾病在退伍军人中普遍存在。 公共卫生相关性： 我们的初步结果显示斯钙素-1抑制巨噬细胞，稳定血管，减少肾小球肾炎的肾脏炎症。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。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抑制炎症的新治疗靶点。

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.