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，锡钙素-1(STC1)降低了巨噬细胞对化学诱导剂的反应和跨越内皮单分子层的迁移。STC1还可能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途径。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。在抗肾小球基底膜(GBM)疾病过程中，STC1转基因小鼠血清水平升高，巨噬细胞和内皮细胞优先表达，肾小球内炎性巨噬细胞减少，从而达到肾脏保护作用。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。在目标I中，我们将确定超氧化物在STC1介导的抑制小鼠巨噬细胞中的NF-：B中的作用。在目标II中，我们将确定STC1对细胞因子诱导的原代培养的肾内皮细胞紧密连接蛋白表达和组装的影响。在目标III中，我们将在抗GBM疾病的背景下，检测肾内皮细胞特异性或巨噬细胞特异性STC1过表达或缺失后，天然肾血管的内皮通透性，以及肾脏的炎症和功能。对退伍军人保健的潜在影响：这些研究的结果可能导致开发肾脏炎症性疾病的新治疗目标，并扩大了解和治疗退伍军人常见的肾脏疾病、心脏病和中风等领域的慢性疾病及其并发症的工作。 公共卫生相关性： 我们的初步结果显示，锡钙素-1抑制巨噬细胞，稳定血管，减少肾小球肾炎引起的肾脏炎症。我们计划研究锡钙素-1如何抑制巨噬细胞，以及它如何在炎症期间稳定血管。现有的传统炎症治疗方法往往与显著的副作用有关，我们拟议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.