Stanniocalcin-1, a novel anti-inflammatory protein

Stanniocalcin-1，一种新型抗炎蛋白

• 批准号: 7687670
• 负责人: DAVID SHEIKH-HAMAD
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687670
• 关键词: Adverse effects; Anti-Glomerular Basement Membrane Disease; Anti-Inflammatory Agents; Anti-inflammatory; Area; Blood Vessels; Chemotactic Factors; Chronic Disease; Data; Development; Endothelial Cells; Endothelium; Exhibits; Generations; Glomerulonephritis; Health; Healthcare; Heart Diseases; Inflammation; Inflammation Mediators; Inflammatory; Kidney; Kidney Diseases; Lead; Mediating; Mus; Outcome Study; Pathway interactions; Permeability; Proteins; Role; Serum; Stroke; Superoxides; Tight Junctions; Transgenic Mice; UCP2 protein; Veterans; Work; abstracting; conventional therapy; cytokine; human STC1 protein; macrophage; migration; monolayer; new therapeutic target; novel; overexpression; protein expression; research study; response

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.

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 (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 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转基因小鼠的血清水平升高，并且在巨噬细胞和内皮细胞中优先表达STC1，在抗肾小球基底膜（GBM）疾病期间，肾小球中的炎症巨噬细胞较少，从而实现肾脏保护。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 介导的小鼠巨噬细胞 NF-:B 抑制中的作用。在目标 II 中，我们将确定 STC1 对培养的原代肾内皮细胞中细胞因子诱导的紧密连接蛋白表达和组装变化的影响。在目标 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 STC1 过度表达或缺失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，这在退伍军人中很常见。 公共卫生相关性： 我们的初步结果表明 stanniocalcin-1 可以抑制巨噬细胞、稳定血管并减少肾小球肾炎引起的肾脏炎症。我们计划研究 stanniocalcin-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着的副作用相关，我们提出的实验可能会产生抑制炎症的新治疗靶点。

项目成果

Stanniocalcin-1 Is an Ocular Hypotensive Agent and a Downstream Effector Molecule That Is Necessary for the Intraocular Pressure-Lowering Effects of Latanoprost.

Stanniocalcin-1 是一种降眼压剂，也是拉坦前列素降低眼压作用所必需的下游效应分子。

• DOI: 10.1167/iovs.16-21004
• 发表时间: 2017
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Roddy,GavinW;Viker,KimberlyB;Winkler,NelsonS;Bahler,CindyK;Holman,BradleyH;Sheikh-Hamad,David;RoyChowdhury,Uttio;Stamer,WDaniel;Fautsch,MichaelP
• 通讯作者: Fautsch,MichaelP