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Stanniocalcin-1, a novel anti-inflammatory protein

Stanniocalcin-1，一种新型抗炎蛋白

基本信息

批准号：
8515390
负责人：
DAVID SHEIKH-HAMAD
金额：
$ 31.58万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515390
关键词：
A Mouse Adherence Adherens Junction Adipocytes Adverse effects Anti-Glomerular Basement Membrane Disease Anti-Inflammatory Agents Anti-inflammatory Apical Apoptosis Attenuated Biotin Blood Vessels Bone Marrow Calcium Cell Adhesion Molecules Cell Proliferation Chemotactic Factors Confocal Microscopy Cycloheximide Cytomegalovirus Dactinomycin Data Dextrans Diphtheria Toxin Disease Endothelial Cells Endothelium Evans blue stain Exhibits Flow Cytometry Gene Delivery Generations Glomerulonephritis Half-Life Histology Homologous Gene ITGAM gene Immunofluorescence Microscopy Infiltration Inflammation Inflammation Mediators Inflammatory Injection of therapeutic agent Injury Kidney Label Lead Mediating Messenger RNA Methods Microbubbles Mitochondria Molecular Weight Mus Pathogenesis Pathway interactions Permeability Pharmaceutical Preparations Phase Plasmids Play Post-Transcriptional Regulation Production Proteins Reactive Oxygen Species Recombinants Recovery Regulation Renal function Reporter Resolution Role Serum Small Interfering RNA Staging Superoxides Surface T-Lymphocyte TNF gene Texas red Thermogenesis Tight Junctions Transgenic Mice Translations UCP2 protein Ultrasonography Up-Regulation Vascular Permeabilities Western Blotting attenuation cadherin 5 chemokine claudin-1 protein conventional therapy cytokine dextran glomerular basement membrane human STC1 protein in vivo macrophage migration monolayer novel occludin overexpression protective effect protein expression protein kinase C zeta research study response small hairpin RNA transgene expression

项目摘要

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.

巨噬细胞是炎症的重要介质。我们的数据显示，锡钙素-1(STC1)减少巨噬细胞对趋化物质的反应和跨越内皮单分子层的迁移。STc1也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，并抑制核因子-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张性变化连接蛋白的表达。STC1转基因小鼠，表现出较高的血清水平和优先 STC1在巨噬细胞和内皮细胞中的表达，显示肾小球中炎症较轻的巨噬细胞在抗肾小球基底膜(GBM)疾病期间，导致肾脏保护。总括假设：STC1通过抑制巨噬细胞募集和功能来抑制炎症，并且细胞因子诱导的内皮通透性增加。在具体目标一中，我们将确定 STc1上调UCP2表达及超氧化物在STc1抑制巨噬细胞核因子-βB中的作用在特定的目标II中，我们将确定STC1在细胞因子诱导的表达变化和在原代培养的肾内皮细胞中组装紧密连接蛋白。在具体目标三中，在在抗GBM疾病的背景下，我们将检测自体肾血管的内皮通透性，以及肾内皮细胞特异性或巨噬细胞特异性过度表达后的肾脏炎症和功能或STc1的删除。