Stanniocalcin-1, a novel anti-inflammatory protein

Stanniocalcin-1，一种新型抗炎蛋白

基本信息

批准号：
7899903
负责人：
DAVID SHEIKH-HAMAD
金额：
$ 36.47万
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 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7899903
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 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 Immunologic 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 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 public health relevance research study response small hairpin RNA transgene expression

项目摘要

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.

描述（由申请人提供）：巨噬细胞是重要的炎症介质。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-κB 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。在具体目标 I 中，我们将确定 STC1 上调 UCP2 的机制以及超氧化物在 STC1 介导的巨噬细胞中 NF-κB 抑制中的作用。在特定目标 II 中，我们将确定 STC1 对细胞因子诱导的培养原代肾内皮细胞中紧密连接蛋白表达和组装变化的影响。在特定目标 III 中，在抗 GBM 疾病的背景下，我们将在肾脏内皮特异性或巨噬细胞特异性过度表达或删除 STC1 后检查天然肾血管的内皮通透性，以及肾脏炎症和功能。公共健康相关性：我们的初步结果表明 stanniocalcin-1 蛋白可抑制巨噬细胞、稳定血管并减少肾脏炎症。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。这很重要，因为现有的炎症常规疗法通常与显着的副作用相关，而我们提出的实验可能会导致识别治疗炎症的新药物。