Stanniocalcin-1, a novel anti-inflammatory protein

Stanniocalcin-1，一种新型抗炎蛋白

基本信息

批准号：
7729602
负责人：
DAVID SHEIKH-HAMAD
金额：
$ 36.84万
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/7729602
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）：巨噬细胞是炎症的重要介体。我们的数据表明，stanniocalcin-1（STC1）降低了对趋化剂的巨噬细胞反应，并在内皮单层中迁移。 STC1还通过诱导解偶联蛋白-2（UCP2）并抑制NF-？B途径来减少巨噬细胞中的超氧化物的产生。在培养的内皮细胞中，STC1抑制细胞因子诱导的渗透性变化和紧密连接蛋白表达。 STC1转基因小鼠在巨噬细胞和内皮中表现出升高的血清水平和STC1的优先表达，在抗粘膜基地基膜（GBM）疾病期间，肾小球中的炎症巨噬细胞较少，导致肾脏保护。总体假设：STC1通过抑制巨噬细胞募集和功能来抑制炎症，以及细胞因子诱导的内皮渗透性的增加。在特定的目标I中，我们将确定STC1上调UCP2上调的机理，以及超氧化物在STC1介导的巨噬细胞中NF-？B的抑制作用中的作用。在特定的目标II中，我们将确定STC1对培养的原代肾脏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。在特定的目标III中，在抗GBM疾病的背景下，我们将检查天然肾脏血管的内皮渗透性，以及肾脏炎症和功能，在肾脏内皮特异性特异性或巨噬细胞特异性过表达或STC1的缺失之后。公共卫生相关性：我们的初步结果表明stanniocalcin-1蛋白会抑制巨噬细胞，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在炎症过程中如何稳定血管。这很重要，因为可用的传统炎症疗法经常与重大副作用有关，我们提出的实验可能导致鉴定出新的药物来治疗炎症。