Stanniocalcin-1: New paradigms for cytoprotection and anti-inflammation

Stanniocalcin-1：细胞保护和抗炎的新范例

• 批准号: 8824828
• 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: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824828
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adherence; Adherens Junction; Apical; Attenuated; Biological Preservation; Blood Vessels; Bone Marrow; Cessation of life; Chemotactic Factors; Confocal Microscopy; Cytoprotection; Data; Development; Diphtheria Toxin; Disease; Endothelial Cells; Endothelium; Engineering; Evans blue stain; Exhibits; Extravasation; Flow Cytometry; Generations; Herpes zoster disease; Hypoxia; ITGAM gene; Immunofluorescence Microscopy; Infiltration; Inflammation; Inflammatory Response; Injury; Ischemia; Kidney; Kidney Failure; Lead; Maintenance; Mediating; Microbubbles; Mus; N-terminal; Organ; Phosphotransferases; Plasmids; Play; Proteins; Reactive Oxygen Species; Regulation; Renal function; Reperfusion Injury; Reperfusion Therapy; Resistance; Role; Serum; Small Interfering RNA; Superoxides; Surface; T-Lymphocyte; TNF gene; Therapeutic; Tight Junctions; Transgenic Mice; Transgenic Organisms; UCP2 protein; Ultrasonography; Western Blotting; cadherin 5; claudin-1 protein; cytokine; human STC1 protein; in vivo; macromolecule; macrophage; migration; monolayer; occludin; overexpression; protein expression; public health relevance; research study; response; small hairpin RNA; therapeutic target; transgene expression; vascular endothelial dysfunction

Summary Reactive oxygen species (ROS), endothelial injury and macrophages play critical roles in ischemia/reperfusion (I/R) kidney injury. Our data show stanniocalcin-1 (STC1) diminishes superoxide generation in macrophages, through induction of uncoupling protein-2 (UCP2), decreases the response of macrophages to chemoattractants- and migration across an endothelial monolayer. In cultured endothelial cells, STC1 preserve barrier function. STC1: diminishes superoxide generation; inhibits cytokine-induced activation of Jun-N- terminal kinase (JNK) and loss of tight junction proteins expression. STC1 transgenic mice, which exhibit elevated serum levels and preferential expression of STC1 in macrophages and endothelium, display resistance to I/R kidney injury. Overall hypothesis: STC1 protects from I/R kidney injury through: suppression of superoxide generation; maintenance of normal endothelial barrier function following I/R kidney injury; and inhibition of macrophages. In Objective I, we will determine the role of superoxide and Daxx in STC1-mediated inhibition of JNK in endothelial cells. In Objective II, we will determine the effect of STC1 on hypoxia/reoxygenation (H/RO)-induced changes in the expression and assembly of tight junction proteins in cultured primary kidney endothelial cells. In the context of I/R kidney injury, Objective III will examine endothelial leakage to macromolecules, kidney inflammation and function after kidney endothelium-specific or macrophage-specific overexpression or deletion of STC1. Few therapeutic options are currently available for acute kidney injury (AKI). Our data identify STC1 as a potential therapeutic target for ischemic injury in the kidney and other organs, and our proposed studies will further elucidate STC1 mechanisms of action.

概括 活性氧（ROS），内皮损伤和巨噬细胞在缺血/再灌注中起关键作用 （I/R）肾脏受伤。我们的数据显示，stanniocalcin-1（STC1）减少了巨噬细胞中的超氧化物的产生， 通过诱导解耦蛋白2（UCP2），降低了巨噬细胞对 化学吸引剂和跨内皮单层迁移。在培养的内皮细胞中，STC1保留 屏障功能。 STC1：减少超氧化物的产生；抑制细胞因子诱导的Jun-N-激活 末端激酶（JNK）和紧密连接蛋白表达的丧失。 STC1转基因小鼠，展示 血清水平升高和STC1在巨噬细胞和内皮中的优先表达，显示 抵抗I/R肾脏损伤。总体假设：STC1通过：抑制保护I/R肾脏损伤 超氧化物的产生；维持I/R肾脏损伤后正常内皮屏障功能；和 抑制巨噬细胞。在目标I中，我们将确定超氧化物和DAXX在STC1介导的 在内皮细胞中抑制JNK。在目标II中，我们将确定STC1对 缺氧/re氧（H/RO）诱导的紧密连接蛋白表达和组装的变化 培养的原代肾脏内皮细胞。在I/R肾脏损伤的背景下，目标III将检查 内皮泄漏到大分子，肾脏炎症和肾脏内皮特异性后的功能 巨噬细胞特异性的过表达或STC1的缺失。目前很少有治疗选择可用于 急性肾脏损伤（AKI）。我们的数据将STC1识别为潜在的缺血性损伤的治疗靶点 肾脏和其他器官以及我们提出的研究将进一步阐明STC1作用机理。