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: 9339510
• 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/9339510
• 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; Cost of Illness; Cytoprotection; Data; Diphtheria Toxin; 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; Knockout Mice; Lead; Maintenance; Mediating; Microbubbles; Mus; N-terminal; Organ; Phosphotransferases; Plasmids; Play; Proteins; Reactive Oxygen Species; Regulation; Renal function; Reperfusion Injury; Reperfusion Therapy; Resistance; Role; STC1 gene; Serum; Small Interfering RNA; Superoxides; Surface; T-Lymphocyte; TNF gene; Therapeutic; Tight Junctions; Transgenic Mice; Transgenic Organisms; UCP2 protein; Ultrasonography; Western Blotting; beta catenin; cadherin 5; claudin-1 protein; cytokine; experimental study; in vivo; knock-down; macromolecule; macrophage; migration; monolayer; nephrogenesis; novel therapeutics; occludin; overexpression; protein expression; public health relevance; response; small hairpin RNA; therapeutic target; transgene expression; vascular endothelial dysfunction

DESCRIPTION (provided by applicant): 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 endothelil 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.

描述（由申请人提供）： 摘要 活性氧 (ROS)、内皮损伤和巨噬细胞在缺血/再灌注 (I/R) 肾损伤中发挥着关键作用。我们的数据显示，斯钙素-1 (STC1) 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，降低巨噬细胞对化学引诱剂的反应以及跨内皮单层的迁移。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 末端激酶 (JNK) 激活和紧密连接蛋白表达的丧失。 STC1 转基因小鼠的血清水平升高，并且 STC1 在巨噬细胞和内皮细胞中优先表达，表现出对 I/R 肾损伤的抵抗力。总体假设：STC1 通过以下方式防止 I/R 肾损伤： 抑制超氧化物的产生； I/R 肾损伤后维持正常的内皮屏障功能；和巨噬细胞的抑制。在目标 I 中，我们将确定超氧化物和 Daxx 在 STC1 介导的内皮细胞 JNK 抑制中的作用。在目标 II 中，我们将确定 STC1 对缺氧/复氧 (H/RO) 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 I/R 肾损伤的背景下，目标 III 将检查肾内皮特异性或巨噬细胞特异性 STC1 过度表达或缺失后内皮渗漏到大分子、肾脏炎症和功能。目前可用于急性肾损伤（AKI）的治疗方案很少。我们的数据确定 STC1 是肾脏和其他器官缺血性损伤的潜在治疗靶点，我们提出的研究将进一步阐明 STC1 的作用机制。