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）： 活性氧、内皮细胞损伤和巨噬细胞在缺血/再灌注（I/R）肾损伤中起关键作用。我们的数据显示，斯钙素-1（STC 1）通过诱导解偶联蛋白-2（UCP 2）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物的反应-以及穿过内皮单层的迁移。在培养的内皮细胞中，STC 1保持屏障功能。STC 1：减少超氧化物的产生;抑制精氨酸诱导的Jun-N-末端激酶（JNK）活化和紧密连接蛋白表达的丧失。STC 1转基因小鼠，表现出升高的血清水平和优先表达的STC 1在巨噬细胞和内皮细胞，显示抵抗I/R肾损伤。总体假设：STC 1通过以下方式保护I/R肾损伤：抑制超氧化物生成;在I/R肾损伤后维持正常内皮屏障功能;以及抑制巨噬细胞。在目的I中，我们将确定超氧化物和Daxx在STC 1介导的内皮细胞JNK抑制中的作用。在目的II中，我们将确定STC 1对缺氧/复氧（H/RO）诱导的原代培养的肾内皮细胞中紧密连接蛋白的表达和组装的变化的影响。在I/R肾损伤的背景下，目的III将检查在肾内皮特异性或巨噬细胞特异性过表达或缺失STC 1后内皮素向大分子的渗漏、肾脏炎症和功能。急性肾损伤（阿基）目前几乎没有治疗选择。我们的数据将STC 1确定为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STC 1的作用机制。