Involvement of Serum and Glucocorticoid Inducible Kinase 1 (SGK1) in VSMC Profile

血清和糖皮质激素诱导激酶 1 (SGK1) 在 VSMC 谱中的参与

基本信息

批准号：
7289499
负责人：
Sharon C Francis
金额：
$ 10.5万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-27 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7289499
关键词：
Acceleration Acute Affect Atherosclerosis Biological Assay Biological Models Biology Blood Vessels Cardiovascular Diseases Carotid Arteries Cell Cycle Cell Cycle Progression Cell Proliferation Cell physiology Cells Cellular biology Characteristics Chronic Class Complementary DNA Condition Cyclic AMP-Responsive DNA-Binding Protein Cyclin-Dependent Kinase Inhibitor Cyclins Cytosol Data Development Diabetes Mellitus Disease Disease Progression Dose Employee Strikes Epithelial Cells Event Family Foundations Future Genes Genetic Transcription Glucocorticoids Growth Human Hyperplasia Hypertension Immediate-Early Genes Immunohistochemistry In Vitro Inflammatory Injury Intracellular Transport Investigation Ion Transport Ions Kidney Diseases Lesion Light Link Localized Mechanics Medial Mediating Mediator of activation protein Messenger RNA Methods Mitogens Mitotic Cell Cycle Molecular Monitor Nuclear Nuclear Translocation PDPK1 gene Pathology Phase Phosphatidylinositols Phosphorylation Phosphotransferases Plasmids Platelet-Derived Growth Factor Play Polymerase Chain Reaction Process Proliferating Protein Kinase Protein-Serine-Threonine Kinases Proteins Range Rattus Regulation Regulator Genes Research Role Series Serine Serine/Threonine Phosphorylation Serum Signal Pathway Signal Transduction Smooth Muscle Myocytes Staining method Stains Stimulus Study of serum Testing Threonine Time Transcriptional Activation Transmembrane Transport Transport Process Up-Regulation Vascular Diseases Vascular remodeling Week Western Blotting Work adiponectin base blood pressure regulation cell growth extracellular forkhead protein genetic regulatory protein in vivo in vivo Model injured insight loss of function mRNA Expression member novel novel therapeutics platelet-derived growth factor BB protein expression research study response restenosis small hairpin RNA solute therapeutic target vascular smooth muscle cell migration vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): SGK1 is an inducible serine/threonine kinase that has been implicated in membrane transport processes in epithelial cell. Studies have shown that SGK1 is transcriptionally induced and subject to stimulus-dependent post-translational phosphorylation. Hyperphosphorylation of SGK1 leads to activation of its kinase activity and has been linked to changes in cellular proliferation, survival and intracellular ion and transport processes. Phosphorylation also controls nuclear/cytoplasmic shuttling of SGK1 such that hyperphosphorylation on serine/threonine residues leads to nuclear translocation from the cytosol. Although much progress has been made regarding the role of SGK1 in epithelial cell biology, its role in vascular smooth muscle cell function and in the development of lesion formation in particular is completely unknown. Therefore, this application seeks to define the role of SGK1 in regulation of vascular smooth muscle cell fate, specifically as it relates to growth. In preliminary studies we found that the potent mitogen, PDGF, dramatically and transiently increases SGK1 mRNA expression in vascular smooth muscle cells implicating a role for this kinase in vascular smooth muscle cell growth. We also found that PDGF stimulation is associated with increased phosphorylation of SGK1, suggesting that PDGF may mediate activation of SGK1 kinase activity. Interestingly, immunohistological staining of injured carotid artery revealed that SGK1 is up-regulated in neointimal vascular lesions. In light of these findings, we hypothesize that SGK1 is an important mediator of vascular smooth muscle cell proliferation and that alterations in its expression and/or activity leads to the subsequent development of vascular neointimal lesion formation. We will test this hypothesis in the following aims: (1) to investigate the effects of mitogenic stimuli on SGK1 expression, activity and compartmentalization in VSMC in vitro; (2) to investigate the effect of constitutive SGK1 knockdown and over-expression on regulation of VSMC growth in vitro; (3) to investigate the effect of mechanical vascular injury on SGK1 expression and activity in a rat carotid artery balloon-injury model in vivo. Overall, this series of experiments will provide insight into the role of SGK1 in vascular smooth muscle cell proliferation and provide the basis for future studies to define the role of SGK1 in pathological vascular remodeling. Ultimately, these studies identify SGK1 as a novel therapeutic target for occlusive vascular diseases that occur as a consequence of atherosclerosis, restenosis or hypertension.

描述（由申请人提供）：SGK1 是一种诱导型丝氨酸/苏氨酸激酶，与上皮细胞的膜转运过程有关。研究表明，SGK1 是转录诱导的，并且会发生刺激依赖性翻译后磷酸化。 SGK1 的过度磷酸化会导致其激酶活性激活，并与细胞增殖、存活以及细胞内离子和运输过程的变化有关。磷酸化还控制 SGK1 的核/细胞质穿梭，使得丝氨酸/苏氨酸残基上的过度磷酸化导致细胞质中的核转位。尽管关于 SGK1 在上皮细胞生物学中的作用已经取得了很大进展，但其在血管平滑肌细胞功能，特别是在病变形成发展中的作用完全未知。因此，本申请旨在明确 SGK1 在调节血管平滑肌细胞命运中的作用，特别是与生长相关的作用。在初步研究中，我们发现强效丝裂原 PDGF 会显着且短暂地增加血管平滑肌细胞中 SGK1 mRNA 的表达，表明该激酶在血管平滑肌细胞生长中发挥作用。我们还发现 PDGF 刺激与 SGK1 磷酸化增加相关，表明 PDGF 可能介导 SGK1 激酶活性的激活。有趣的是，受损颈动脉的免疫组织学染色显示，SGK1 在新内膜血管病变中表达上调。根据这些发现，我们假设 SGK1 是血管平滑肌细胞增殖的重要介质，其表达和/或活性的改变导致血管新内膜病变形成的后续发展。我们将通过以下目的检验这一假设：（1）研究有丝分裂刺激对体外VSMC中SGK1表达、活性和区室化的影响； (2)体外研究SGK1的组成型敲低和过表达对VSMC生长的调节作用； (3)在体内大鼠颈动脉球囊损伤模型中研究机械性血管损伤对SGK1表达和活性的影响。总的来说，这一系列实验将深入了解SGK1在血管平滑肌细胞增殖中的作用，并为未来研究定义SGK1在病理性血管重塑中的作用提供基础。最终，这些研究将 SGK1 确定为动脉粥样硬化、再狭窄或高血压引起的闭塞性血管疾病的新治疗靶点。