SGK1 Signaling Pathways in Vascular Remodeling

血管重塑中的 SGK1 信号通路

基本信息

批准号：
8688335
负责人：
Sharon C Francis
金额：
$ 28.02万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8688335
关键词：
Acceleration Acetylation Affect Angioplasty Animals Apolipoprotein E Apoptosis Apoptotic Area Arterial Fatty Streak Arteries Atherosclerosis Attenuated Biochemical Bioinformatics Biological Models Biology Blood Vessels Bromodeoxyuridine Carotid Arteries Cell Cycle Progression Cell Proliferation Cell Survival Cell physiology Cellular biology DNA Nucleotidylexotransferase Data Deacetylase Deoxyuridine Development Electrophoresis Epithelial Cells Genes Glucocorticoids Growth Histone Deacetylase Homologous Gene Hypertension In Vitro Inflammatory Injury Knock-out Knockout Mice Knowledge Label Lesion Light Link Mass Spectrum Analysis Mating Types Mediating Mediator of activation protein Mitochondria Modeling Molecular Orthologous Gene Pathology Pathway interactions Phenotype Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Process Productivity Protein Microchips Protein-Serine-Threonine Kinases Proteome Proteomics RNA Rattus Reaction Regulation Research Resources Role Serine Serum Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Stroke TdT-Mediated dUTP Nick End Labeling Assay Testing Up-Regulation Vascular Diseases Vascular remodeling Work base cell growth cell type gain of function genetic regulatory protein in vivo in vivo Model injured insight loss of function mRNA Expression migration mouse model mutant neoplastic cell new therapeutic target novel protein expression protein function research study response restenosis stable cell line two-dimensional vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): Aberrant vascular smooth muscle cells (SMC) proliferation and survival is a hallmark vascular pathology underlying atherosclerosis and restenosis following vascular injury. Mitogenic signaling cascades that become activated upon injury stimulate serine/threonine protein kinases that rapidly regulate the phosphorylation of key genes and regulatory proteins that control cell cycle progression and cell survival processes. In this regard, emerging data indicate that the activity of serum and glucocorticoid inducible kinase 1 (SGK1) is linked to changes in cellular proliferation and survival processes in tumor cells. 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. We have shown that over-expression of activated SGK1 induces a proliferative and survival phenotype in A7r5 rat aortic SMC. This correlated with an acceleration of cell cycle progression owing to an increase in G1 to S transition. Further, we found that SGK1 activity is enhanced in injured carotid arteries. To elucidate the molecular mechanism underlying these effects, we conducted a kinase substrate protein microarray to screen for novel SGK1 targets. Our initial studies identified the mitochondrial deacetylase, Sirt3 as a putative SGK1 target. In light of these findings, we hypothesize that SGK1 promotes neointimal lesion development in vivo by stimulating vascular SMC growth and inhibiting vascular SMC apoptosis via a mechanism that relies upon SGK1-mediated phosphorylation of Sirt3 and modulation of mitochondrial function. To test this hypothesis, we established a unique SMC-specific SGK1 knockout mouse model. We will use SMC isolated from this model as well as SMC stable cell lines in loss- and gain-of-function experiments. In addition, we will utilize these resources as we examine the following specific aims: 1) to test the hypothesis that vascular SMC-targeted knockout of SGK1 attenuates the development of neointimal formation in response to wire-induced vascular injury, 2) to test the hypothesis that SGK1 can directly phosphorylate Sirt3 and thereby regulate its protein function, 3) to demonstrate that a SGK1/Sirt3 signaling pathway is a critical determinant of vascular SMC growth and survival.

描述（由申请人提供）：异常的血管平滑肌细胞（SMC）增殖和生存是血管损伤后动脉粥样硬化和再狭窄的标志性血管病理学。受伤后激活的有丝分裂信号传导刺激丝氨酸/苏氨酸蛋白激酶，这些激酶迅速调节关键基因的磷酸化和控制细胞周期进程和细胞存活过程的调节蛋白的磷酸化。在这方面，新兴数据表明血清和糖皮质激素诱导激酶1（SGK1）的活性与肿瘤细胞中细胞增殖和存活过程的变化有关。尽管SGK1在上皮细胞生物学中的作用已经取得了很多进展。它在血管平滑肌细胞功能和病变形成的发展中的作用；特别是完全未知。我们已经表明，激活的SGK1的过表达在A7R5大鼠主动脉SMC中诱导增生和存活表型。由于G1到S转变的增加，这与细胞周期进程的加速相关。此外，我们发现受伤的颈动脉中SGK1活性增强了。为了阐明这些作用的分子机制，我们进行了激酶底物蛋白微阵列以筛选新的SGK1靶标。我们的初步研究确定线粒体脱乙酰基酶SIRT3是推定的SGK1靶标。鉴于这些发现，我们假设SGK1通过刺激血管SMC生长并通过SGK1介导的SIRT 3和MITochrial功能的调节的机制来促进体内新内膜病变的发育并抑制血管SMC凋亡。为了检验这一假设，我们建立了独特的SMC特异性SGK1基因敲除鼠标模型。我们将使用从该模型中分离出来的SMC，以及在功能障碍实验中的SMC稳定细胞系。此外，我们将在检查以下具体目的时利用这些资源：1）测试以下假设：SGK1的血管靶向SMC靶向敲除响应电线诱导的血管损伤的新形成形成的发展，2）假设SGK1可以直接磷酸化SIRT3，从而调节其蛋白质功能，3）证明SGK1/SIRT3信号传导途径是血管SMC生长和存活的关键决定因素。