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首页> 外文学位 >Fibroblast growth factor receptor-1 (FGFR1) in vascular smooth muscle cell phenotypic switch.
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Fibroblast growth factor receptor-1 (FGFR1) in vascular smooth muscle cell phenotypic switch.

机译：成纤维细胞生长因子受体1（FGFR1）在血管平滑肌细胞表型转换中。

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摘要

Vascular smooth muscle cells (VSMCs) play a critical role in the physiological maintenance of the cardiovascular system. In contrast to skeletal and cardiac muscle cells, VSMCs have the capacity to modulate their phenotype from contractile to synthetic and proliferative states. This phenotypic switch plays an important role in pathological processes, including hypertension, atherosclerosis, and restenosis alter angioplasty. Understanding the molecular mechanism of how VSMCs modulate their phenotype is an important step in the understanding of cardiovascular disease.;My studies have focused on examining the mechanism of VSMC phenotypic modulation by fibroblast growth factor receptor-1 (FGFR1). I have developed a set of FGFR1 pathway-deficient mutants to examine the signaling pathway(s) mediated by FGFR1 that control VSMC phenotype. My results showed that the FGFR1-mediated FRS2 pathway, but not the Crk or PLCgamma pathways, is required for regulating VSMC phenotype. This is the first reported evidence that FRS2 participates in VSMC phenotypic modulation.;In addition to FGF, platelet-derived growth factor (PDGF) is a well documented growth factor that regulates switching of VSMC from a contractile phenotype to proliferative and synthetic phenotype. I found that FGF2 and PDGF-BB modulate VSMC phenotype including increase cell proliferation and decrease smooth muscle marker gene expression. I also found that FGFR1 co-immunoprecipitated with PDGFRbeta. This complex formation does not require receptor activation and is mediated through both the extracellular and intracellular domains. Moreover, FRS2 knockdown in VSMC reversed FGF2 and PDGF-BB mediated downregulation of smooth muscle marker gene expression; while leaving PDGF-BB-induced ERK activation and cell proliferation intact.;FRS2 is an adaptor protein linking FGFR to downstream MAP kinase and Akt/mTOR signaling. My biochemical studies showed that mTOR is a downstream target of FGFR1/FRS2. FGFR1 activation phosphorylated mTOR at Ser2448 site and mTOR inhibitor rapamycin partially reversed FGFR1-mediated VSMC phenotypic switch by increasing SM alpha-actin protein synthesis. In addition, mTOR was co-immunoprecipitated with activated FGFR1/FRS2.;In summary, the results of this study will provide information on FGFR1 signaling in VSMC phenotypic switch and also set the stage for future design of new drugs that may selectively block FGFR1 signaling for pharmacological interventions.
机译：血管平滑肌细胞（VSMC）在心血管系统的生理维持中起关键作用。与骨骼肌和心肌细胞相反，VSMC具有调节其表型从收缩状态到合成状态和增殖状态的能力。这种表型转换在包括高血压，动脉粥样硬化和再狭窄改变血管成形术在内的病理过程中起着重要作用。理解VSMC如何调节其表型的分子机制是理解心血管疾病的重要步骤。我的研究集中于研究成纤维细胞生长因子受体1（FGFR1）调节VSMC表型的机制。我已经开发了一组FGFR1途径缺陷型突变体，以研究由FGFR1介导的控制VSMC表型的信号传导途径。我的结果表明，调节VSMC表型需要FGFR1介导的FRS2途径，而不是Crk或PLCgamma途径。这是关于FRS2参与VSMC表型调节的第一个报道证据。除FGF外，血小板衍生生长因子（PDGF）是一个有据可查的生长因子，可调节VSMC从收缩表型向增生和合成表型的转换。我发现FGF2和PDGF-BB调节VSMC表型，包括增加细胞增殖和降低平滑肌标志物基因表达。我还发现FGFR1与PDGFRbeta共免疫沉淀。这种复杂的形成不需要受体激活，并且通过细胞外和细胞内结构域介导。此外，VSMC中FRS2的敲低逆转了FGF2和PDGF-BB介导的平滑肌标记基因表达的下调。 FRS2是将FGFR连接到下游MAP激酶和Akt / mTOR信号转导的衔接子蛋白。我的生化研究表明，mTOR是FGFR1 / FRS2的下游靶标。 FGFR1激活在Ser2448位点磷酸化了mTOR，而mTOR抑制剂雷帕霉素则通过增加SMα-肌动蛋白的合成，部分逆转了FGFR1介导的VSMC表型转换。此外，mTOR与活化的FGFR1 / FRS2共免疫沉淀。总之，本研究结果将提供有关VSMC表型转换中FGFR1信号传导的信息，并为将来可能选择性阻断FGFR1信号传导的新药物设计奠定基础。用于药物干预。

著录项

  • 作者

    Chen, Pei-Yu.;

  • 作者单位

    The University of Maine.;

  • 授予单位 The University of Maine.;
  • 学科 Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 108 p.
  • 总页数 108
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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