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首页> 外文学位 >Extracellular matrix regulation in retinal pigment epithelial cells and role in retinal fibrosis.
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Extracellular matrix regulation in retinal pigment epithelial cells and role in retinal fibrosis.

机译：视网膜色素上皮细胞中的细胞外基质调节及其在视网膜纤维化中的作用。

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摘要

The research in our laboratory is focused on the response of the retinal pigment epithelium (RPE) to injury and how RPE structure and function are altered in pathologic retinal disorders such as proliferative vitreoretinopathy (PVR). RPE cells regulate the balanced homeostasis of growth factors and extracellular matrix (ECM) proteins. We hypothesized that fibronectin EDA (FN-EDA), an ECM molecule implicated in excessive scar formation and chronic fibrosis, is expressed and regulated by activated RPE cells and thus plays an essential role in PVR pathogenesis.;Using primary cultures of human RPE cells, we detected FN-EDA protein under normal conditions but not in serum-deprived cells. We found that serum increases the content of FN-EDA in these cultures in a dose-dependent manner. Therefore, all subsequent experiments were carried out in the absence of serum to eliminate any serum-related effects on FN-EDA regulation by RPE cells. In frozen sections of normal human retinas, though FN-EDA was present in retinal and choroidal vessels, the RPE monolayer was devoid of FN-EDA. These results suggest that resting RPE cells do not express FN-EDA.;In growth factor-stimulated cultures of RPE cells, we found that FN-EDA mRNA and protein were induced by transforming growth factor-beta2 (TGFbeta2) in a time- and dose-dependent manner but not by connective tissue growth factor (CTGF). By co-stimulating RPE cultures with TGFbeta2 and CTGF, we demonstrated that CTGF, through its N-terminal domain, augments the TGFbeta2-induced expression of FN-EDA at the protein level. Using CTGF domain-specific antibodies, we blocked this synergistic effect. By protein-protein interaction studies, we established that CTGF directly interacts with TGFbeta2 and its receptor TGFbetaRII at its N- and C-terminal domains, respectively. Our results therefore suggest that CTGF modulates TGFbeta2 responses and provide further evidence for CTGF as a down-stream mediator of TGFbeta2.;Finally, we demonstrate that FN-EDA is abundantly expressed in PVR membranes in a pattern that co-localizes with TGFbeta2 and CTGF. FN-EDA upregulates type I collagen in cultures of RPE cells as do TGFbeta2 and CTGF. These findings suggest that FN-EDA is an important mediator of retinal fibrosis, making it a potential target for therapy.
机译：我们实验室的研究集中在视网膜色素上皮（RPE）对损伤的反应以及病理性视网膜疾病（如增生性玻璃体视网膜病变（PVR））中RPE结构和功能的改变。 RPE细胞调节生长因子和细胞外基质（ECM）蛋白的平衡稳态。我们假设纤连蛋白EDA（FN-EDA）是一种涉及过度疤痕形成和慢性纤维化的ECM分子，由活化的RPE细胞表达和调控，因此在PVR发病机理中起着至关重要的作用。我们在正常条件下检测到FN-EDA蛋白，但在血清缺乏的细胞中未检测到。我们发现血清以剂量依赖的方式增加了这些培养物中FN-EDA的含量。因此，所有随后的实验均在无血清的条件下进行，以消除RPE细胞对FN-EDA调节的任何血清相关影响。在正常人视网膜的冰冻切片中，尽管视网膜和脉络膜血管中存在FN-EDA，但RPE单层不含FN-EDA。这些结果表明，静止的RPE细胞不表达FN-EDA。在生长因子刺激的RPE细胞培养物中，我们发现FN-EDA mRNA和蛋白是通过在一定的时间内转化生长因子β2（TGFbeta2）诱导的。剂量依赖性，但不依赖结缔组织生长因子（CTGF）。通过与TGFbeta2和CTGF共同刺激RPE培养物，我们证明CTGF通过其N末端结构域在蛋白质水平上增强了TGFbeta2诱导的FN-EDA表达。使用CTGF域特异性抗体，我们阻断了这种协同作用。通过蛋白质间相互作用研究，我们确定CTGF分别在其N端和C端结构域直接与TGFbeta2及其受体TGFbetaRII相互作用。因此，我们的结果表明CTGF调节TGFbeta2反应，并为CTGF作为TGFbeta2的下游介质提供进一步的证据。 。 FN-EDA像TGFbeta2和CTGF一样上调RPE细胞培养物中的I型胶原。这些发现表明FN-EDA是视网膜纤维化的重要介质，使其成为治疗的潜在靶标。

著录项

  • 作者

    Khankan, Rima.;

  • 作者单位

    University of Southern California.;

  • 授予单位 University of Southern California.;
  • 学科 Health Sciences Pathology.;Health Sciences Ophthalmology.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 138 p.
  • 总页数 138
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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