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首页> 外文学位 >Targeting of retroviral vectors to specific cell types mediated by soluble retroviral receptor-ligand bridge proteins.
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Targeting of retroviral vectors to specific cell types mediated by soluble retroviral receptor-ligand bridge proteins.

机译：将逆转录病毒载体靶向由可溶性逆转录病毒受体-配体桥蛋白介导的特定细胞类型。

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摘要

We developed a novel approach for targeting retroviral vectors to specific cell types. This technique relies on the use of a bridge protein composed of the extracellular domain of a retroviral receptor fused to a cellular ligand. The retroviral receptor-ligand bridge protein was predicted to be a bi-functional reagent that could bind both to cell surface cognate ligand receptors and to the viral envelope. Upon the binding of this bridge protein to cells, the extracellular domain of the retroviral receptor would then mediate viral entry into cells.;As a model system, we constructed a bridge protein composed of the extracellular domain of Tva, the cellular receptor for subgroup A avian leukosis virus (ALV-A), fused to the N-terminus of the mature form of human epidermal growth factor (EGF). A proline-rich linker was inserted between the two domains, to favor their independent folding and function. The Tva-EGF bridge protein bound specifically to cells expressing EGF receptors (EGFR) and mediated specific ALV-A entry, but cells that did not express EGFR were not infected. ALV-A entry into cells mediated by Tva-EGF was on average 23% relative to a control cell line that expressed Tvasyn, a transmembrane form of Tva.;To explore the versatility of this approach, we tested other cellular ligands and a single chain antibody for their ability to mediate ALV-A entry into cells expressing their cognate ligand receptors or antigens. Bridge proteins, Tva-herbeta1, Tva-VEGF110, and Tva-MR1, in which the EGF-like domain of heregulin beta1, the 110 N-terminal amino acids of vascular endothelial growth factor, or a single chain antibody, MR1, respectively, were fused at the C-terminus of the extracellular domain of Tva were generated. These bridge proteins bound to cells that expressed their cognate ligand receptors or antigens and mediated specific ALV-A entry into these cells. In the future, this method of viral targeting may prove to be a versatile means to deliver retroviral vectors to specific cell types in vivo.
机译：我们开发了一种将逆转录病毒载体靶向特定细胞类型的新颖方法。该技术依赖于桥蛋白的使用，该桥蛋白由与细胞配体融合的逆转录病毒受体的胞外域组成。逆转录病毒受体-配体桥蛋白被认为是一种双功能试剂，可以与细胞表面同源配体受体和病毒包膜结合。该桥蛋白与细胞结合后，逆转录病毒受体的胞外域将介导病毒进入细胞。作为模型系统，我们构建了由Tva胞外域（A亚型的细胞受体）组成的桥蛋白。禽白血病病毒（ALV-A），与人表皮生长因子（EGF）成熟形式的N端融合。在两个结构域之间插入了富含脯氨酸的接头，以支持它们的独立折叠和功能。 Tva-EGF桥蛋白与表达EGF受体（EGFR）的细胞特异性结合并介导特异性ALV-A进入，但不表达EGFR的细胞没有被感染。相对于表达Tvasyn（Tva的跨膜形式）的对照细胞系，ALV-A进入由Tva-EGF介导的细胞平均占23％；为探索这种方法的多功能性，我们测试了其他细胞配体和单链抗体介导ALV-A进入表达其同源配体受体或抗原的细胞的能力。桥蛋白Tva-herbeta1，Tva-VEGF110和Tva-MR1，其中调蛋白beta1的EGF样结构域，血管内皮生长因子的110个N端氨基酸或单链抗体MR1，在Tva的胞外结构域的C-末端融合。这些桥蛋白与表达其同源配体受体或抗原并介导特异性ALV-A进入这些细胞的细胞结合。将来，这种病毒靶向方法可能被证明是将逆转录病毒载体体内递送至特定细胞类型的通用手段。

著录项

  • 作者

    Snitkovsky, Sophie.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Biology Microbiology.;Biology Molecular.
  • 学位 Ph.D.
  • 年度 2000
  • 页码 173 p.
  • 总页数 173
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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