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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A gene therapy approach for long-term normalization of blood pressure in hypertensive mice by ANP-secreting human skin grafts
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A gene therapy approach for long-term normalization of blood pressure in hypertensive mice by ANP-secreting human skin grafts

机译：通过分泌ANP的人类皮肤移植物使高血压小鼠的血压长期正常化的基因治疗方法

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摘要

The use of bioengineered human skin as a bioreactor to deliver therapeutic factors has a number of advantages including accessibility that allows manipulation and monitoring of genetically modified cells. We demonstrate a skin gene therapy approach that can regulate blood pressure and treat systemic hypertension by expressing atrial natriuretic peptide (ANP), a hormone able to decrease blood pressure, in bioengineered human skin equivalents (HSE). Additionally, the expression of a selectable marker gene, multidrug resistance (MDR) type 1, is linked to ANP expression on a bicistronic vector and was coexpressed in the human keratinocytes and fibroblasts of the HSE that were grafted onto immunocompromised mice. Topical treatments of grafted HSE with the antimitotic agent colchicine select for keratinocyte progenitors that express both MDR and ANP. Significant plasma levels of human ANP were detected in mice grafted with HSE expressing ANP from either keratinocytes or fibroblasts, and topical selection of grafted HSE resulted in persistent high levels of ANP expression in vivo. Mice with elevated plasma levels of human ANP showed lower renin levels and, correspondingly, had lower systemic blood pressure than controls. Furthermore, mice with HSE grafts expressing human ANP did not develop elevated blood pressure when fed a high-salt diet. These findings illustrate the potential of this human skin gene therapy approach to deliver therapeutic molecules systemically for long-term treatment of diverse diseases.
机译：使用生物工程化的人类皮肤作为生物反应器来传递治疗因子具有许多优势，包括可访问性，该可访问性允许对基因修饰的细胞进行操作和监控。我们展示了一种皮肤基因疗法，可通过在生物工程人体皮肤等效物（HSE）中表达心房利钠肽（ANP）（一种能够降低血压的激素）来调节血压并治疗全身性高血压。此外，选择性标记基因1的多重耐药性（MDR）类型的表达与双顺反子载体上的ANP表达相关，并且在移植到免疫功能低下的小鼠的人角质形成细胞和HSE成纤维细胞中共表达。用抗有丝分裂剂秋水仙碱对嫁接的HSE进行局部治疗，可以选择表达MDR和ANP的角化细胞祖细胞。在移植有来自角质形成细胞或成纤维细胞的表达HSE的HSE的小鼠中检测到人ANP的显着水平，并且局部选择移植的HSE导致体内ANP的表达持续高水平。血浆人ANP水平升高的小鼠显示肾素水平较低，相应地，其全身血压也低于对照组。此外，喂食高盐饮食时，带有表达人ANP的HSE移植物的小鼠不会出现血压升高。这些发现说明了这种人类皮肤基因治疗方法具有潜力，可以全身性地输送治疗分子，以长期治疗各种疾病。

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  • 作者

    Jean-Philippe Therrien; Soo Mi Kim; Atsushi Terunuma; Yan Qin; Christine L. Tock; Wolfgang Pfuetzner; Manabu Ohyama; Jurgen Schnermann; Jonathan C. Vogel;

  • 作者单位

    Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    National Institute of Digestive and Diabetes and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;

    Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    National Institute of Digestive and Diabetes and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;

    Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Department of Dermatology and Allogology, University of Giessen and Marburg, 35037 Marburg, Germany;

    Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan;

    National Institute of Digestive and Diabetes and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;

    Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 Dermatology Branch National Cancer Institute, NIH Bldg. 10 / Room 12N260, 10 Center Drive, MSC 1908, Bethesda, MD 20892-1908;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    keratinocytes; human engineered skin; hypertension; multi-drug resistance gene; retroviral vectors;

    机译：角质形成细胞人体工程皮肤高血压;多药耐药基因逆转录病毒载体;

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