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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Adenosine kinase inhibition selectively promotes rodent and porcine islet p-cell replication
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Adenosine kinase inhibition selectively promotes rodent and porcine islet p-cell replication

机译：腺苷激酶抑制作用选择性促进啮齿动物和猪胰岛p细胞复制

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摘要

Diabetes is a pathological condition characterized by relative insulin deficiency, persistent hyperglycemia, and, consequently, diffuse micro- and macrovascular disease. One therapeutic strategy is to amplify insulin-secretion capacity by increasing the number of the insulin-producing β cells without triggering a generalized prolifera tive response. Here, we present the development of a small-molecule screening platform for the identification of molecules that increase β-cell replication. Using this platform, we identify a class of compounds [adenosine kinase inhibitors (ADK-ls)] that promote replication of primary β cells in three species (mouse, rat and pig). Furthermore, the replication effect of ADK-ls is cell type-selective: treatment of islet cell cultures with ADK-ls increases replication of β cells but not that of α cells, PP cells, or fibroblasts. Short-term in vivo treatment with an ADK-I also increases p-cell replication but not exo crine cell or hepatocyte replication. Therefore, we propose ADK in hibition as a strategy for the treatment of diabetes.
机译：糖尿病是一种病理状况，其特征是相对胰岛素缺乏，持续性高血糖症，以及弥漫性微血管和大血管疾病。一种治疗策略是通过增加产生胰岛素的β细胞的数量来扩增胰岛素分泌能力，而不触发普遍的增殖反应。在这里，我们提出了一种小分子筛选平台的开发，用于鉴定增加β细胞复制的分子。使用该平台，我们鉴定了一类可促进三种物种（小鼠，大鼠和猪）中原代β细胞复制的化合物[腺苷激酶抑制剂（ADK-ls）]。此外，ADK-1s的复制作用是细胞类型选择性的：用ADK-1s处理胰岛细胞培养物可增加β细胞的复制，但不能增加α细胞，PP细胞或成纤维细胞的复制。用ADK-1进行的短期体内治疗也会增加p细胞的复制，但不会增加卵泡细胞或肝细胞的复制。因此，我们提出抑制性ADK作为糖尿病的治疗策略。

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  • 作者

    Justin P. Annes; Jennifer Hyoje Ryu; Kelvin Lam; Peter J. Carolan; Katrina Utz; Jennifer Hollister-Lock; Anthony C. Arvanites; Lee L. Rubin; Gordon Weir; Douglas A. Melton;

  • 作者单位

    Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138,Division of Genetics, Department of Medicine,Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138;

    Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138;

    Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;

    Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138;

    Sectionof Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School,Boston, MA 02115;

    Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138;

    Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138;

    Sectionof Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School,Boston, MA 02115;

    Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138,Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138;

  • 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

    chemical screening; regeneration;

    机译：化学筛选;再生;

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