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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes
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Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes

机译:单基因糖尿病患者血细胞中疾病等位基因依赖性小分子敏感性

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摘要

Even as genetic studies identify alleles that influence human disease susceptibility, it remains challenging to understand their functional significance and how they contribute to disease phenotypes. Here, we describe an approach to translate discoveries from human genetics into functional and therapeutic hypotheses by relating human genetic variation to small-molecule sensitivities. We use small-molecule probes modulating a breadth of targets and processes to reveal disease allele-dependent sensitivities, using cells from multiple individuals with an extreme form of diabetes (maturity onset diabetes of the young type 1, caused by mutation in the orphan nuclear receptor HNF4α). This approach enabled the discovery of small molecules that show mechanistically revealing and therapeutically relevant interactions with HNF4α in both lympho-blasts and pancreatic β-cells, including compounds that physically interact with HNF4α. Compounds including US Food and Drug Administration-approved drugs were identified that favorably modulate a critical disease phenotype, insulin secretion from β-cells. This method may suggest therapeutic hypotheses for other non-blood disorders.
机译:即使遗传学研究确定了影响人类疾病易感性的等位基因,理解它们的功能重要性以及它们如何促进疾病表型仍然具有挑战性。在这里,我们描述了一种通过将人类遗传变异与小分子敏感性相关的方法,将人类遗传学发现转化为功能和治疗假设的方法。我们使用小分子探针来调节靶点和过程的广度,以揭示疾病等位基因依赖性的敏感性,并使用来自多个个体的细胞,这些个体患有糖尿病的一种极端形式(由孤儿核受体突变导致的年轻1型糖尿病) HNF4α)。这种方法使得能够发现在淋巴母细胞和胰腺β细胞中与HNF4α具有机理性揭示和治疗相关作用的小分子,包括与HNF4α物理相互作用的化合物。确定了包括美国食品药品监督管理局批准的药物在内的化合物,它们可以很好地调节关键疾病的表型,即β细胞的胰岛素分泌。这种方法可能提出其他非血液疾病的治疗假说。

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  • 作者单位

    Center for Systems Biology, Massachusetts General Hospital, Simches Research Center, 185 Cambridge Street, Boston, MA 02114,Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115,Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142;

    Center for Systems Biology, Massachusetts General Hospital, Simches Research Center, 185 Cambridge Street, Boston, MA 02114;

    Center for Systems Biology, Massachusetts General Hospital, Simches Research Center, 185 Cambridge Street, Boston, MA 02114;

    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142,Howard Hughes Medical Institute and Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, 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

    synthetic interactions; chemical screen;

    机译:综合相互作用;化学筛;

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