期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 2, 页码 492-497出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1016789108
关键词
synthetic interactions; chemical screen
资金
- National Institutes of Health [K08 HL077186, GM38627]
- Gunzburg Family Foundation at Massachusetts General Hospital
- National Institutes of Health/National Cancer Institute [N01-CO-12400]
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 HNF4 alpha). This approach enabled the discovery of small molecules that show mechanistically revealing and therapeutically relevant interactions with HNF4 alpha in both lymphoblasts and pancreatic beta-cells, including compounds that physically interact with HNF4 alpha. Compounds including US Food and Drug Administration-approved drugs were identified that favorably modulate a critical disease phenotype, insulin secretion from beta-cells. This method may suggest therapeutic hypotheses for other non-blood disorders.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据