ArticleProceedings of the National Academy of Sciences of the United States of America2011
Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
What it found
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Who cites it
10 citing papers in PubMed, 11 citations in OpenAlex.
- Closing the 'phenotype gap' in precision medicine: improving what we measure to understand complex disease mechanisms.Mammalian genome : official journal of the International Mammalian Genome Society · 2019Review
- Article
- Integrating phenotypic small-molecule profiling and human genetics: the next phase in drug discovery.Trends in genetics : TIG · 2015Review
- Applying the logic of genetic interaction to discover small molecules that functionally interact with human disease alleles.Methods in molecular biology (Clifton, N.J.) · 2015Article
- Selective modulation of autophagy, innate immunity, and adaptive immunity by small molecules.ACS chemical biology · 2013Article
- Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Human genetics in rheumatoid arthritis guides a high-throughput drug screen of the CD40 signaling pathway.PLoS genetics · 2013Article
- Phenotyping patient-derived cells for translational studies in cardiovascular disease.Circulation · 2011Review
- Genetic links between circulating cells and cardiovascular risk.Circulation. Cardiovascular genetics · 2011Article
- Organic synthesis toward small-molecule probes and drugs.Proceedings of the National Academy of Sciences of the United States of America · 2011Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
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 lymphoblasts 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 nonblood disorders.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.