Identifying therapeutic targets by combining transcriptional data with ordinal clinical measurements View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-09-20

AUTHORS

Leila Pirhaji, Pamela Milani, Simona Dalin, Brook T. Wassie, Denise E. Dunn, Robert J. Fenster, Julian Avila-Pacheco, Paul Greengard, Clary B. Clish, Myriam Heiman, Donald C. Lo, Ernest Fraenkel

ABSTRACT

The immense and growing repositories of transcriptional data may contain critical insights for developing new therapies. Current approaches to mining these data largely rely on binary classifications of disease vs. control, and are not able to incorporate measures of disease severity. We report an analytical approach to integrate ordinal clinical information with transcriptomics. We apply this method to public data for a large cohort of Huntington’s disease patients and controls, identifying and prioritizing phenotype-associated genes. We verify the role of a high-ranked gene in dysregulation of sphingolipid metabolism in the disease and demonstrate that inhibiting the enzyme, sphingosine-1-phosphate lyase 1 (SPL), has neuroprotective effects in Huntington’s disease models. Finally, we show that one consequence of inhibiting SPL is intracellular inhibition of histone deacetylases, thus linking our observations in sphingolipid metabolism to a well-characterized Huntington’s disease pathway. Our approach is easily applied to any data with ordinal clinical measurements, and may deepen our understanding of disease processes. More... »

PAGES

623

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-017-00353-6

    DOI

    http://dx.doi.org/10.1038/s41467-017-00353-6

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1091790087

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28931805


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    32 schema:description The immense and growing repositories of transcriptional data may contain critical insights for developing new therapies. Current approaches to mining these data largely rely on binary classifications of disease vs. control, and are not able to incorporate measures of disease severity. We report an analytical approach to integrate ordinal clinical information with transcriptomics. We apply this method to public data for a large cohort of Huntington’s disease patients and controls, identifying and prioritizing phenotype-associated genes. We verify the role of a high-ranked gene in dysregulation of sphingolipid metabolism in the disease and demonstrate that inhibiting the enzyme, sphingosine-1-phosphate lyase 1 (SPL), has neuroprotective effects in Huntington’s disease models. Finally, we show that one consequence of inhibiting SPL is intracellular inhibition of histone deacetylases, thus linking our observations in sphingolipid metabolism to a well-characterized Huntington’s disease pathway. Our approach is easily applied to any data with ordinal clinical measurements, and may deepen our understanding of disease processes.
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