Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation

Conventional drug discovery approaches require a priori selection of an appropriate molecular target, but it is often not obvious which biological pathways must be targeted to reverse a disease phenotype. Phenotype-based screens offer the potential to identify pathways and potential therapies that i...

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Bibliographic Details
Published in:Nature biotechnology 2004-05, Vol.22 (5), p.595-599
Main Authors: Peterson, Randall T, Shaw, Stanley Y, Peterson, Travis A, Milan, David J, Zhong, Tao P, Schreiber, Stuart L, MacRae, Calum A, Fishman, Mark C
Format: Article
Language:English
Subjects:
Agriculture
Animals
Aortic Coarctation - genetics
Aortic Coarctation - prevention & control
Base Sequence
Bioinformatics
Biological and medical sciences
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Biomedicine
Biotechnology
Danio rerio
Disease Models, Animal
DNA Primers
Fundamental and applied biological sciences. Psychology
letter
Life Sciences
Mutation
Physiology
Zebrafish - genetics
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Summary:Conventional drug discovery approaches require a priori selection of an appropriate molecular target, but it is often not obvious which biological pathways must be targeted to reverse a disease phenotype. Phenotype-based screens offer the potential to identify pathways and potential therapies that influence disease processes. The zebrafish mutation gridlock (grl, affecting the gene hey2) disrupts aortic blood flow in a region and physiological manner akin to aortic coarctation in humans. Here we use a whole-organism, phenotype-based, small-molecule screen to discover a class of compounds that suppress the coarctation phenotype and permit survival to adulthood. These compounds function during the specification and migration of angioblasts. They act to upregulate expression of vascular endothelial growth factor (VEGF), and the activation of the VEGF pathway is sufficient to suppress the gridlock phenotype. Thus, organism-based screens allow the discovery of small molecules that ameliorate complex dysmorphic syndromes even without targeting the affected gene directly.
ISSN:1087-0156
1546-1696
DOI:10.1038/nbt963