Nuclear receptors are ligand-dependent transcription factors that are therapeutic targets for many diseases, from cancers to inflammation. Unfortunately, existing drugs target nuclear receptors broadly and are hampered by severe and potentially fatal side effects. The discovery of cell type-specific nuclear receptor ligands would dramatically improve our ability to target nuclear receptors and lead to improved treatments for many diseases.

Our goal is to identify small molecules that target nuclear receptors specifically, so that receptors in a diseased tissue can be targeted without causing side effects in normal tissues. Current approaches to identify selective nuclear receptor modulators rely on in vitro or cell culture methods and rational drug design. We believe that the zebrafish is uniquely suited for unbiased chemical screens to identify small molecules that activate a particular nuclear receptor in a tissue-specific manner.

Estradiol (3 nM) activates receptors in the liver (arrow head) and in the heart valves (arrows), whereas genistein (18.5 nM) preferentially activates receptors in the heart valves. Scale bars = 500 μm

We have used transgenic zebrafish that report estrogen receptor activity and identified compounds that preferentially activate receptors in the heart compared to the liver. We are currently expanding this approach to identify selective glucocorticoid receptor modulators that are more potent in certain cell types, such as T-cells, compared to other cell types. The compounds we identify could revolutionize our knowledge of nuclear receptor structure-activity relationships, be used as tools for basic research and serve as the basis to design small molecules for therapeutic use.

Publications

Romano SN, Gorelick DA. Semi-automated Imaging of Tissue-specific Fluorescence in Zebrafish Embryos. Journal of Visualized Experiments 87:e51533 (2014)

Gorelick DA and Halpern ME. Visualization of estrogen receptor transcriptional activation in zebrafish. Endocrinology 152: 2690 (2011)