Illustrating rapid receptor-specific estrogen signaling.

Historically, estrogen receptor α and β have been connected to estrogen signaling on both genomic and non-genomic levels. Further evidence for estrogens’ involvement in rapid non-genomic signaling arose with the characterization consequent studies of a G protein-coupled estrogen receptor (GPER) which bound estrogen and subsequently induced downstream signaling. Through virtual screening and high-throughput analysis, several selective ligands have been discovered and shown possible physiological roles of GPER. Studies have revealed that this new mechanism of estrogen signaling may prove to be important in the treatment of estrogen sensitive cancers and vital in neuroprotection.

The long-term goal of this research is to design ligands that bind to GPER, identify selective agonists and antagonists, characterize their interactions with the receptor, analyze those interactions to develop biased ligands which can modulate receptor function, and determine their therapeutic potential. These studies are significant because further understanding of the receptor-ligand interaction could ultimately lead to new therapeutics and better understanding of several types of cancer and the neuroprotective effects of estrogens.     

Developing fluorescent probes for induced pluripotent stem cells.

Induced pluripotent stem (iPS) cells offer an alternative route to study stem cells. Currently, iPS cells are generated by reprogramming somatic cells by introducing multiple transcription factors that are essential for pluripotency. Several markers have been used to test if the subsequent iPS cells are indeed pluripotent, but inconsistent results have plagued measurements of varying cell colonies. Therefore, there is a need for additional markers and measurements for pluripotency.   

To help address this critical research need, our lab has been developing specialized fluorescent probes to monitor pluripotency in iPS cells. The research relies on targeting key proteins, which correlate to pluripotency, with fluorescently labeled exogenous and endogenous ligands that specifically target those proteins. These newly synthesized probes will be used to aid researchers in iPS cell measurements.

Revealing the mechanism behind how environmental factors impact DNA modification.

DNA modifications moderate gene expression and are vital for development, genomic stability, and stem cell pluripotency (ability to differentiate into different cell types). As such, changes in DNA modification have been shown to have profound effects in stem cell biology, cancer biology, and neurobiology. One of the most prevalent DNA modifications, cytosine methylation, selectively inactivates genes by preventing the DNA from being transcribed. Until recently, this process was thought to be enzymatically irreversible; however, a family of ten-eleven translation (TET) enzymes was found to actively facilitate DNA demethylation by converting 5-methylcytosine (5mc) to 5-hydroxymethylcytosine (5hmc) which can then be further oxidized back to cytosine. This activity has extraordinary implications since it is a paradigm shift in our understanding of how dynamic DNA methylation states affect biological processes. Overall, exploring this interaction with chemical probes could lead to a greater understanding of TET activity, provide new techniques for their study and potentially lead to novel therapeutics.