Kelly O’Rourke
Targeting Nurr1-RXRa Activation for Parkinson's Disease Therapeutics
Abstract
Nurr1 is an orphan nuclear receptor (NR) transcription factor highly expressed in midbrain dopaminergic neurons that regulates gene programs driving dopamine biosynthesis, neuron development, and maintenance. Nurr1 dysfunction is correlated with Parkinsonian phenotypes such as motor and cognitive deficits, making it a promising therapeutic target for Parkinson’s Disease. Nurr1 functions alone or as a heterodimer with another NR called RXRa. Our lab discovered that RXRa ligands activate transcription of Nurr1-RXRa through a nonclassical mechanism via dissociation of the heterodimer. This project will extend and challenge this model by studying how RXRa ligands influence Nurr1 and RXRa chromatin occupancy, subcellular localization, and by performing a pharmacological screen. Successful outcomes of these studies will validate a novel approach to modulate the Nurr1-RXRa heterodimer through the discovery and validation of small molecule protein-protein interaction (PPI) inhibitors.
I am honored to receive the Predoctoral Fellowship in Drug Discovery, which will advance my research in challenging a noncanonical mechanism of nuclear receptor activation to explore new avenues of targeting Parkinson’s disease.
