Chair and Professor Pharmacology and Toxicology
The central focus of work in the Neubig lab is on G protein-coupled receptor (GPCR) signaling and intracellular modulators of that signaling. We also undertake academic drug discovery projects in this area. GPCRs are the targets of over 25% of current drugs and we are discovering novel ways to control their function. There are three major programs in the lab:
- Regulator of G protein Signaling (RGS) proteins control the actions of G protein coupled receptors. Blocking their action should enhance signaling while enhancing their action should suppress it. Using high throughput screening, whole genome RNA interference, structure-based drug design, and animal models, we have identified chemical modulators of RGS proteins with potential in neuropsychiatric disorders such as depression, pain, epilepsy, and Parkinson’s disease. We are current examining compound mechanisms and optimizing them for in vivo use.
- Gene transcriptional signaling downstream of the GTPases RhoA/C plays key roles in cancer metastasis and in diseases of fibrosis (scleroderma, pulmonary fibrosis, Crohn’s). We have identified two series of chemical inhibitors of Rho/MRTF/SRF-regulated gene transcription. These compounds show efficacy in models of skin fibrosis and melanoma metastasis.
- Physiological control of G proteins by RGS proteins in brain is explored with mutant mouse models. GNAO1 is mutated in human epilepsy syndromes such as epileptogenic encephalopathy and a mouse model that we have developed shows the same effect of seizures and sudden death. The mechanism of this is being explored relevant to epilepsy and potential therapies. RGS proteins also modulate functions in Fragile X syndrome which may also be a target of RGS therapeutics.
Department of Pharacology and Toxicology bio.