Research
Cardiovascular disease is a growing problem worldwide and the leading cause of death in the United States. Phospholipase C (PLC) enzymes, in particular PLCβ and PLCε, are essential for normal cardiovascular function and generate the second messengers diacylglycerol (DAG) and inositol phosphates (IPs), which in turn lead to increases in intracellular calcium and activation of protein kinase C. Abnormally high levels of DAG and IPs can cause cardiac arrhythmias, hypertrophy, and heart failure. PLCβ and PLCε respond to various extracellular signals that serve to regulate the production of these second messengers. PLCβ is activated downstream of G protein-coupled receptors, such as the angiotensin receptor, via direct interactions with the heterotrimeric G protein subunits Gαq and Gβγ. PLCε integrates and amplifies signals from both G protein-coupled receptors, such as the β-adrenergic receptor, and receptor tyrosine kinases, such as the epidermal growth factor receptor, via direct interactions with small molecular weight G proteins including Ras and Rho. Recently, PLCε has also been identified as having tumor suppressor function, in particular in gastric, esophogeal, and colon cancers.
The goal of our lab is to understand the molecular mechanisms regulating PLCβ and PLCε under basal and activating conditions. These studies incorporate biochemical and cell-based functional assays with a combination of electron microscopy, X-ray crystallography, and small angle X-ray scattering. Taken together, these studies will provide much needed insight into two key enzymes that contribute to cardiovascular function and disease, and will ultimately aid in the identification and development of novel therapeutics that modulate signaling by these enzymes.