How are calcium oscillations generated and maintained
My research interrogates the mechanisms which elicit and maintain hormone-induced Ca2+ oscillations in primary hepatocytes. In liver hepatocytes hormonal regulation of Ca2+ signaling underlies many of the primary functions of the organ including glucose metabolism, mitochondrial physiology and gene expression. Hormones which couple to phospholipase C (PLC), Gq-linked G-protein coupled receptors (GPCRs), hydrolysis the membrane phosphoinositide lipid PIP2 to generate inositol 1,4,5-trisphosphate (IP3), and diacylglycerol (DAG), which in turn regulate cell function via Ca2+ release and PKC activation. Hepatocytes display stimulus-strength regulated Ca2+ oscillations and waves importantly the pattern of intracellular Ca2+ fluctuations encodes complex spatial and temporal information to regulate cell function. We utilize single cell digital fluorescent imaging techniques combined with biochemical techniques to dissect the mechanisms which generate, maintain and regulate Ca2+ oscillations. These studies address the ongoing debate, whether Ca2+ oscillations arise due to Ca2+ feedback on the IP3 receptor or as a consequence of fluctuations in IP3, hence phospholipase C activity. Our studies have provided compelling evidence that Ca2+ oscillations in hepatocytes depend on IP3 fluctuations arising from positive Ca2+ feedback on PLC.
The role of calcium dysregulation in the development of liver disease
Non-alcoholic fatty liver disease (NAFLD) is linked to type 2 diabetes and a number of other major comorbidities. In the liver the normal balance of carbohydrate and lipid metabolism is maintained by lipogenic hormones including insulin, and glucogenic and lipolytic hormones including glucagon and catecholamines. A common signaling pathway involved in the control of catabolic metabolism in liver involves activation of PLC by GPCRs to produces the Ca2+-mobilizing second messenger IP3, and DAG. These GPCRs generate cytosolic Ca2+ oscillations in single hepatocytes, which are integrated into intercellular Ca2+ waves that propagate across entire lobules in the intact liver. Our preliminary data show that short-term high fat diet (HFD) feeding of mice attenuates PLC-linked Ca2+ signaling in hepatocytes and impairs propagation of Ca2+ waves in intact liver. Zonation of liver metabolism across the porto-central axis is an essential feature of healthy liver physiology. I investigate the effects of this loss of signal transduction throughout the liver and how this effects lipid and carbohydrate metabolism and the leads to steatosis and NALFD.
EDUCATION AND POSITIONS
2017 - Present
Rutgers - New Jersey Medical School
Assistant Professor
2007-2017
UMDNJ
Postdoctoral Researcher
2003-2007
University of Leicester
PhD