|Ph.D., 1993, Biochemistry, Indian Institute of Science in Bangalore, India|
|Postdoctoral research: Department of Biology at the University of California, San Diego|
|Office:||University of Massachusetts Medical School
364 Plantation Street, LRB-515
Worcester, MA 01605
Sphingolipids are essential structural components of membranes and are also bioactive lipids that regulate diverse cellular functions. We aim to elucidate physiological functions for these lipids, define mechanisms that integrate these functions with other cellular processes and understand networks that maintain sphingolipid homeostasis. We combine genetic, molecular, biochemical and cell biological approaches and our model systems include fruit flies, mammalian cells and mice. Links between sphingolipid imbalances and human pathologies underscore the importance of sphingolipid homeostasis and we hope that understanding these mechanisms will provide opportunities for therapeutic strategies to treat diseases including sphingolipidoses, neurodegeneration, cancer, metabolic syndrome and diabetes.
Project 1: Identify components involved in the regulation of triglycerides by CG6277 and CG 8093 lipases through a genetic approach
We have identified two novel AKT/FOXO regulated lipases, CG6277 and CG8093, which regulate triglyceride hydrolysis and cardiac function. These lipases play a critical role in increased ceramide environment. We have initiated a simple enhancer / suppressor screen in Drosophila with a view to identifying interactors and components of the pathways that are regulated by CG8093 and CG6277. These are RNAi based genetic screens that take advantage of the increased starvation sensitivity phenotype and augmented accumulation of neutral lipids in the gut of flies upon targeted RNAi knockdown of each of these lipases. In a pilot screen, we have identified genetic interactors that either increase or decrease the starvation sensitivity of each of these lipases. Students will have the opportunity to participate in the ongoing RNAi screen, identify additional modifiers and study their functions in triglyceride and energy metabolism using cell biological and biochemical methods.
Project 2: Exploring the sphingolipid-NAD-sirtuin axis to delineate links between sphingolipid and NAD metabolism
Metabolomic profiling of Drosophila ceramide kinase mutants (dcerk) that accumulate ceramide have revealed specific changes in metabolites of nicotinamide adenine dinucleotide (NAD) metabolism and genetic and biochemical experiments have shown that a decrease in NAD+ level increases acetylation of proteins in different cellular compartments. This is because NAD+ is a cofactor for sirtuin activity. In this project, students will use various sphingolipid mutants that accumulate or are deficient in specific sphingolipids and test if protein deacetylation is also altered in these mutants. A second line of investigation includes genetic experiments to address if some of the phenotypes of these sphingolipid mutants such as increased sensitivity to different stress is due in part to changes in sirtuin activity.
A postdoctoral position is available to understand how novel lipases regulate triglyceride metabolism and cardiac function in physiological and pathological states. Please send CV's to Usha Acharya