Alexander Moise photoAlexander Moise
Assistant Professor, Pharmacology and Toxicology
University of Kansas

Structural characterization of cysteine-dependent acyltransferases

Mentor: Rick Dobrowsky, Professor, Pharmacology and Toxicology
The University of Kansas

Obesity is a rising epidemic in our society and requires a concerted research and clinical effort to understand its causes and to develop effective treatments. Inflammation is an underlying feature of obesity. Inhibition of inflammation is a new and potentially important approach in treating obesity and related disorders. Moise proposes to develop inhibitors of proinflammatory enzymes using structural and high-throughput methodologies.

The human genome codes for more than 30 PLA2 phospholipases. Though they catalyze the same reaction of hydrolyzing the sn-2 fatty acid from phospholipids, PLA2 impact on a vast and diverse array of physiological processes and play fundamentally important roles in lipid and membrane biology and in mediating autocrine and paracrine cell signaling. Due to their important contribution to the pathophysiology of major diseases, several PLA2 inhibitors are being explored for their use in the treatment of inflammatory diseases, asthma, coronary artery disease, atherosclerosis, cerebral ischemia-reperfusion and prostate cancer.

Despite the high potential of PLA2 as drug targets there has been a paucity of structural models to help understand their mechanism and allow for structure-based drug design. Moise proposes to determine the structure and enzymatic mechanism of Adipose Phospholipase A2 (AdPLA) which regulates adipose tissue lipolysis. Utilizing this knowledge of the mechanism and structure of AdPLA will allow for the design of specific AdPLA inhibitors that increase adipose tissue lipolysis. Genetic ablation of AdPLA in a knockout mouse model leads to resistance to diet induced obesity and increases in energy expenditure, adipose tissue lipolysis and fatty acid oxidation. Moise proposes that pharmacological inhibition of AdPLA could offer the potential to increase the rate of lipolysis and mimic the effect seen in Adpla-/- mice. As the net rate of lipolysis is an important determinant of whole-body insulin sensitivity our studies are paving the way towards development of a unique and potentially important therapeutic approach in the treatment of obesity and metabolic syndrome.