Michael Johnson Receives the 2012 American Foundation for Pharmaceutical Education (AFPE) Pre-Doctoral Fellowship in Pharmaceutical Sciences
Michael Johnson, a doctoral candidate working under the guidance of Professor Alex Makriyannis in the Center for Drug Discovery was awarded the prestigious AFPE Pre-Doctoral Fellowship. Michael’s dissertation research is entitled “The Development of a Highly Selective, Theranostic Nano-Platform to Inhibit and Image Human Monoacylglycerol Lipase - A Pathogenic Driver of Breast Cancer”.
Epidemiological data forecast, that more than 12% of female newborns in the United States will be diagnosed with breast cancer within their lifetime. Those with aggressive forms of the disease will have less than a 25% chance of surviving 5 years after diagnosis. Without pharmacological intervention, breast cancer will remain a significant, global health problem for the foreseeable future. Currently, the limiting step in the breast cancer drug discovery initiative is the identification of highly selective imaging and therapeutic agents for the diagnosis and treatment of the disease. I purpose the discovery, design, and characterization of a novel, multimodal, “theranostic” nanoplatform, which has the unique ability to diagnose disease states while showing real-time, traceable therapeutic efficacy. I argue that this platform will also increase the efficiency of translation of new, medically relevant discoveries and technologies from the lab bench to the clinic.
Monoacylglycerol lipase (MGL) is a serine hydrolase that regulates endocannabinoid signaling. MGL has a typical serine-histidine-aspartate catalytic triad, belongs to the α/β hydrolase family, and is the major enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG); an endocannabinoid that is synthesized and localized in the membrane bilayer. Increased levels of 2-AG are considered antinociceptive, antiallodynic, anti-inflammatory and therapeutic for neurodegenerative disorders. Overexpression of MGL, and the resultant over-hydrolysis of 2-AG, elevates the level of protumorigenic signaling lipids in cancer cells. As such, MGL regulates a fatty acid network that promotes cancer pathogenesis. MGL inhibition has been shown to attenuate the growth, migration and invasion of aggressive/metastatic, prostate and breast cancer cells. The development of a highly selective imaging modality for examining functional MGL will be a key step in our understanding of the complete metabolic role this potential biomarker for breast cancer plays.
MGL transiently associates with cell membranes. To completely understand the mechanism of action of this enzyme, it is vital that we first unravel the structural dynamics of the MGL-membrane interaction and also MGL’s intracellular localization. MGL, like most lipases, exhibits interfacial activation and undergoes a transition from a “solution,” to a “membrane-associated” conformation; a process that involves attachment of part of its lid domain to the phospholipid bilayer. As a prerequisite for developing small molecule drugs that target MGL, it is essential to unravel how these conformational and spatial dynamics come about.