Daniel K. Nomura
Mapping Dysregulated Metabolic Pathways in Disease
Dysregulated metabolism contributes to the pathophysiology of a large number of complex human diseases including cancer, pain, inflammation, neurodegenerative disease, atherosclerosis, obesity, and diabetes. These changes not only include fundamental rewiring of cell metabolism, but also impact the levels of metabolites and activities of enzymes that regulate them. We utilize advanced proteomic and metabolomic approaches to globally and comprehensively map altered biochemical pathways that underlie disease progression towards identifying, characterizing, and developing next-generation therapeutic strategies for combatting human disease through targeting nodal points of control in metabolism.
One of the major focuses of our lab is investigating the role of monoacylglycerol lipase (MAGL), which we have discovered to be one such nodal enzyme that regulates diverse lipid signaling pathways in human disease. We have found that MAGL is highly upregulated across multiple types of aggressive human cancer cells and primary tumors where it controls the release of fatty acids that are used as building blocks for making cancer-promoting lipids. Blocking MAGL suppresses cancer cell aggressiveness and tumor growth through suppressing the lipid signals that fuel the malignancy of cancer. In the brain, we find that MAGL plays a different role in linking the anti-inflammatory cannabinoid pathway (that marijuana acts on) and the pro-inflammatory eicosanoid system (that is suppressed by aspirin and ibuprofen) through breaking down the endogenous cannabinoid ("endocannabinoid") signaling lipid 2-arachidonoylglycerol to the arachidonic acid precursor required for eicosanoid biosynthesis. We find that blocking MAGL exhibits many of beneficial effects of both marijuana and aspirin, while avoiding their psychotropic or gastrointestinal side-effects. Specifically, blocking MAGL exhibits analgesic effects through enhancing endocannabinoid signaling and exerts profound anti-inflammatory and neuroprotective effects against neurodegeneration through suppressing eicosanoid pathways.
Our studies on MAGL and other enzymes have fueled our interest in how dysregulated metabolism can affect complex human diseases such as cancer and pathologies which have an inflammatory basis including neurodegenerative diseases, arthritis, pain, and atherosclerosis. Our goal is to use our innovative functional proteomic and metabolomic platforms to identify dysregulated metabolic pathways in these diseases in the hopes of finding novel targets, like MAGL, for therapeutic intervention.