My sole career objective is to secure a faculty position at a major research university or research institute. My undergraduate (B.A. in molecular and cell biology) and graduate (Ph.D. in molecular toxicology) research experience at the UC Berkeley under Prof John Casida focused on elucidating off-targets of organophosphorus (OP) nerve agents that are used as insecticides and chemical warfare agents. This yielded in 12 publications that 1) established a role for the unannotated serine hydrolase KIAA1363 as the primary OP detoxification enzyme in the brain and 2) demonstrated that dual blockade of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) resulted in dramatic elevations in brain endocannabinoid levels and robust cannabinoid behaviors, including antinociception. My postdoctoral studies have focused on annotating dysregulated metabolic pathways in cancer. For the duration of my postdoctoral tenure, I plan to hone my research and mentoring skills so that I am prepared for my independent career. Research Career Development Plan. The research group of Prof. Ben Cravatt is perfectly suited for the continuation of my training, as his group has pioneered the development and application of diverse techniques at the interface of chemistry and biology that I will be able to learn and apply towards my research. This lab is also highly collaborative, allowing me to expand my scientific breadth. Prof. Cravatt and I will focus on my continued independent development of experimental plans, and my ability to present and defend these plans and broader hypotheses, while I also participate in several training courses to further cultivate the skills essential to becoming a successful investigator and attend several conferences to gain experience in presenting my work and establish relationships with other scientists. Research. Lipid signaling molecules control a wide range of cellular and physiological processes. Imbalances in major lipid signaling pathways contribute to the pathogenesis of chronic inflammation, cancer, and metabolic and degenerative diseases. Many lipid transmitters, their modifying enzymes, and their downstream targets are interconnected giving rise to highly integrated metabolic and signaling networks. This network connectivity allows for potential coordinate perturbation and control of lipid signaling pathways by targeting key nodal control points. My current research has uncovered that monoacylglycerol lipase (MAGL) is one such nodal enzyme that controls a diverse array of (patho)physiologically relevant lipid signaling pathways. In cancer cells, MAGL not only mediates the endocannabinoid 2-arachidonoylglycerol but also regulates a diverse fatty acid network that generates an array of protumorigenic lipid signaling molecules. In brain, MAGL controls endocannabinoids and prostaglandins- both important in neuroinflammation. This proposal will focus on dissecting the function and therapeutic potential of MAGL in controlling lipid signaling networks in cancer and neuroinflammatory disorders. These goals fall under the missions of the National Institute of General Medical Sciences (NIGMS).

Public Health Relevance

Our preliminary results show that monoacylglycerol lipase (MAGL) is a nodal enzyme in cancer and in the brain where it controls multiple pathologically relevant signaling pathways. Our preliminary results show that blockade of MAGL causes diverse perturbation in lipid signaling molecules which lead to impairments in cancer malignancy as well as neuroinflammation. The results yielded from this study should not only clarify the role that MAGL plays in controlling multiple lipid signaling pathways in different disease contexts, but also shine light on this enzyme as a promising therapeutic target for cancer and neuroinflammatory disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Career Transition Award (K99)
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Special Emphasis Panel (ZGM1-BRT-9 (KR))
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Rapaka, Rao
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Scripps Research Institute
La Jolla
United States
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Mulvihill, Melinda M; Benjamin, Daniel I; Ji, Xiaodan et al. (2014) Metabolic profiling reveals PAFAH1B3 as a critical driver of breast cancer pathogenicity. Chem Biol 21:831-40
Cao, Zongxian; Mulvihill, Melinda M; Mukhopadhyay, Partha et al. (2013) Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice. Gastroenterology 144:808-817.e15
Morrison, Brad E; Marcondes, Maria Cecilia Garibaldi; Nomura, Daniel K et al. (2012) Cutting edge: IL-13R?1 expression in dopaminergic neurons contributes to their oxidative stress-mediated loss following chronic peripheral treatment with lipopolysaccharide. J Immunol 189:5498-502
Kinsey, Steven G; Nomura, Daniel K; O'Neal, Scott T et al. (2011) Inhibition of monoacylglycerol lipase attenuates nonsteroidal anti-inflammatory drug-induced gastric hemorrhages in mice. J Pharmacol Exp Ther 338:795-802
Chang, Jae Won; Nomura, Daniel K; Cravatt, Benjamin F (2011) A potent and selective inhibitor of KIAA1363/AADACL1 that impairs prostate cancer pathogenesis. Chem Biol 18:476-84
Nomura, Daniel K; Casida, John E (2011) Activity-based protein profiling of organophosphorus and thiocarbamate pesticides reveals multiple serine hydrolase targets in mouse brain. J Agric Food Chem 59:2808-15
Ahn, Kay; Smith, Sarah E; Liimatta, Marya B et al. (2011) Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain. J Pharmacol Exp Ther 338:114-24
Ramesh, Divya; Ross, Gracious R; Schlosburg, Joel E et al. (2011) Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice. J Pharmacol Exp Ther 339:173-85
Nomura, Daniel K; Morrison, Bradley E; Blankman, Jacqueline L et al. (2011) Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334:809-13
Nomura, Daniel K; Lombardi, Donald P; Chang, Jae Won et al. (2011) Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer. Chem Biol 18:846-56

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