The candidate, Dr. Lakshmi Devi is a Professor in the Department of Pharmacology Systems Therapeutics, Mount Sinai School of Medicine. She is currently funded by two independent grants: DA 08863 from NIDA/NIH- to study post-translational regulation of opioid receptors and NS 26880 from NINDS/NIH-to study regulation of neuropeptide biosynthesis. The long-term career goals of the candidate are to explore the contribution of opioid receptor characteristics to development of drug addiction and to identify molecules and pathways involved in this process with the intent of developing pharmacological tools to help in the prevention and/or treatment of drug abuse. Mount Sinai School of Medicine provides the intellectual environment for synergistic and collaborative interactions necessary to achieve this goal. The Senior Scientist Research and Mentorship Award will facilitate this by relieving considerable amount of teaching and administrative duties. The focus of studies in Dr. Devi's laboratory has been to explore molecular mechanisms modulating opioid receptor function. The activity of opioid receptors is modulated by multiple mechanisms. For example, the activity is modulated at the level of the receptors themselves as well as at the level of endogenous peptides (that activate the receptors). In recent years the candidate's research has focused on both these mechanisms. The studies in this application are to further explore these two mechanisms.
The specific aims are: (i) to investigate signaling, maturation and regulation of 5-4 receptors by morphine administration in vivo;(ii) to study the role of heterodimerization between opioid receptors and other heptahelical receptors, and (iii) to explore the physiological involvement of recently identified non-classical processing enzymes in the regulation of opioid and other neuropeptide levels. The studies described in this grant application will provide critical information on early events that regulate opioid receptor function. Elucidation of the cellular pathways involved in modulation of receptor function is a compelling strategy for identifying appropriate pharmacological interventions for drug addiction. This Award will allow the candidate to focus on research in the field of opioid peptides and their receptors. In addition, this Award will help mentor the next generation of researchers interested in exploring novel mechanisms and identifying novel targets for the treatment of drug abuse disorders.

Public Health Relevance

The studies described in this application use a combination of classical techniques with novel tools and state-of-the art technology to characterize the role of heterodimerization in modulating receptor signaling, maturation/upregulation, to explore the physiological significance of heterodimerization in vivo and to explore the role of non-classical processing enzymes in the generation of opioid peptides. These studies will open new avenues and/or targets for intervention in drug abuse and addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Award (K05)
Project #
5K05DA019521-08
Application #
8257170
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Wu, Da-Yu
Project Start
2005-05-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$122,958
Indirect Cost
$9,108
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Ferré, Sergi; Casadó, Vicent; Devi, Lakshmi A et al. (2014) G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol Rev 66:413-34
Gupta, Achla; Gomes, Ivone; Wardman, Jonathan et al. (2014) Opioid receptor function is regulated by post-endocytic peptide processing. J Biol Chem 289:19613-26
Toniolo, Elaine F; Maique, Estêfani T; Ferreira Jr, Wilson A et al. (2014) Hemopressin, an inverse agonist of cannabinoid receptors, inhibits neuropathic pain in rats. Peptides 56:125-31
Kivell, Bronwyn; Uzelac, Zeljko; Sundaramurthy, Santhanalakshmi et al. (2014) Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism. Neuropharmacology 86:228-40
Fujita, Wakako; Gomes, Ivone; Devi, Lakshmi A (2014) Revolution in GPCR signalling: opioid receptor heteromers as novel therapeutic targets: IUPHAR review 10. Br J Pharmacol 171:4155-76
Matsumoto, Kenjiro; Narita, Minoru; Muramatsu, Naotaka et al. (2014) Orally active opioid ?/? dual agonist MGM-16, a derivative of the indole alkaloid mitragynine, exhibits potent antiallodynic effect on neuropathic pain in mice. J Pharmacol Exp Ther 348:383-92
Stockton Jr, Steven D; Devi, Lakshmi A (2014) An integrated quantitative proteomics and systems biology approach to explore synaptic protein profile changes during morphine exposure. Neuropsychopharmacology 39:88-103
Yang, Lili; Rozenfeld, Raphael; Wu, Defeng et al. (2014) Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy. Free Radic Biol Med 68:260-7
Gomes, Ivone; Fujita, Wakako; Gupta, Achla et al. (2013) Identification of a *-ýý opioid receptor heteromer-biased agonist with antinociceptive activity. Proc Natl Acad Sci U S A 110:12072-7
Gomes, Ivone; Fujita, Wakako; Chandrakala, Moraje V et al. (2013) Disease-specific heteromerization of G-protein-coupled receptors that target drugs of abuse. Prog Mol Biol Transl Sci 117:207-65

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