This program uses biodiversity for basic biomedical research, with direct therapeutic and diagnostic applications. The program focuses on the discovery, characterization and development of powerful pharmacological agents targeted to signaling molecules (e.g., receptors and ion channels). The source of these are >10,000 species of venomous marine snails (particularly the cone snails, Conus). The venoms of these snail are complex, containing ca. 100 different peptides ("conopeptides, conotoxins"), each highly selective for a particular receptor or ion channel. Because of the molecular complexity of their targets, conopeptides have been particularly useful for understanding the function of molecular isoforms of these signaling molecules. Increasingly, they have become standard reagents in neuropharmacology, and serve as an essential complement to molecular genetics for understanding neuronal function and the circuitry of the nervous system. The basis of physiological circuits is chemical and electrical communication between cells, which is mediated by a vast diversity of different signaling molecules. A barrier to investigating physiological circuits is the intrinsic molecular complexity of receptors and ion channels;protein subunits encoded by gene families form multimeric complexes (most commonly tetramers or pentamers). Because of the intrinsic combinatorial nature of functional multimeric ion channel complexes, a large complement of different receptors and ion channels can be generated from a few genes. For understanding receptor and ion channel function, it is optimal to use highly selective ligands that distinguish between closely-related receptor and ion channel isoforms. Our program uses the peptides that have been evolved by venomous marine snails to interact with their prey, predators and competitors as a prime source of such highly selective ligands. It is estimated that there are over 2 million biologically active peptides in marine snail venoms, which are the basis for developing the pharmacological tools to investigate the molecular complexity of receptors and ion channels, and to define the functional roles of the vast array of receptor/ion channel isoforms. A sufficiently large number of diversely targeted conopeptides have been developed by this program to allow these to be used in combination. The primary goal is to use these conopeptide combinations to investigate the distinct complement of receptor/ion channel isoforms present in each neuronal subclass. This leads to a new paradigm for using pharmacologically active compounds, which we refer to as "Constellation Pharmacology".

Public Health Relevance

This research program focuses on using marine biodiversity (i.e., 13,000 species of venomous marine snails) for biomedical applications. Compounds discovered in our research have promise for understanding and treating pain. In the long term, our goal is to enable following the progression of diseases of the nervous system, and ultimately, to learn to halt the disease progression. OVERALL PROGRAM:

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM048677-21A1
Application #
8740921
Study Section
Special Emphasis Panel (ZRG1-MDCN-G (40))
Program Officer
Dunsmore, Sarah
Project Start
1997-01-01
Project End
2019-07-31
Budget Start
2014-09-10
Budget End
2015-07-31
Support Year
21
Fiscal Year
2014
Total Cost
$2,376,903
Indirect Cost
$572,309
Name
University of Utah
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Richter, K; Mathes, V; Fronius, M et al. (2016) Phosphocholine - an agonist of metabotropic but not of ionotropic functions of α9-containing nicotinic acetylcholine receptors. Sci Rep 6:28660
Safavi-Hemami, Helena; Li, Qing; Jackson, Ronneshia L et al. (2016) Rapid expansion of the protein disulfide isomerase gene family facilitates the folding of venom peptides. Proc Natl Acad Sci U S A 113:3227-32
Green, Brad R; Gajewiak, Joanna; Chhabra, Sandeep et al. (2016) Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin μO§-GVIIJ. J Biol Chem 291:7205-20
Hone, Arik J; McIntosh, J Michael; Rueda-Ruzafa, Lola et al. (2016) Therapeutic concentrations of varenicline in the presence of nicotine increase action potential firing in human adrenal chromaffin cells. J Neurochem :
Espino, Samuel S; Dilanyan, Taleen; Imperial, Julita S et al. (2016) Glycine-rich conotoxins from the Virgiconus clade. Toxicon 113:11-7
Zuo, Wanhong; Xiao, Cheng; Gao, Ming et al. (2016) Nicotine regulates activity of lateral habenula neurons via presynaptic and postsynaptic mechanisms. Sci Rep 6:32937
Curtice, Kigen J; Leavitt, Lee S; Chase, Kevin et al. (2016) Classifying neuronal subclasses of the cerebellum through constellation pharmacology. J Neurophysiol 115:1031-42
Yorgason, J T; Rose, J H; McIntosh, J M et al. (2015) Greater ethanol inhibition of presynaptic dopamine release in C57BL/6J than DBA/2J mice: Role of nicotinic acetylcholine receptors. Neuroscience 284:854-64
Lee, Hee-Kyoung; Zhang, Liuyin; Smith, Misty D et al. (2015) A marine analgesic peptide, Contulakin-G, and neurotensin are distinct agonists for neurotensin receptors: uncovering structural determinants of desensitization properties. Front Pharmacol 6:11
Aman, Joseph W; Imperial, Julita S; Ueberheide, Beatrix et al. (2015) Insights into the origins of fish hunting in venomous cone snails from studies of Conus tessulatus. Proc Natl Acad Sci U S A 112:5087-92

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