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
Robinson, Samuel D; Li, Qing; Bandyopadhyay, Pradip K et al. (2017) Hormone-like peptides in the venoms of marine cone snails. Gen Comp Endocrinol 244:11-18
Backhaus, Sören; Zakrzewicz, Anna; Richter, Katrin et al. (2017) Surfactant inhibits ATP-induced release of interleukin-1? via nicotinic acetylcholine receptors. J Lipid Res 58:1055-1066
Robinson, Samuel D; Li, Qing; Lu, Aiping et al. (2017) The Venom Repertoire of Conus gloriamaris (Chemnitz, 1777), the Glory of the Sea. Mar Drugs 15:
Amati, Anca-Laura; Zakrzewicz, Anna; Siebers, Kathrin et al. (2017) Chemokines (CCL3, CCL4, and CCL5) Inhibit ATP-Induced Release of IL-1? by Monocytic Cells. Mediators Inflamm 2017:1434872
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Romero, Haylie K; Christensen, Sean B; Di Cesare Mannelli, Lorenzo et al. (2017) Inhibition of ?9?10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain. Proc Natl Acad Sci U S A 114:E1825-E1832
Memon, Tosifa; Chase, Kevin; Leavitt, Lee S et al. (2017) TRPA1 expression levels and excitability brake by KV channels influence cold sensitivity of TRPA1-expressing neurons. Neuroscience 353:76-86
Li, Qing; Barghi, Neda; Lu, Aiping et al. (2017) Divergence of the Venom Exogene Repertoire in Two Sister Species of Turriconus. Genome Biol Evol 9:2211-2225
Estakhr, Jasem; Abazari, Danya; Frisby, Kaitlyn et al. (2017) Differential Control of Dopaminergic Excitability and Locomotion by Cholinergic Inputs in Mouse Substantia Nigra. Curr Biol 27:1900-1914.e4

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