. An overarching problem in biology is the difficulty in understanding complex levels of integration from genes through systems. Intensive research is conducted at both ends of the spectrum, but there is a dearth of understanding at certain intermediate levels of integration. We address such unexplored levels of integration in nervous systems. First, at the molecular level we address the integration of different ion-channel subunits in heteromeric combinations. Second, at the cellular level we address the myriad neuronal cell types that are differentiated by cell-specific combinations of signaling proteins.
Our first aim i s to identify different neuronal subclasses in mammalian nervous systems, while simultaneously investigating the cell-specific constellations of receptors and ion channels expressed in each subclass. The identification and characterization of different neuronal subclasses is increasingly recognized as an important goal toward understanding integrated brain functions. To this end, we employ calcium imaging of dissociated cells to identify different neuronal cell types by probing their expression of cell-specific receptor- and ion-channel subtypes using selective pharmacological agents. We call this experimental approach, Constellation Pharmacology. Calcium imaging is used because: 1) it is the only viable option for assaying function in >100 neurons simultaneously and 2) changes in cytoplasmic calcium concentration are a common endpoint of nearly all electrical signaling in nervous systems. We started this initiative with sensory neurons because their physiological roles can be determined more easily than neurons from other cell populations (e.g. some neurons mediate sensory modalities that can be assayed in culture). We have extended this research into lower centers of the CNS, such as spinal cord and brainstem, with plans to expand our research to higher centers in the brain.
Our second aim builds upon our knowledge gained in aim 1 for the discovery of new venom peptides with unique targeting-selectivity profiles. Such ligands are, in turn, used to further characterize neuronal subclasses. We demonstrate proof-of-principle that we can use Constellation Pharmacology for discovery of venom peptides that target voltage-gate Na, Ca and K channels.

Public Health Relevance

Project I Relevance. Many diseases of the nervous system are presently intractable, presumably because our understanding of nervous-system complexity is inadequate. We propose an approach to identify specific neuronal cell types and study them. We have tracked changes in a specific neuronal cell type as a function of development, suggesting that we can track changes in specific neuronal cell types as a function of disease, injury, learning or aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM048677-25
Application #
9534107
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
25
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Hiller, Sebastian Daniel; Heldmann, Sarah; Richter, Katrin et al. (2018) ?-Nicotinamide Adenine Dinucleotide (?-NAD) Inhibits ATP-Dependent IL-1? Release from Human Monocytic Cells. Int J Mol Sci 19:
Peng, Can; Yan, Yijin; Kim, Veronica J et al. (2018) Gene editing vectors for studying nicotinic acetylcholine receptors in cholinergic transmission. Eur J Neurosci :
Chen, De-Jie; Gao, Fen-Fei; Ma, Xiao-Kuang et al. (2018) Pharmacological and functional comparisons of ?6/?3?2?3-nAChRs and ?4?2-nAChRs heterologously expressed in the human epithelial SH-EP1 cell line. Acta Pharmacol Sin 39:1571-1581

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