Visinin-like protein-1 modulation of nicotinic receptors
Active Project Grant Awarded Last action
- Award ID
- R16GM150455
- Recipient
-
University Of Alaska Fairbanks UEI FDLEQSJ8FF63 Part of University Of Alaska Systems
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $793,792
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date 82% complete
- Place of performance
- Fairbanks, AK 99775, USA
Award details come from USAspending.gov.
Description
- Abstract
- Tobacco use is the world's leading cause of preventable death, according to the world health organization. Within the US, cigarette smoking cases approximately one in five deaths, accounting for more than 480K deaths each year. Tobacco users who strive to quit usually relapse. In 2018, approximately 55% of adults in the US who smoked tobacco had made a quit attempt within the past year; only roughly 8% successfully quit for 6-12 months. Because of this, novel approaches are necessary to improve nicotine cessation success rates. Nicotine, a compound highly involved in nicotine use disorder (NUD), binds to neuronal nicotinic acetylcholine receptors (NACHRS) to activate brain reward and positive reinforcement circuits. Further, nicotine use results in cholinergic tone imbalance caused, in part, by dysregulation of the nachr A4SS2 subtype. The neuronal A4SS2 subtype expresses in two isoforms with high and low sensitivity to nicotinic agonist (HS (A4SS2)2SS2 and LS (A4SS2)2A4, respectively). Nicotine upregulates functional A4SS2 NACHRS and enriches plasma membrane expression of the HS (A4SS2)2SS2 isoform. These changes result in hypersensitive brain reward (MESOCORTICOLIMBIC) circuits while enhancing dopamine levels that reinforce rewarding behavior, contributing to NUD. Restoring the cholinergic tone to be less sensitive and comparable to pre-nicotine levels, is likely to be critical in the development of an efficacious approach to treating NUD. Little is known regarding chaperone protein regulation of A4SS2 nachr isoforms, a key proposal mission, and the ability of chaperone proteins to counteract nicotine-driven A4SS2 isoform imbalance. To begin to answer some of these questions, we propose to define the basis of visinin-like protein-1 (VILIP-1) functional effects on receptor physiology, the interaction site, and VILIP-1-driven changes in A4SS2 nachr plasma membrane expression. Our preliminary data consistently show VILIP-1 attenuates A4SS2 nachr function and enhances plasma membrane expression. These underlying findings led US to our hypothesis that leveraging the interactions between VILIP-1 and A4SS2 NACHRS by a small molecule may be a novel approach to treating NUD. Defining the VILIP-1/A4SS2 nachr interaction site, as proposed here, will remove critical barriers that stymie scientific and clinical NUD work, in addition to other conditions affected by A4SS2 nachr dysregulation. We will pursue the aims of this proposal by combining electrophysiology studies of receptor function with live cell confocal microscopy. Funding of this application will provide foundational support for PI weltzin's progress towards becoming an independent and established researcher by demonstrating project fundability and feasibility, assay advancement, preliminary data generation, and senior-author publications. Her mentorship team includes DRS. Miwa and whiteaker, established nachr experts. In addition, the proposal will provide hands-on research support for underrepresented students in biomedical science. Activities supported by this proposal will sustenance and enrich the research environment at the university of alaska fairbanks.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $198,448 | |
| Amendment | $198,448 | |
| Amendment | $198,448 | |
| Original award | $198,448 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Virginia Commonwealth University | $19,064 |
Quick answers
Who received award R16GM150455?
R16GM150455 was awarded to University Of Alaska Fairbanks by National Institute of General Medical Sciences (National Institutes of Health) on August 1, 2023.
How much is award R16GM150455 worth?
$793,792 has been obligated on R16GM150455.
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