Text Size
A A A
U. S. Department of Health and Human Services
Skip Navigation

Home > RePORTER > Project Information

Project InformationProject Information Help

Project Number: 3R21DA027070-02S1 Contact PI / Project Leader: CHEN, XIANGNING
Title: VARIANTS IN CHRNA5/CHRNA3/CHRNB4 AND NICOTINE DEPENDENCE Awardee Organization: VIRGINIA COMMONWEALTH UNIVERSITY
Description
Abstract Text:
DESCRIPTION (provided by applicant): Tobacco smoking is addictive and thought to be driven by nicotine dependence (ND). For decades, data have suggested genetic bases for an increased risk of ND. More recently, several studies validated the association of rs16969968 with nicotine dependence. rs16969968 is a non-synonymous SNP, changing the 398th amino acid from aspartic acid (D) to asparagine (N) (D398N) in the CHRNA5 gene. We hypothesize that this non-synonymous variant in the CHRNA5 gene may alter the functional properties of nAChRs containing 5 subunit, ultimately altering risks for tobacco smoking and ND. To test this hypothesis, the project has four aims: 1. To generate stably transfected cell lines expressing human a4b2*- or a3b4*-nAChRs containing wild- type or variant a5 subunits and use these cell lines as model system to study the properties of major subtypes (a4b2* and a3b4*) in vitro. 2. To characterize functional and pharmacological effects of the presence of wild-type or D398N a5 subunits on a4b2*- and a3b4*-nAChR using patch-clamp technique. 3. To test whether rs16969968 is involved in smoking initiation and to test for gene-environment interactions -that is, to determine if the impact of environmental exposures on smoking behaviors are modified by the rs16969968 genotypes. 4. To establish roles of a5-containing nAChR subtypes in ND using a5 knock-out mice. The goal is to define how the presence or absence of a5 subunits in native nAChR affects acute responses to nicotine (anxiety and locomotor activity), nicotine reward (conditioned place preference, CPP), and subjective effects (nicotine discrimination). PUBLIC HEALTH RELEVANCE: Tobacco smoking and nicotine dependence is a major public health issue. Many epidemiology studies have provided compelling evidence that genetic factors play a significant role in the development of nicotine dependence. More recently, several large scale genetic studies have found that several variants in the nicotinic receptor alpha 5, alpha 3 and beta 4 genes are significantly associated with heavy smoking and nicotine dependence, including one functional polymorphism rs16969968 or D398N. This current study is designed to create model systems to examine the effects of D398N at the levels of cultured cells, animal model and human behaviors. The approaches we take are 1) To develop a cellular model system to study molecular, pharmacological and electrophysiological properties of N398D; 2) To examine how genetic variants at rs16969968 interact with environmental factors and eventually lead to smoking addiction and dependence; and 3) To study the behavioral effects of these genes in animal models.
Public Health Relevance Statement:
Tobacco smoking and nicotine dependence is a major public health issue. Many epidemiology studies have provided compelling evidence that genetic factors play a significant role in the development of nicotine dependence. More recently, several large scale genetic studies have found that several variants in the nicotinic receptor alpha 5, alpha 3 and beta 4 genes are significantly associated with heavy smoking and nicotine dependence, including one functional polymorphism rs16969968 or D398N. This current study is designed to create model systems to examine the effects of D398N at the levels of cultured cells, animal model and human behaviors. The approaches we take are 1) To develop a cellular model system to study molecular, pharmacological and electrophysiological properties of N398D; 2) To examine how genetic variants at rs16969968 interact with environmental factors and eventually lead to smoking addiction and dependence; and 3) To study the behavioral effects of these genes in animal models.
NIH Spending Category:
Behavioral and Social Science; Brain Disorders; Drug Abuse (NIDA only); Genetics; Smoking and Health; Substance Abuse; Tobacco
Project Terms:
15q25; acetylcholine receptor agonist; Acute; addiction; Affect; Agonist; Alcoholism; Amino Acids; Animal Model; Animals; Anxiety; Asparagine; base; Behavior; behavior influence; Behavioral; Binding (Molecular Function); Biological Assay; Biological Models; Bupropion; Candidate Disease Gene; Cell Line; Cell model; Cells; Cholinergic Receptors; Chromosomes; Cigarette; Cocaine Dependences; Code; Comparative Study; Complex; Cultured Cells; D-Aspartic Acid; Data; Dependence; desensitization; design; Development; Discrimination (Psychology); Environmental Exposure; Environmental Risk Factor; epidemiology study; Epithelial Cells; Equation; established cell line; Evaluation; Follow-Up Studies; Foundations; Future; gene environment interaction; Genes; Genetic; Genetic Polymorphism; genetic variant; Genotype; Goals; Human; Immunoprecipitation; In Vitro; Knock-in Mouse; Knockout Mice; Lead; Ligands; Malignant neoplasm of lung; Measures; Mecamylamine; Modeling; Molecular; Motor Activity; Nicotine; Nicotine Dependence; Nicotinic Receptors; patch clamp; Patch-Clamp Techniques; Pharmaceutical Preparations; Physiologic pulse; Play; preference; Property; public health medicine (field); public health relevance; radioligand; receptor; receptor expression; response; Rewards; Risk; Role; Single Nucleotide Polymorphism; Smoke; Smoking; Smoking Behavior; Structure; Syndrome; Techniques; Testing; Time; Tobacco smoking; Transgenic Organisms; Twin Multiple Birth; varenicline; Variant



The RePORTER database is available to all public users at http://exporter.nih.gov/. As the data are available for bulk download, the RePORTER system reserves the right to block IP addresses that fail to adhere to instructions in the system’s robots.txt files or submit requests at a rate that negatively impacts service delivery to other users. RePORTER reserves the right to terminate any automated query to the RePORTER application that negatively affects service delivery to other users.

Page Last Updated on February 17, 2013
This site is best viewed with Internet Explorer (7.0 or higher) or Mozilla Firefox (3.0).

NIH...Turning Discovery Into Health®
RePORTER2