The overall goal of this proposal is to dissect transcription mechanisms in the human dopamine transporter gene (hDAT). The dopamine transporter (DAT) regulates the spatio-temporal domains of dopamine neurotransmission by reuptake and release of dopamine and thus contributes to locomotion, motivation, cognition and attention, working memory, behavioral organization and hormone release. It is well recognized that expression of the DAT gene in the brain is highly circumscribed, varies among individual subjects and can be regulated by endogenous and exogenous factors such as cocaine abuse. Altered DAT expression may contribute to hDAT-associated pathophysiological states such as substance abuse. However, information about how hDAT expression is regulated and how DNA sequence variation influences the regulated expression remains sporadic. The hypothesis to be tested in this proposal is that transcriptional antagonisms play a major role in regulating hDAT activity. Our preliminary studies show that different cis-acting elements across the entire gene display either enhancing or silencing activities. Therefore, two specific aims of this project are to: 1) demonstrate transcriptional antagonisms between the cis-acting elements and their correlation with hDAT expression;and 2) identify transcription factors that bind to the cis-acting elements around the hDAT promoter in human postmortem brain tissues. The results will add fundamental knowledge on lead sites through which hDAT is regulated by external factors including drugs of abuse and confers risks for related brain disorders.

Public Health Relevance

Patients with neuropsychiatric disorders (attention deficit/hyperactivity disorder, drug addiction, schizophrenia, bipolar disorder, Parkinson's disease among many others) often carry altered activity in the human dopamine transporter gene (hDAT). This proposal aims to identify molecular mechanisms by which regulated hDAT activity is altered, enabling our understanding of the genetic etiologies of the hDAT-related diseases. Our ultimate goal is to provide evidence-based guidelines for individualized medicine.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Caulder, Mark
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Mclean Hospital
United States
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Kennedy, James L; Xiong, Nian; Yu, Jinlong et al. (2016) Increased Nigral SLC6A3 Activity in Schizophrenia Patients: Findings From the Toronto-McLean Cohorts. Schizophr Bull 42:772-81
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Xiong, Nian; Li, Nuomin; Martin, Eden et al. (2016) hVMAT2: A Target of Individualized Medication for Parkinson's Disease. Neurotherapeutics 13:623-34
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Zhai, Desheng; Li, Songji; Zhao, Ying et al. (2014) SLC6A3 is a risk factor for Parkinson's disease: a meta-analysis of sixteen years' studies. Neurosci Lett 564:99-104
Zhao, Ying; Xiong, Nian; Liu, Yang et al. (2013) Human dopamine transporter gene: differential regulation of 18-kb haplotypes. Pharmacogenomics 14:1481-94
Xiong, Nian; Huang, Jinsha; Chen, Chunnuan et al. (2012) Dl-3-n-butylphthalide, a natural antioxidant, protects dopamine neurons in rotenone models for Parkinson's disease. Neurobiol Aging 33:1777-91
Zhao, Ying; Zhou, Yanhong; Xiong, Nian et al. (2012) Identification of an intronic cis-acting element in the human dopamine transporter gene. Mol Biol Rep 39:5393-9
Lin, Zhicheng; Canales, Juan J; Björgvinsson, Thröstur et al. (2011) Monoamine transporters: vulnerable and vital doorkeepers. Prog Mol Biol Transl Sci 98:1-46
Xiong, Nian; Xiong, Jing; Khare, Ghanshyam et al. (2011) Edaravone guards dopamine neurons in a rotenone model for Parkinson's disease. PLoS One 6:e20677

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