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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA021409-07
Application #
8675815
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Caulder, Mark
Project Start
2006-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
$248,850
Indirect Cost
$91,350
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
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