Monitoring DAT in Live Mice Abstract Expressed exclusively in dopaminergic neurons, the dopamine transporter gene (DAT/SLC6A3) is a risk factor for many diseases including drug abuse, depression and bipolar disorder, based on hundreds of association studies. Since DNA sequence variation in the human DAT is correlated with striatal DAT protein levels in humans, it is postulated that altered DAT activity confers the risk. However, it is not known whether or not altered DAT activity is indeed correlated with abnormal behaviors or diseases. To fill in this critical knowledge gap, here we propose to develop a mouse line where DAT carries a reporter gene that encodes a secreted Gaussia luciferase (GLuc) with desired reporter qualities such as short in vivo half-life, high sensitivity and large dynamic range. This DAT-GLuc line will allow monitoring DAT activity sequentially in the same live mice under various environments including drugs of abuse, simply by measuring GLuc activity in the circulated fluid. DAT-GLuc aims to follow the DAT activity and correlate the activity with behaviors or efficacy of DAT-related medications in mice. This gene activity-reporting mouse line will complement the current in vivo technologies including brain imaging (for proteins) and microdialysis (for small molecules).

Public Health Relevance

Monitoring DAT in live mice Project Narrative This research will generate a mouse line that uses luciferase to report the activity of the dopamine transporter gene (DAT), whose human orthologue is a risk factor for more than ten neuropsychiatric diseases. This DAT-reporting line will provide the research community a new tool to model and treat DAT-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA031573-01A1
Application #
8322983
Study Section
Special Emphasis Panel (ZDA1-SXC-E (12))
Program Officer
Wu, Da-Yu
Project Start
2012-03-15
Project End
2014-02-28
Budget Start
2012-03-15
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$197,500
Indirect Cost
$72,500
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Onaivi, E S; Schanz, N; Lin, Z C (2014) Psychiatric disturbances regulate the innate immune system in CSF of conscious mice. Transl Psychiatry 4:e367