My long-term academic career goal is to conduct independent research into the discovery of new molecular pathways involved in toxicity of drugs that affect dopaminergic system, particularly methamphetamine (MA), in order to develop better treatments for their abusers. Ubiquitination is emerging as a multifunctional signal in cellular processes;therefore, it is a potential novel signal in MA neurotoxicity. There is no data on the role of ubiquitination after high-dose MA;therefore, my immediate goal is to investigate the involvement of ubiquitination-mediating E3 ligases (particularly parkin) in regulation of proteins known to be affected by MA toxic actions, and vice versa, namely ubiquitin proteasomal system, mitochondrial electron chain proteins, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2), in animal model of MA toxicity. Since parkin protects against a variety of cellular stressors, including agents affecting mitochondrial function, it is planned to determine whether parkin (or other E3 ligases) protects dopaminergic neurons against MA in vivo.
The specific aims are: (1) to examine the effect of parkin on MA neurotoxicity, (2) to investigate the effect of MA on parkin function and the catalytic properties of the proteasome, (2) to investigate the interactions between decreased parkin function and mitochondrial electron transport chain activity, (3) (4) to investigate ubiquitination-mediated DAT trafficking after MA, and (5) to determine the molecular link between the DAT, parkin and VMAT2 after MA. The proposed mentored research will allow me to develop skills needed for independent career and to learn new techniques, particularly to acquire solid experience working with animal model of MA toxicity. Such knowledge and experience will help me with my independent studies directed toward the identification of new targets that may hopefully drive the development of novel drugs that can treat or prevent neurodegeneration caused by MA. Since factors involved in neurotoxicity interact with each other, it is very important to understand their interactions in order to elucidate points for pharmaceutical intervention. To date, there are no safe and tested medications for treating MA addiction and new MA antidotes for use by emergency room physicians to treat MA-related overdoses are needed. The results from my studies will assist the development of pharmacological therapies to ameliorate potential neuronal damage and cognitive impairments due to MA abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Transition Award (R00)
Project #
5R00DA023085-05
Application #
8314099
Study Section
Special Emphasis Panel (NSS)
Program Officer
Frankenheim, Jerry
Project Start
2010-09-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$241,530
Indirect Cost
$76,988
Name
Wayne State University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Pharmacy
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202