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NIDA Proteomics Center
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Investigators
> Paul Greengard
The Role of miRNAs in Neuronal
Cell Survival and Function
Paul Greengard, Laboratory of Molecular and Cellular Neuroscience,
The Rockefeller University
Understanding of the molecular mechanisms of drug
addiction is essential for the development of novel approaches for the treatment
of this debilitating disease. Recent findings showed that development of
addictive behavior in mice is associated with stable changes in gene and protein
expression. We found that establishment of cocaine addiction in mice is
associated with expression changes of numerous miRNAs in the striatum, a brain
area responsible for drug addiction. Given the potent role of miRNAs in
regulation of protein expression, we hypothesize that cocaine-regulated miRNAs
contribute to the establishment of the protein expression network that supports
addiction. To evaluate the contribution of cocaine induced miRNAs to the
development and maintenance of cocaine addiction we propose to address the
impact of striatum specific alteration of individual miRNAs on addiction. We
will test whether correction of miRNA levels affected by chronic cocaine
treatment affects the development of addictive behavior in vivo. Additionally,
we will attempt to identify the striatal targets of individual miRNAs using a
proteomic approach. Inactivation of miRNA that are induced by cocaine treatment
will be achieved by injection of the RNA based cell-permeable specific miRNA
inhibitors into the striatum. In turn, striatum specific normalization of miRNA
that are suppressed by cocaine will be achieved by using miRNA expressing adeno-associated
virus (AAV). Identification of specific miRNAs and their targets that play a
role in the development and maintenance of cocaine addiction may help to reveal
the molecular networks controlling dopamine signaling in health and disease.
Furthermore, targeting of the addiction-associated miRNAs by synthetic miRNA
antagonists may lead to development of novel and highly specific approach for
treatment of addiction. |
