Rationale: Cocaine is a powerfully addictive drug which leads to several social issues and serious health problems. Accordingly, understanding its molecular mechanisms to develop an effective treatment for cocaine addiction is necessary. Recently, cocaine abuse has been indicated to cause gene expression changes, and these genes probably correlate to drug addictive development. However, the molecular mechanisms how cocaine affects genes expression remain unclear. Preliminary results: Cocaine is an agonist of sigma-1 receptor (Sig-1R). Our preliminary results indicated that Sig-1R seems involving in the regulation of cocaine-altered gene expression. These results include: (1) cocaine suppressed the expression of monoamine oxidase B (MAOB), but had no effects on Sig-1R knockout mice. (2) Cocaine reduced histone H4 acetylation of MAOB core promoter. (3) Upon cocaine treatment, Sig-1R translocalized into nuclear envelope (NE) and (4) interacted with NE resident protein emerin as well as transcriptional co-repressor complex, BAF-HDAC1/2. In addition, post- translational modifications (PTMs) have been known to regulate protein’s subcellular localizationwe. At present, (5) we found that Sig-1R was modified by acetylation in vivo. Hypothesis: Hence, we assume cocaine alters the acetylation of Sig-1R causing Sig-1R NE translocalization. Subsequently, Sig-1R forms a co-repressor complex with emerin-BAF- HDACs targeting to MAOB promoter, and thereby inhibits promoter activity via histones deacetylation. Specific aims: Based on the hypothesis, several issues are aimed to study the transcriptional mechanism of cocaine-suppressed MAOB expression. First, we will confirm cocaine- induced NE localization of Sig-1R in primary neurons and animal models. Second, we will investigate that acetylation indeed alters Sig-1R subcellular localization. Third, we will examine whether Sig-1R is a key factor for the formation of emerin-BAF-HDACs co- repressor complex. Fourth, we will analyze MAOB promoter to understand how Sig-1R- induced co-repressor complex target on MAOB promoter causing histones deacetylation upon cocaine treatment. Novelty and application: Taken together, by performing this project to proof the transcriptional mechanism, we will understand that cocaine not only blocks DAT to increase synaptic dopamine levels, but also regulates MAOB gene expression to affect dopamine metabolism. In addition, Sig-1R is a potential trigger for cocaine-altered gene expression. Therefore, we expect to provide more notions for a functional target in drug addictive therapy.
|Effective start/end date||8/1/16 → 10/31/17|
- gene regulation