Opiate addiction is now a national epidemic marked by an increased incidence of abuse and overdose of heroin and elevated misuse of prescription opioids which also bears a high incidence of overdose death. Despite this growing opiate problem there remains a lack of knowledge about the molecular neuropathology of this human disorder. A fundamental core of our reverse translational research efforts has thus been to fill critical gaps of knowledge by direct investigation of the brains of human heroin abusers. Such efforts have identified the transcription factor ets-like kinase 1 (ELK1) as a central candidate in human heroin abusers. ELK1 disturbance was downstream of the mu opioid receptor (the pharmacological target of heroin metabolites and prescription opiates) and mitogen-activated protein kinase (MAPK) pathway and it was found by in silico analysis of microarray data to target the promoters of a large percentage of down-regulated genes in the nucleus accumbens (NAc) of heroin abusers. Surprisingly, very limited knowledge exist about ELK1 in relation to drug abuse, but this transcription factor has been implicated in other fields in cellular differentiation and synaptic plasticity that are highly relevant to the pathophysiology of addictio disorders. We hypothesize that heroin abuse leads to dysregulated ELK1-mediated transcriptional activity of target genes involved in the reorganization of striatal synapses and tht modulate drug-seeking behaviors. We propose: (1) to determine ELK1-mediated transcriptional regulation in neurons within striatal and mesocorticolimbic brain regions of human heroin abusers by conducting ELK1 ChIP in combination with high throughput sequencing (ChIP-seq) on the nucleus accumbens, dorsal striatum and medial orbitofrontal cortex of heroin abusers. This data will also be integrated with transcriptome analysis to determine the relationship to gene expression. (2) To identify the epigenetic landscape across the ELK1 gene that contributes to its dysregulation in heroin abusers. (3) To investigate the causal role of ELK1 in structural plasticity and heroin seeking behavior by use of animal models. The multidisciplinary approach will expand significant insights about novel targets for treatment interventions and the dataset accrued by this body of work will be a unique and valuable resource to the field given the current lack of such human brain data.
The abuse of opiates including heroin continues to be a growing major public health problem given the alarming epidemic rise in opiate abuse. By focusing research efforts that expand insights about discrete molecular impairments directly in the brains of the human drug abusers, we will obtain valuable information to guide the development of new targeted medications to treat addiction disorders.
|Xu, Jin; Lu, Zhigang; Xu, Mingming et al. (2014) A heroin addiction severity-associated intronic single nucleotide polymorphism modulates alternative pre-mRNA splicing of the ? opioid receptor gene OPRM1 via hnRNPH interactions. J Neurosci 34:11048-66|
|Linnertz, Colton; Lutz, Michael W; Ervin, John F et al. (2014) The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease. Hum Mol Genet 23:4814-21|
|Xu, Jin; Xu, Ming; Brown, Taylor et al. (2013) Stabilization of the *-opioid receptor by truncated single transmembrane splice variants through a chaperone-like action. J Biol Chem 288:21211-27|
|Manini, A F; Jacobs, M M; Vlahov, D et al. (2013) Opioid receptor polymorphism A118G associated with clinical severity in a drug overdose population. J Med Toxicol 9:148-54|
|Jacobs, Michelle M; Murray, Jacinta; Byrd, Desiree A et al. (2013) HIV-related cognitive impairment shows bi-directional association with dopamine receptor DRD1 and DRD2 polymorphisms in substance-dependent and substance-independent populations. J Neurovirol 19:495-504|
|Sillivan, Stephanie E; Whittard, John D; Jacobs, Michelle M et al. (2013) ELK1 transcription factor linked to dysregulated striatal mu opioid receptor signaling network and OPRM1 polymorphism in human heroin abusers. Biol Psychiatry 74:511-9|
|Manini, Alex; Jacobs, Michelle; Vlahov, David et al. (2013) On the role of genetic testing for personalized drug overdose management. J Med Toxicol 9:294-5|
|Mazei-Robison, Michelle S; Koo, Ja Wook; Friedman, Allyson K et al. (2011) Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons. Neuron 72:977-90|
|Okvist, Anna; Fagergren, Pernilla; Whittard, John et al. (2011) Dysregulated postsynaptic density and endocytic zone in the amygdala of human heroin and cocaine abusers. Biol Psychiatry 69:245-52|
|Lachmann, Alexander; Xu, Huilei; Krishnan, Jayanth et al. (2010) ChEA: transcription factor regulation inferred from integrating genome-wide ChIP-X experiments. Bioinformatics 26:2438-44|
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