Molecular Mechanisms of Opioid Use Disorder in Human Brain Models

<p>Opioid use disorder (OUD) is a national and global public health crisis with no end in sight. While studies from animal models hint at widespread epigenetic and transcriptomic alterations of opioid drugs, the molecular consequences of long-term exposure to opioid drugs in human brain is still unclear, and human-centered translational models are necessary to discern the human cell type-specific effects of OUD.</p> <p>Using postmortem brain Brodmann area 9 (BA9) from the UTHealth Brain Collection for Research on Psychiatric Disorders, I identified angiogenic gene networks perturbed in the RNA and protein of OUD subjects, as well as downregulation of many neuron-correlated synaptic genes. Using single-nuclei RNA sequencing, I found global suppression of cell-cell signaling networks across all cell types, particularly involved in synaptic and growth factor signaling. Finally, using a novel postmortem fibroblast-derived induced pluripotent stem cell model of neuronal morphine exposure, I identify gene expression caused by chronic morphine exposure and compare these expression signatures to the source subjects’ brain.</p> <p>Integrating results from all studies, I propose a hypothesis whereby opioid use disorder convergently dysregulates both synaptogenesis and angiogenesis through perturbation of the PI3K/Akt and MAPK/Erk second messenger systems and dysregulation of immediate early genes. The mechanistic insights from these human models may aid the discovery of novel pharmaceutical targets to treat OUD or prevent long-term consequences of drug exposure.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2024

Authors dc:creator

• Mendez, Emily
• <p>0000-0002-8046-6905</p>

Contributors dc:contributor

• Consuelo Walss-Bass
• Fabricio Do Monte
• Ruth Heidelberger

• Opioid Use Disorder
• Postmortem
• Overdose
• RNAseq
• Proteomics
• Polygenic Risk Score
• iPSC
• snRNAseq
• Transcriptomics
• Behavioral Neurobiology
• Bioinformatics
• Medical Neurobiology
• Molecular and Cellular Neuroscience
• Neurosciences
• Psychiatric and Mental Health
• Substance Abuse and Addiction

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1327

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2384