The role of microRNAs in pain

Rehman Ahmed Qureshi

doi:10.17918/etd-7008

Chronic pain drastically impairs quality of life and is one of the most common causes for seeking medical treatment. The classification of chronic pain syndromes has remained largely subjective and available therapies provide better than moderate pain relief in only one third of patients. This thesis investigates microRNAs (miRNAs) as potential biomarkers for chronic pain conditions in order to achieve an objective classification of pain syndromes and to improve outcomes through personalized therapies. miRNAs are a class of small non-coding RNAs that are involved in transcriptional regulation of gene expression by targeting mRNA molecules. miRNAs have been found to maintain their stability in blood despite significant RNase activity, making them ideal biomarkers. We have developed and implemented a data analysis pipeline for miRNA expression: from qPCR experiments to biological pathway enrichment. We have developed an improved miRNA qPCR data normalization method that achieves more stable expression profiles than other methods and a novel weighted gene set enrichment method that incorporates fold-change levels to identify the affected biological pathways. The data analysis pipeline has been applied to study circulating miRNAs in patients with Complex Regional Pain Syndrome (CRPS), a debilitating chronic pain disorder. We have found 18 differentially expressed miRNAs in CRPS patients, discovered a patient subpopulation that may share the same underlying mechanism of the disease, and also found circulating miRNAs strongly correlated with a number of comorbid conditions. In order to translate our specific findings in CRPS to general pain pathology, several animal models of neuropathic, inflammatory, and chemically induced pain have been evaluated for changes in circulating miRNA expression. A number of miRNAs were found to have altered expression in circulation across different models of pain and in CRPS patients. miRNA target prediction was employed, and enrichment of the predicted targets was performed in order to identify the molecular pathways being altered in acute and chronic pain. While some of the miRNAs and pathways we have found corroborate existing research in pain, we have generated hypotheses for the investigation of additional mechanisms of pain. The miRNAs, identified herein, are candidate biomarkers which can be used to enhance drug development, in addition to the insights that they provide into the molecular biology of pain.

The role of microRNAs in pain

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The role of microRNAs in pain

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