Molecular and Cellular Mechanisms of Pain Hypersensitivity
BackgroundChronic pain is the leading cause of long-term disability and suffering in humans. Common chronic pain conditions include headache, low back pain, cancer pain, arthritis pain, and neuropathic pain. Available treatments have limited efficacy, and only 30-40% of chronic pain patients report satisfactory pain relief. Long-lasting sensitization of the peripheral and central nociceptive circuits is one of the main underlying causes of pain hypersensitivity in chronic pain conditions. The pathophysiology of the sensitization is not well understood and is the subject of intensive research. Alterations in primary sensory neurons, spinal neurons, and non-neuronal cells contribute to the long-lasting sensitization, which rely on de novo gene expression to support biochemical and structural reorganization of the pain pathway.
Gene expression can be modulated at different steps, including transcription, RNA splicing, mRNA translation, and post-translational modification of proteins. Most studies hitherto have focused on transcriptional regulation; however, recent work has shown that the abundance of proteins in the cell is determined predominantly by the rate of mRNA translation. Inhibition of mRNA translation alleviates chronic pain in animal models; however, the molecular and cellular mechanisms underlying the beneficial effect of translation inhibitors remain elusive.
ResearchWe aim to decipher mechanisms by which mRNA translation promotes pain sensitization by identifying mRNAs mediating these phenomena and studying their function. Our research is directed toward identification of novel molecular targets and ultimately developing better therapeutics to relieve pain and improve quality of life of individuals living with pain.
Additionally, we study the role of translational control in synaptic plasticity and memory formation (in collaboration with Nahum Sonenberg, McGill University), and investigate how aberrant translation leads to neurodevelopmental disorders such as autism (in collaboration with Christos Gkogkas, The University of Edinburgh).
The lab currently has projects in the following topics:
Memory formation and brain disorders
- Genome-wide translational profiling of chronic pain
- Testing different classes of translational modulators in chronic pain
- Investigating the role of mTORC2/Rictor in pain plasticity
- Cell type-specific effects of eIF2a/mTOR pathways
- Modulation of extracellular matrix in neuropathic pain
- Translational control in non-neuronal cells in learning and memory
- The role of eIF2a in Fragile X Syndrome