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. Long-lasting sensitization of the peripheral and central nociceptive circuits is one of the main underlying causes of pain hypersensitivity in chronic pain conditions. 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. We also study the role of mTORC2-dependent structural plasticity in peripheral and central nociceptive circuits in the development of pain hypersensitivity. 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.
Mechanisms underlying brain disorders
BackgroundRegulation of cellular proteome at the level of mRNA translation is essential for normal brain function, and dysregulation of translational control might cause neuropsychiatric disorders. Deviations from the optimal level of synaptic protein synthesis can lead to impaired synaptic circuitry, and may contribute to the development of cognitive deficits and autistic traits. Several brain disorders, with high rates of autism, are associated with loss of function of translational repressors. Mutations in TSC1/2, PTEN and FMR1 genes cause Tuberous Sclerosis, PTEN hamartoma syndrome and Fragile X syndrome, respectively and lead to intellectual disability, autistic-like behavior, epileptic seizures and language impairment. Despite the prevalence of these neuropsychiatric disorders, there is a slow progress in understanding the pathophysiology and development of effective therapies.
ResearchWe study the role of translational control in synaptic plasticity and memory formation, and investigate how aberrant translation leads to neuropsychiatric disorders such as Fragile X syndrome and autism. We use a multidisciplinary approach combining electrophysiology, behavioural analysis, imaging and genome-wide transcriptional/ translational profiling to decipher the molecular underpinnings of these disorders.
The lab currently has projects in the following topics:
Memory formation and brain disorders
- Genome-wide translational profiling of 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
- The role of eIF2a in Fragile X Syndrome
- Extracellular matrix and MMPs in Fragile X syndrome
- Translational control in non-neuronal cells in memory
- Cell type-specific mechanisms of eIF2a-dependent translational control in learning and memory