Cell & Developmental Biology
Div of Biosciences
Epigenetic regulation of chronic pain states
Chronic pain currently affects 1 in 5 European adults and is one of the most important unsolved problems in medicine today and predicting whether an individual is susceptible to develop chronic pain, which would allow early and preventive treatment, is an extremely difficult challenge. This is because pain is a sensory experience not only determined by the intensity of the injury but also by a number of factors including our past experiences. Past experiences can indeed strongly influence human behaviour. For example, traumatic early life events can leave a lasting trace and influence our way of coping in stressful situations in adult life. This is due to a chemical mark, attributed to so-called epigenetic mechanisms, left on the chromatin. In other words, epigenetic mechanisms imprint environmental experiences onto our fixed genome. These mechanisms provide a bridge between the genes and the environment by refining neural networks according to experience and allow the environment to elicit long-life biological changes. Currently, my lab is exploring the hypothesis that long lasting epigenetic modifications in the dorsal horn could be responsible for the unpredictable transition from acute to chronic pain.
FKBP51, a stress regulator that modulates chronic pain.
My research into the regulation of pain states by epigenetic mechanisms has led to the identification of a potential new target for the management of pain. My team has indeed elucidated the role of the protein FKBP51 in the maintenance of chronic pain states. The mechanisms that connect mood disorders and chronic pain states have remained poorly understood but a regulator common to both conditions now appears to be the FKBP51 protein. FKBP51 modulates the glucocorticoid receptor (GR) sensitivity and is therefore important for the regulation of the stress response. Single nucleotide polymorphisms of the FKBP5 gene have been repeatedly associated with anxiety related disorders, including major depression and post-traumatic stress disorder (PTSD). Moreover, inhibition or deletion of the protein in mice reduced anxiety-related behaviour. Our recent study published in Science Translational Medicine (Maiarù et al. 2016) has shown that mice that lack FKBP51 have reduced chronic pain after joint inflammation and nerve damage. Moreover, deletion of FKBP51 at the level of the spinal cord using silencing RNA could interrupt a pre-existing chronic pain states. This suggested that FKBP51 regulates pain independently from its effect on mood. Crucially, it was recently reported that genetic variants in FKBP5 influence the severity of musculoskeletal pain symptoms experienced after motor vehicle collision and sexual assault, suggesting that targeting FKBP51 would be beneficial for the treatment of chronic pain in humans. The first specific inhibitors of FKBP51 have been recently developed by our collaborator, Professor Felix Hausch, at the Max Planck Institute of Psychiatry, Munich. We have tested one of these compounds in our traditional rodent paradigms and found that FKBP51 antagonism was as effective as local or global deletion in relieving inflammatory and neuropathic pain. We are currently testing these inhibitors in clinically relevant models.
Doctor of Philosophy
|University College London|
Diplôme d'Ingénieur Chimiste
|Ecole Nationale Superieure de Chimie de Montpellier|
Master of Science
|University of West England|
Dr. Sandrine Géranton is a Lecturer at University College London (UCL), UK. Her research focuses on the understanding of the molecular biology of pain states. Currently, research in her lab is organised around 2 themes: 1. the role of epigenetic mechanisms and environmental influences in the development of chronic pain conditions and 2. the role of the stress regulator FKBP51 in the maintenance of long term pain states. Dr. Géranton and her team have recently uncovered an important role for FKBP51 in the control of chronic pain states and the outcome of their research was published in Science Translational Medicine.
Dr. Géranton studied organic chemistry and biochemistry at the “Ecole Nationale Supérieure de Chimie de Montpellier” in France. She then went to the UK where she obtained an MSc in biotechnology at the University of the West of England. After a short visit to the Complutense University in Madrid, Spain, where she acquired basic molecular techniques, Dr. Géranton joined UCL where she carried out a PhD in the then department of Pharmacology. She went on learning about pain mechanisms as a post-doctoral researcher with the London Pain Consortium, under the supervision of Prof. Stephen Hunt. Dr. Géranton has always been keen on applying her multidisciplinary background to further her understanding of the molecular biology of pain states. She has been at the forefront of the investigation of the role of epigenetic mechanisms in the development of pain states, a field for which she has been asked to write numerous reviews.