Epigenetic modifications and their contribution to persistent pain states

Lead Research Organisation: University College London
Department Name: Unlisted

Abstract

In both animals and humans, life experiences leave an enduring trace in the brain. This is associated with so-called epigenetic changes ? structural modifications to DNA that alter the activity of genes without altering the genes themselves. These epigenetic changes are dynamic and reversible but can also result in stable alterations. For example, animal studies have shown that maternal care can modulate the activity of stress-related genes and thus influence the resilience of adult animals to stressful life events. Thus, epigenetics provides a bridge between the genes and the environment, refining neural networks according to experience.
Pain, whether caused through injury, disease or surgery, is usually temporary and serves to protect the body from further injury. As the body heals the pain diminishes and finally disappears. However, in some cases, pain persists and becomes a chronic pain state. Chronic pain is an area of an immense unmet medical need with 19% of adult Europeans suffering from chronic pain of moderate to severe intensity. New and improved treatments are required for these patients as only around one half receive adequate pain management. To develop these treatments we need a better understanding of the mechanisms responsible for the pain that persists after the injury has healed. Could these mechanisms be related to epigenetic processes? I will use my knowledge of pain mechanisms to ask how epigenetic events contribute to the establishment of persistent pain states and more generally modify the plasticity of the nervous system. This proposal will tell us a great deal about the way epigenetic regulators work and how the nervous system adapts to injury.
By reaching sufficient understanding of these epigenetic mechanisms we will gain insight into the way persistent pain states develop. With this knowledge we will design new and specific pharmacological tools for the treatment of chronic pain. This study will also inform other research on mental retardation and neuropsychiatric disorders since deregulation of epigenetic processes has been associated with a broad spectrum of neurological disorders.

Technical Summary

Persistent pain, whether caused through injury, disease or surgery, is usually temporary but involves adaptations in the spinal cord nociceptive circuitry, including central sensitization of dorsal horn neurons. This is a complex process that effectively amplifies incoming signals to prevent further damage while the body is repairing. These changes are supported by specific patterns of gene expression that are dynamic and evolve with time. Sometimes the pain persists after the injury has resolved and becomes a chronic pain state indicating maintained sensitization of spinal cord nociceptive networks. Could this be due to aberrant epigenetic modifications?
Epigenetic modifications such as DNA methylation and chromatin remodelling regulate high-order chromatin structure crucial to the regulation of gene expression. Epigenetic processes imprint environmental experiences such as social interactions onto the fixed genome and therefore provide a bridge between the genes and the environment by refining neural networks according to experience. These processes are dynamic and reversible but can also result in stable alterations. Their de-regulation has been associated with a broad spectrum of neurological disorders.
I will investigate the epigenetic processes that contribute to gene repression and activation in dorsal horn neurons in a model of joint inflammation. 1) DNA methylation is known to inhibit gene transcription. I will investigate DNA methylation status of a small number of genes previously identified. 2) Post-translational modifications of histone proteins, specifically at residues known to modify neuronal network function, regulate access to DNA. These modifications will be mapped onto nociceptive pathways during different phases of joint inflammation. 3) Descending controls from the brain and early life injury modulate pain behaviour. I will look at how descending controls and early life injury can regulate DNA methylation and histone modifications and I will investigate the correlation between epigenetic changes and pain behaviour. 4) Finally, to strengthen this correlation, I will modulate the expression of selected genes under epigenetic controls during joint inflammation and analyse their contribution to the pain state. This will include the investigation of micro-RNAs predicted by gene expression analysis and thought to fine tune neural circuits.
This investigation will provide insights into the complex roles of epigenetics in central nervous system plasticity and set the stage for a deeper understanding of the molecular changes that contribute to chronic pain, an area of immense unmet clinical needs.

Publications

10 25 50
 
Description Arthritis Research UK Grant
Amount £350,000 (GBP)
Funding ID 21972 
Organisation Versus Arthritis 
Start 09/2018 
End 03/2022
 
Description Clinical Research and Development Committee Research Funding from the BRC/UCLH Charities - Fast Track Grant
Amount £40,000 (GBP)
Funding ID 168138 
Organisation University College London Hospital 
Department University College London Hospitals Charity (UCLH)
Sector Charity/Non Profit
Country United Kingdom
Start 11/2015 
End 10/2016
 
Description No funding scheme; I was personally approached by Mundipharma Research Limited.
Amount £270,000 (GBP)
Organisation Mundipharma Research Ltd 
Start 12/2017 
End 11/2019
 
Description Treating chronic pain by inhibiting FKBP51: An investigation in clinically relevant rodent models
Amount £30,000 (GBP)
Organisation Pain Relief Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2016 
End 10/2017
 
Description Inhibitors of FKBP51 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Country Germany 
Sector Academic/University 
PI Contribution My team is testing the efficacy of compounds provided by Darmstadt, encapsulated in a gel at LMU, to reduce chronic pain states in rodent models.We use behavioural and molecular techniques to investigate the effects of these compounds.
Collaborator Contribution Our collaborators provide us with new inhibitors, encapsulated in state-of-the-art vesicular phospholipid gel, as well as the information necessary for in vivo use in rodents.
Impact Maiarù M., Tochiki K.K., Cox M.B., Annan L.V., Bell C. G., Feng X., Hausch F. and Géranton S.M. (2016) The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signalling. Science Translational Medicine. 10; 8(325):325ra19. Discipline involved: US: neuroscience, pain and animal behaviour. Collaborators: chemistry and neuroscience.
Start Year 2015
 
Description Inhibitors of FKBP51 
Organisation Max Planck Society
Department Max Planck Institute of Psychiatry
Country Germany 
Sector Public 
PI Contribution My team is testing the efficacy of compounds provided by Darmstadt, encapsulated in a gel at LMU, to reduce chronic pain states in rodent models.We use behavioural and molecular techniques to investigate the effects of these compounds.
Collaborator Contribution Our collaborators provide us with new inhibitors, encapsulated in state-of-the-art vesicular phospholipid gel, as well as the information necessary for in vivo use in rodents.
Impact Maiarù M., Tochiki K.K., Cox M.B., Annan L.V., Bell C. G., Feng X., Hausch F. and Géranton S.M. (2016) The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signalling. Science Translational Medicine. 10; 8(325):325ra19. Discipline involved: US: neuroscience, pain and animal behaviour. Collaborators: chemistry and neuroscience.
Start Year 2015
 
Description Inhibitors of FKBP51 
Organisation Technical University of Darmstadt
Country Germany 
Sector Academic/University 
PI Contribution My team is testing the efficacy of compounds provided by Darmstadt, encapsulated in a gel at LMU, to reduce chronic pain states in rodent models.We use behavioural and molecular techniques to investigate the effects of these compounds.
Collaborator Contribution Our collaborators provide us with new inhibitors, encapsulated in state-of-the-art vesicular phospholipid gel, as well as the information necessary for in vivo use in rodents.
Impact Maiarù M., Tochiki K.K., Cox M.B., Annan L.V., Bell C. G., Feng X., Hausch F. and Géranton S.M. (2016) The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signalling. Science Translational Medicine. 10; 8(325):325ra19. Discipline involved: US: neuroscience, pain and animal behaviour. Collaborators: chemistry and neuroscience.
Start Year 2015
 
Description PPI 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Met with arthritis patients in Enfield to present my work and recruit for some PPI activities.
Year(s) Of Engagement Activity 2018,2019
 
Description Press coverage for the FKBP51 study 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I have given a number of interviews for medical websites and blogs. As a result, our work on FKBP51 published January 2016 in Science Translational Medicine is now described in least 50 medical websites / blogs.
1. http://www.medicalnewstoday.com/articles/306359.php
2. http://www.the-scientist.com/?articles.view/articleNo/45305/title/Blocking-a-Stress-Related-Gene-Relieves-Chronic-Pain/
3. http://medicalxpress.com/news/2016-02-blocking-stress-protein-relieves-chronic.html
4. http://www.ucl.ac.uk/news/news-articles/0116/110216-chronic-pain-treatment-mice
5. http://www.upi.com/Health_News/2016/02/11/Chronic-pain-in-mice-relieved-by-blocking-protein/4611455208043/
6. http://www.hngn.com/articles/177944/20160210/chronic-pain-new-study-reveals-relationship-stress-related-protein.html
7. http://www.medicaldaily.com/chronic-pain-stress-protein-373038
8. http://www.forbes.com/sites/emilymullin/2016/02/11/mood-enhancing-drugs-could-also-provide-relief-for-chronic-pain/#7a4352603cd0
9. http://www.bioworld.com/content/stress-chronic-pain-share-common-receptor-0
10. http://www.engineering.ucl.ac.uk/blocking-stress-protein-relieves-chronic-pain-in-mice/
11. http://www.lifescience.net/news/614/blocking-stress-protein-may-relieve-chronic-pain/
12. http://www.counselheal.com/articles/21478/20160212/new-study-reveals-relationship-chronic-pain-stress-related-protein.htm
13. http://www.ndtv.com/health/blocking-stress-protein-relieves-chronic-pain-1276643
14. http://sevilla.abc.es/salud/enfermedades/abci-dolor-cronico-podria-minimizado-farmaco-experimental-para-estres-201602110325_noticia.html
15. http://sahafaharabiah.net/news2786986.html
16. http://www.scienceworldreport.com/articles/37130/20160211/chronic-pain-protein-blocks-problem-in-mice.htm
17. https://www.wessexlifescience.co.uk/news/entry/blocking-stress-protein-relieves-chronic-pain-in-mice
18. http://only24news.com/news?id=50556
19. http://padronel.net/2016/02/12/ms-el-dolor-crnico-podra-ser-minimizado-con-un-frmaco-experimental-para-el-estrs/
20. http://www.graffitiblog.it/bloccando-la-proteina-dello-stress-si-puo-ridurre-il-dolore-cronico364/
21. http://www.infosalus.com/salud-investigacion/noticia-bloquear-proteinas-estres-alivia-dolor-cronico-20160212071933.html
22. http://www.coriglianocalabro.it/index.php/notizie/84-attualita/11556-una-ragazza-di-calabria-che-ce-l-ha-fatta.html
23. http://www.medical-tribune.co.kr/news/articleView.html?idxno=66284
24. http://vashaspina.ru/news/blokirovanie-stressovogo-belka-mozhet-pomoch-umenshit-xronicheskuyu-bol/25382/
25. http://www.cariatinet.it/linizio-di-una-nuova-era-per-lo-sviluppo-di-farmaci-per-il-trattamento-del-dolore-cronico/
26. http://timesofindia.indiatimes.com/life-style/health-fitness/de-stress/Blocking-stress-protein-relieves-chronic-pain/articleshow/50959137.cms
27. http://noticias.lainformacion.com/salud/enfermedad/bloquear-la-proteina-que-provoca-el-estres-podria-ser-la-solucion-al-dolor-cronico_3iLIW9bsuMhb65OPrVTVJ2/
28. http://purebarta.com/blocking-a-stress-supermolecule-might-treat-chronic-pain/
29. http://m.hkn24.com/news/articleView.html?idxno=152405
30. http://www.mundop2p.es/page/3/
31. https://in.news.yahoo.com/blocking-stress-protein-relieves-chronic-pain-073306346.html
32. http://newsfisher.io/article/xXHiPh7aoTdgcdNu6
33. http://diseasestreatment.info/mood-enhancing-drugs-could-also-provide-relief-for-chronic-pain/
34. http://www.sciencecodex.com/blocking_stress_protein_relieves_chronic_pain_in_mice-175358
35. http://www.myscience.org.uk/news/2016/blocking_stress_protein_relieves_chronic_pain_in_mice-2016-UCL
36. http://gephardtdaily.com/health/chronic-pain-mice-relieved-blocking-protein/
37. http://www.breitbart.com/news/chronic-pain-in-mice-relieved-by-blocking-protein/
38. http://www.laboratoryequipment.com/news/2016/02/blocking-stress-protein-relieves-chronic-pain-mice
39. http://www.scienceandtechnologyresearchnews.com/blocking-stress-protein-relieves-chronic-pain-in-mice/
40. http://www.daijiworld.com/news/news_disp.asp?n_id=380350
41. http://www.alnmag.com/news/2016/02/blocking-stress-protein-relieves-chronic-pain-mice
42. http://www.abc.es/salud/enfermedades/abci-dolor-cronico-podria-minimizado-farmaco-experimental-para-estres-201602110325_noticia.html
43. http://styles7.com/2016/02/11/blocking-a-stress-protein-may-treat-chronic-pain/
44. http://www.mangalorean.com/blocking-stress-protein-relieves-chronic-pain/
45. http://www.newkerala.com/news/2016/fullnews-19806.html
46. http://gomedoc.com/blocking-a-stress-protein-may-treat-chronic-pain/
47. http://expofarmacia.com.ar/nota.php?id=2507
48. http://csrproductions.com/chronic-pain-in-mice-relieved-by-blocking-protein/
49. http://www.newsx.com/lifestyle/20502-blocking-stress-protein-relieves-chronic-pain
50. http://www.medicalworldnigeria.com/2016/02/blocking-a-stress-protein-may-treat-chronic-pain/#.Vr7zZLKLSUk
51. http://www.ourladiesandgentlemen.com/medical-news-today-blocking-a-stress-protein-may-treat-chronic-pain/
52. http://www.siasat.com/news/blocking-stress-protein-relieves-chronic-pain-916087/
53. http://www.business-standard.com/article/news-ians/blocking-stress-protein-relieves-chronic-pain-116021200344_1.html
54. http://www.neurexpert.com/blog/Blog24022016.html
Year(s) Of Engagement Activity 2016
URL http://www.forbes.com/sites/emilymullin/2016/02/11/mood-enhancing-drugs-could-also-provide-relief-fo...