Revealing the mechanisms of chronic pain in dystrophic EB. (Veldhuis 1)Ongoing
|Project lead||Nicholas Veldhuis, PhD|
|Organisation||Monash Institute of Pharmaceutical Sciences, Monash University, AUSTRALIA|
|Project budget||EUR 268,074.00|
|Start date / Duration||07. Sep 2021 / 36 months|
|Funder(s) / Co-Funder(s)||DEBRA Austria, MSAP/EBEP Recommended|
|Research area||Symptom prevention & relief|
Publications related to the projectsMouse models for dominant dystrophic epidermolysis bullosa carrying common human point mutations recapitulate the human disease
Short lay summary
Chronic pain is a major problem for many patients with EB, but is poorly understood and necessitates long-term use of analgesics, including opioids, which are frequently ineffective and associated with adverse effects. To better understand chronic pain in EB and advance discovery of new analgesic options, we recently engineered a novel mouse model for EB pain, by introducing a mutation in the COL17A1 gene that is common in patients with dominant dystrophic EB (DEB). Consistent with previous studies in DEB patients, these mice show sustained hypersensitivity to pain, but the animals are only mildly affected by blistering. Using this model in conjunction with relevant patient samples, our project will apply innovative biochemical, imaging and pharmacological approaches to define the molecular and cellular drivers of chronic pain in EB and, by doing so, support pre-clinical efforts to develop safer, more effective analgesics.
Our proposed research aims to improve understanding of the underlying pathophysiology of chronic pain in EB. To achieve this aim, we will define the critical mediators of chronic pain by employing innovative tools, paradigms and methodologies as follows:
1) We recently generated a unique mouse model for dominant dystrophic EB (DEB). The phenotype of our mice mimics human DEB and includes pain hypersensitivity in the absence of overt skin damage. Although other models have been generated, these mice provide the first pre-clinical model of EB pain in the absence of damage and represent a unique, innovative and clinically relevant tool for not only determining how chronic pain in DEB arises but also developing new analgesic options. At the same time, we have access to one of the world’s leading EB biobanks and will use DEB patient samples to maximise clinical translation of our studies.
2) With access to both mouse and patient tissue samples, we will use innovative methodologies not previously employed in EB to map disruption of cellular networks around the Dermal-Epidermal junction in 3D and spatially profile mediators in skin in an unbiased quantitative manner using confocal and lightsheet microscopy, and mass spectrometry imaging.
3) This will inform subsequent pain behavioural studies in mice as an established preclinical drug discovery approach to rationally target EB pain for the first time. Any drug candidates that are identified to effectively reverse pain in these mice will be considered potential candidates for further drug development and optimisation.
The primary goal of the project is to increase our knowledge of the basic biology of EB by identifying specific molecular pathways that drive EB pain, using a combination of mouse tissue and behavioural analyses, and confirmatory analyses in human biopsies. These new findings have the potential to provide a unique blueprint for changes in EB skin that can be pharmacologically targeted to provide more effective pain relief to EB patients.