Research grants supporting EXPPECT laboratory-based research are shared here.
CB2 receptor agonists as a novel treatment for women with endometriosis-associated pain (2016-2021)
Funded by the MRC under an asset-sharing scheme that provides money to repurpose drugs that have been developed by pharmaceutical companies.
The drug being tested has been provided by Eli Lilly and Company.
Background: The body is equipped with an endocannabinoid system consisting of receptors, ligands and their metabolising enzymes that modulates inflammatory/immune mechanisms and pain processing (reviewed in Woodhams et al., 2015). Cannabinoids act via receptors (CB1 and CB2) that are expressed in cells which play a critical role in the relay and modulation of pain pathways (Pertwee, 2011). CB1 receptors are found in neurons of the central nervous system (CNS), in dorsal root ganglia (DRG) and in peripheral nerves. CB2 receptors are expressed by multiple immune cells and in the nervous system (including specific brain regions, spinal cord and DRG). As the psychotomimetic side effects (‘high’) of cannabinoids are mediated through the CB1 receptor, researchers and pharmaceutical companies have developed synthetic CB2-specific synthetic ligands for pain management. Studies in our group have already established that immune cells play a key role in the neuroinflammation that contributes to the development of pain symptoms in women. We have identified CB2 receptors in immune cells and therefore we hypothesised that they might be a key target for drugs targeting this receptor.
Primary objective: To conduct a pre-clinical study to determine whether the selective CB2 agonist LY2828360 can be repurposed for the treatment of painful symptoms in women with endometriosis. Since the study started we have worked out an effective dose of the compound in mice and shown that the drug changes the numbers and types of immune cells in the peritoneum. We are now planning to test the compound in our mouse model of endometriosis.
Androgens and women’s health: developing new therapies for endometriosis (2016-2021)
Funded by the MRC as a Programme Grant supporting the salaries of three members of staff.
Androgens are steroids that act by binding to androgen receptors (AR) in target tissues; whilst often thought of as ‘male’ hormones, androgens also play an important role in women’s health and fertility. We have shown that AR are present in the normal endometrium and also that androgens can have an impact on fertility. Importantly, androgens can also regulate key processes implicated in the establishment of endometriosis lesions including apoptosis, proliferation and cell migration of human endometrial stromal fibroblasts as well as regulation of some immune cells. For example, studies using brain imaging to measure responses in women taking oral contraceptives revealed that those who had low testosterone suffered increased pain sensitivity.
The planned research is grouped under four interlinked themes:
- Androgen ligand bioavailability, impact on endometrial tissue function and ectopic endometriotic lesions
- The impact of selective AR modulators (a new class of synthetic drugs) on the regulation of human endometrial cells
- The impact of androgens on endometrial processes relevant to establishment of endometriotic lesions (e.g. tissue breakdown and repair during menstruation, peritoneal inflammation)
- Testing the use of androgen receptor agonists, antagonists and Selective Androgen Receptor Modulators (SARMs) for treatment of endometriosis in a preclinical model
IMI-Pain Care – Improving the care of patients suffering from acute or chronic pain (2018-2021)
EU funded. IMI2-2016-10-03C.
We are members of the large multi-European consortium: our grant theme is Translational Research in Pelvic Pain (TriPP) with studies grouped under three work packages focused on testing the hypothesis that ‘Endometriosis-associated pain (EAP) and bladder pain syndrome (BPS) are primarily chronic pain conditions featuring similarities in underlying pain generating and maintaining mechanisms, albeit associated with specific pathological lesions and end-organ symptoms’.
The studies will use a range of patient samples to define common parameters and these will be complemented by multinational comparisons between different preclinical models so that we can develop a platform in which to better test drugs for pain therapy.
The grant started in mid-2018 and at present we are at the stage of setting up the pre-clinical models in multiple locations. Ethical approval for the clinical studies has recently been obtained and much of the data analysis will utilise existing clinical sample sets which also include brain images.