Background: Chronic inflammation is a major contributor to bone and joint damage, disability and co-morbidities associated with several skeletal disorders, including Arthritis and Osteoporosis. A number of treatment approaches that target and antagonize the action of a single pro-inflammatory factor, such as anti-TNFa (Infliximab, Arthritis treatment) and anti-RANKL (Denosumab, Osteoporosis treatment) have been developed and exhibited great clinical success. However, many of these ‘highly-targeted’ agents have been rendered less effective in some patients due to acquired drug resistance. The pro-inflammatory TRAF/NFkB signalling pathway plays a key role in inflammation and bone remodelling, and agents, including Infliximab and Denosumab, inhibit TRAF-mediated NFkB activation in bone and immune cells. The TRAF family constitutes of 7 adaptor proteins that exhibit distinct and overlapping functions. We have recently published studies that showed that a small molecule inhibitor of NFkB that disrupts TRAF6 and CD40 binding exhibited anti-inflammatory, but not osteoprotective, effect in animal models of bone loss, including Rheumatoid Arthritis and Osteoporosis (Marino et al. BCP. 2022). This finding led us to conclude that TRAF6 inhibitors that selectively target the CD40 pocket may be of value in the management of the inflammatory component of bone disease but may not offer protection against bone loss due to age or oestrogen deficiency. Thus, we developed a new family of novel TRAF6 inhibitors that bind to a novel pocket in TRAF6 as well as CD40 pocket. Our unpublished data demonstrated that a compound that belongs to this family exerted potent anti-NFkB and anti-osteoclast effects, when compared to a TRAF6/CD40 inhibitor.
Hypothesis: This PhD programme will build on these findings and our group previous work on the role of the TRAF/NFkB axis in bone diseases, and will evaluate the hypothesis that small-molecules that inhibit TRAF6 by binding to multiple pockets reduce inflammation and offer osteoprotection in in vitro, ex vivo and mouse models of local and systemic osteolysis.
Clinical significance: If successful, the findings of this PhD research will identify small-molecule inhibitors of TRAF6 as a new, inexpensive drugs that can be of value in the management of a variety of diseases characterized by inflammation and/or bone and joint destruction.
Entry Requirements:
Candidates must have a first or upper second-class honors degree. Laboratory hands-on experience in tissue culture techniques is desirable. Experience with transfection techniques and computed tomography would be advantageous.
Enquiries:
Dr Aymen Idris, [Email Address Removed], Tel: 00441142159051.
How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply
Closing date: 01/10/2023
Proposed start date (from): 01/03/2023