Fibroblasts are the major cell type of connective tissue. They play a critical role in maintaining the extracellular matrix, the ‘glue’ in which most cells reside, and maintaining normal function of other types of cells such as epithelial and immune cells. Abnormal function of fibroblasts contributes to the development of many common diseases, such as cancer and a wide range of inflammatory disorders. Many of the diseases in which fibroblasts play a role increase in prevalence and/or severity with age, and a large body of evidence indicates that age-related changes in fibroblasts contribute to their detrimental function in disease. One of the key changes occurring in aged fibroblasts is the development of a pro-inflammatory senescent phenotype. Senescent cells are found in increased numbers in aged tissue and are frequently observed in diseases such as cancer. There is, therefore, a great deal of interest in the possibility of developing therapies targeted to senescent fibroblasts.
One of the key features of cellular ageing is the development of elevated levels of oxidatively modified DNA bases, primarily 8-oxo-7,8-dihydroguanine (8-oxoG). These modifications are repaired by 8-oxoguanine DNA glycosylase 1 (OGG1); binding of OGG1 to 8-oxoG leads to a number of cellular responses, including activation of NFκB. This activation contributes to the development of an inflammatory secretome, implicating OGG1 as a key mediator of age-related inflammation. Little is known, however, of the roles of OGG1 in fibroblast senescence and associated pro-inflammatory effects.
We have recently developed a novel OGG1 active site-specific inhibitor, TH5487, and demonstrated its ability to reduce inflammation in the lung (Visnes et al, 2018, Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. Science 362:834-839. doi: 10.1126/science.aar8048).
The aim of this project is to capitalise on these exciting findings to assess the potential of targeting this inflammatory pathway in fibroblasts. We hypothesise that OGG1 mediates age-associated inflammatory changes in fibroblasts, and that inhibiting OGG1 provides an opportunity to develop a novel therapeutic approach applicable to a wide range of diseases.
The successful applicant will join a vibrant research environment in the investigators’ laboratories in the School of Clinical Dentistry and the Department of Oncology and Metabolism, University of Sheffield, in close collaboration with Christina Kalderen at the Karolinska Institute in Sweden. The supervisors have a very strong record of training PhD students and early career scientists and will provide full training in state-of-the-art facilities.
Applications are invited from enthusiastic candidates holding, or expecting to obtain, the equivalent of at least an upper second (2:1) or First Class degree or MSc in a relevant subject area. Informal enquiries are encouraged prior to application; please contact Dr Dan Lambert ([email protected]
How to apply:
Please complete a University Postgraduate Research Application form available here: http://www.shef.ac.uk/postgraduate/research/apply
Please clearly state the prospective main supervisor in the respective box and select School of Clinical Dentistry as the department.