4 Year Studentship: Crosstalk between intestinal and joint inflammation and its impact on haematopoietic stem cells and progenitors in chronic inflammatory diseases.

Project reference number #20173

Project overview -

Although normal haematopoiesis in healthy individuals is well studied, the regulation of the proliferation and differentiation of haematopoietic stem cells (HSC) during inflammatory diseases is poorly understood. Importantly, HSC are much more reactive to inflammatory stimuli than previously anticipated and it was recently shown that HSC express receptors for microbial molecular patterns and inflammatory cytokines (e.g. receptors for interferons and Toll-like receptors), see King and Goodell, Nature Review Immunology 2011.

This project will build on our novel findings of dysregulated HSC activity in models of colitis, which resulted in exacerbated production of myeloid progenitors and downstream tissue-toxic cells (neutrophils and eosinophils), see Griseri et al. Immunity 2012 and 2015. The goal of this project is to understand by which cellular and molecular mechanisms the inflammation in the joints and in the intestine impacts the proliferation of HSC and their differentiation into various types of progenitor cells (i.e. myeloid, lymphoid and erythroid progenitors), using mouse models of arthritis and colitis. In particular we will take advantage of a model of spondyloarthritis in which inflammation of the joints and the intestine occurs concomitantly (Ruutu et al. Arthritis Rheum. 2012), in order to study the crosstalk between gut and joint inflammation and its impact on haematopoiesis. We will investigate the HSC and progenitor regulation not only in the bone marrow but also at extramedullary sites (e.g. the spleen and targeted tissues) and how this influences the chronicity of disease.

Training opportunities -

The Kennedy Institute is a world-renowned research centre and is housed in a brand new research facility. Full training will be provided in a range of cellular and molecular biology techniques. The student will use state-of-the-art approaches to cellular and molecular immunology and haematology including FACS analysis, RT-PCR, ELISA, genome-wide microarrays, in vitro assays of cell function and microscopy. A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in musculoskeletal sciences, immunology and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Subject-specific training will be received through our group's weekly supervision meetings. Students will also attend cutting edge external national and international scientific conferences where they will be expected to present their research findings.

Further information -

Dr Thibault Griseri, The Kennedy Institute of Rheumatology, University of Oxford, Email: [Email Address Removed]