MRC WIMM PRIZE STUDENTSHIPS 2021
Our group is interested in developing novel immunotherapeutic approaches for leukaemia. Clinical approaches currently used include allogeneic haematopoietic stem cell transplantation, chimeric antigen receptor T cell therapy and immune checkpoint inhibitors. While each of these approaches can be successful, they also fail in many patients as a result of tumour adaptations or diminished function of immune cells. Enhanced immunity can also lead to immune-related adverse events due to on- or off-target effects. We are exploring the mechanisms that underpin these failures and using this information to devise new strategies that can be translated into early phase clinical trials.
My lab is interested in understanding how the genome functions and leveraging this to develop genome editing strategies to treat human disease.
Our focus has been on the cell biology of the T-cell surface. We developed general methods for crystallizing glycoproteins and determined the structures of key T-cell surface proteins including the first adhesion protein (CD2) and its ligand CD58, the costimulatory receptor CD28 and its ligand CD80, and the large tyrosine phosphatase CD45. We also worked out how weak, specific recognition is achieved by these types of proteins and obtained the first insights into the overall composition of the T-cell surface. Most importantly we proposed, with PA van der Merwe, one of the most complete and best-supported explanations for leukocyte receptor triggering, called the kinetic-segregation model (youtube.com/watch?v=HygSTSlycok). Please see http://davislab-oxford.org/ for more details of our lab’s activities.
Identification of key determinants affecting the quality of human cancer specific cytotoxic T cells
Using state-of-the-art laboratory and computational approaches to understand how mammalian genes are switched on and off during development and differentiation and how this goes awry in human genetic diseases.
The Hughes group is interested in the basic mechanisms which control the activities of genes and how sequence changes in the regulatory non-coding portion of the genome alter gene expression and underlie common human diseases
The most common childhood cancer is acute lymphoblastic leukaemia (ALL). There has been amazing progress in treating childhood ALL, but unfortunately a subset of childhood ALL continues to be refractory to treatment. In addition, even for children who are cured, conventional therapies are often quite toxic and can cause long lasting life-altering effects. In the Milne lab, we are trying to better understand how normal gene regulation is disrupted in childhood ALL so that we can better design targeted therapies. Recent work in our lab has focused on a subset of childhood ALL that is caused by rearrangements of the Mixed Lineage Leukaemia (MLL) gene, which create MLL fusion proteins (MLL-FPs). MLL-FPs can directly alter gene expression in the cell through aberrant epigenetic regulation of genes. Work in the lab mainly focuses on gene regulation, specifically using genome wide techniques such as RNA-seq, ATAC-seq, ChIP-seq and 3C techniques to analyse the 3D genome.
Modelling stem cell fate and alterations due to mutations
Nerlov Group - Single Cell Biology of Hematopoietic Stem- and Progenitor Cells in Blood Cancer and Ageing
The focus of the Nerlov laboratory is combining single cell biology (single cell RNAseq, ATACseq and functional analysis) with advanced mouse genetics to study hematopoietic stem– and progenitor cells in normal development and during ageing.
The Porcher lab investigates how Haematopoietic Stem Cells (HSCs, the cells with self-renewal and multilineage potentialities that give rise to the entire blood system) are produced during embryonic development. To do this, we study the developmental pathway of the blood lineage from mesoderm through to production of HSCs (see Figure) at mechanistic and functional levels. In addition to increasing our understanding of this fundamental biological process, better knowledge of how the first HSCs are generated during embryogenesis is critical to inform experiments aiming at producing HSCs in vitro for regenerative medicine purposes and to help explain how these processes, when corrupted, can lead to haematological malignancies (leukaemia) that manifest in early life.
Megakaryocytes, platelets and Malignant Bone Marrow Fibrosis
Understanding the fundamental biological processes underlying normal and malignant haematopoiesis and translate this to improve patient outcomes through new rational therapies.