01865 287600 (PA)
Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN
Professor of Precision Medicine
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory (DIL)
The JDRF/Wellcome Trust DIL is researching the causes of the autoimmune disease type 1 diabetes (T1D) in order to treat and prevent the disease by modulating the causative pathways. We achieve this by linking genetic determinants of disease with phenotypes and pathways in cells and in patients, using a wide range of molecular, metabolic and immunological approaches.
Genetics Identification of T1D genes and their pathways is essential for understanding the biology underpinning disease susceptibility. We are integrating the latest and emerging genomics data - genetic variation, RNA gene expression, methylation, transcription factor binding sites and chromatin phenotypes – to better define the T1D causal genes. For example, identification of contacts between promoter and enhancer sequences is providing major insight to causal gene identification (ImmunoBase; CHiCP).
Phenotypes and mechanisms Identify aberrant cellular interactions and pathways caused by susceptibility genes that mediate a loss of immune tolerance to insulin-producing beta cells culminating in their destruction. These will provide potential targets for therapeutic intervention, as demonstrated by our work in the IL-2 pathway. This knowledge will contribute to understanding cell interactions altered by disease genes, an essential step for prioritizing potential immune-modulating agents to be investigated in experimental studies in T1D patients.
Experimental medicine Our hypothesis is that determination of the optimal dosing regimen of a potential therapeutic in terms of its molecular and cellular responses in vivo will greatly improve the likelihood of a beneficial outcome in future clinical trials. We are testing the utility of this approach in the ongoing investigation of the effects of ultra-low doses of IL-2 in patients with T1D, and will consider and evaluate other potential therapeutics.
The DIL’s core support, a Strategic Award, jointly funded by the Wellcome Trust and the JDRF, was renewed in October 2015 for another five years.
Potential project areas: Diabetes, autoimmunity, genomics, single cells, genetics, statistics, bioinformatics, immunology, experimental medicine, insulin
Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach
Richardson TG. et al, (2022), Nature Communications, 13
Low-dose IL-2 reduces IL-21+ T cell numbers and induces anti-inflammatory gene expression in type 1 diabetes
Zhang J. et al, (2022), Nature Communications
Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage.
Sioofy-Khojine A-B. et al, (2022), Diabetologia
An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci.
Mountjoy E. et al, (2021), Nat Genet, 53, 1527 - 1533
Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes.
Robertson CC. et al, (2021), Nat Genet