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
Whole-genome sequencing of a sporadic primary immunodeficiency cohort
Thaventhiran JED. et al, (2020), Nature
Author Correction: Approaches and advances in the genetic causes of autoimmune disease and their implications
Inshaw JRJ. et al, (2020), Nature Immunology
Interleukin-2 Therapy of Autoimmunity in Diabetes (ITAD): a phase 2, multicentre, double-blind, randomized, placebo-controlled trial
Marcovecchio ML. et al, (2020), Wellcome Open Research, 5, 49 - 49
Assessing the effect of closed-loop insulin delivery from onset of type 1 diabetes in youth on residual beta-cell function compared to standard insulin therapy (CLOuD study): a randomised parallel study protocol.
Boughton C. et al, (2020), BMJ open, 10
Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic β-Cells.
Inshaw JRJ. et al, (2020), Diabetes care, 43, 169 - 177