Immunometabolic cross-talk in the inflamed diabetic heart

Diabetic cardiomyopathy (dbCM) is a complication of type II diabetes (T2D), characterised by systemic inflammation, impaired cardiac function and disrupted metabolism.

However, the impact of systemic inflammation on the development of the myocardial inflammation and cardiac metabolic derangement that lead to dbCM remain unknown.

This study will address how chronic adaptive inflammation driven by systemic metabolic stress in T2D causes cardiac dysfunction.

Specifically, I hypothesise that it is caused by inflammation due to T-cell infiltration and not by direct metabolic perturbations that can lead to impaired energetics (reduced PCr/ATP ratio).

Specifically, the aim is to use integrated experimental approach combining metabolic analysis with T-cell phenotypic profiling in murine and human T2D to address three research challenges: A. Does infiltration of cardiotropic T-cells impair cardiac substrate plasticity and energetics in dbCM? B.

Do myocardial succinate efflux and signalling via SUCNR1 promote cardiac Teff and/or Treg activation by modifying T-cell metabolism and do they enhance pro-inflammatory T-cell differentiation? C.

Does stimulation of GCK-mediated glycolysis increase regulatory T-cell migration to the heart causing a switch in the nature of immune response from pro-inflammatory to immunosuppressive?

Does the resultant reduction in myocardial exposure to pro-inflammatory cytokines improve cardiac function and mitochondrial performance?