NOD2 mediated mitochondrial fission in bacterial handling and inflammation in Crohn's Disease (360G-Wellcome-102291_Z_13_Z)

NOD2 is the most strongly associated genetic variant for Crohn’s disease in Western populations. owever, little is known about downstream signaling from NOD2, precisely how Crohn’s associated polymorphisms lead to impaired autophagy, defective bacterial handling and antigen presentation, and the consequent inappropriate inflammatory response that characterizes Crohn’s. Work by Dr Simmons has suggested that DRP-1, a GTPase that is critical for mitochondrial fission, forms part of the NOD2 pathway. There is emerging evidence that mitochondria play a key role in autophagy, and DRP-1 may be highly relevant in this process. I aim to study DRP-1 in detail, including its relevance in autophagosome production and bacterial handling. I will investigate the functional consequences in Crohn’s donor cells in terms of bacterial persistence, inflammasome activation and the nature of the adaptive immune response. Work by other centres has linked further Crohn’s susceptibility genes to DRP-1, and thus potentially this research may provide hitherto undescribed links between common risk genes. Key goals: Establish role of DRP-1 in membrane formation in xenophagy Establish role of DRP-1 in xenophagy, bacterial handling and destruction in dendritic cells Define key mediators of NOD2 signaling to DRP-1 activation Establish role for defective DRP-1 activation in Crohn’s donor cells