Inflammatory bowel disease (IBD) represents a spectrum of chronic, relapsing, idiopathic inflammatory disorders of the gastrointestinal tract. Currently, over 1.6 million American are diagnosed with IBD and the worldwide incidence of disease is increasing. Studies have demonstrated a decrease in activity of mitochondrial electron transport chain complexes in humans with IBD as well as a dysregulated release of mitochondrially-derived reactive oxygen species (ROS). The primary goal of the proposed study is to identify the root cause of mitochondrial dysfunction during IBD in the hopes of identifying novel targets for therapeutic intervention. We have shown that PGC1?, the master regulatory protein of mitochondrial biogenesis in decreased in the intestines of humans with IBD. Mice lacking PGC1? in the intestine develop a dramatically worse experimental colitis that do their wild-type littermates. Further, these intestinal epithelial PGC1? knockout mice demonstrate a decrease in mitochondrial mass, increased ROS release and reduced oxidative phosphorylation during inflammation. It remains unclear what drives the downregulation in PGC1? during disease and how PGC1? depletion can be prevented. We now show that PGC1? is deactivated during IBD through acetylation. Our preliminary evidence suggests that sirtuin 1 (SIRT1), the primary activator of PGC1?, is unable to deacetylate PGC1? due to a cellular depletion of its cofactor NAD+. Poly (ADP-ribose) polymerase-1 (PARP1), a DNA repair enzyme that is upregulated during colitis is known to deplete NAD+ during multiple disease states, contributing to a decline in SIRT1 activity. Therefore, we hypothesize that PARP1 activation leads to the depletion of NAD+ during IBD. As a result of NAD+ depletion, SIRT1 is deprived of the substrate needed to deacetylate and activate PGC1?, contributing to a decrease in mitochondrial biogenesis. Inactive PGC1? is further targeted for proteasomal degradation. In order to investigate this hypothesis, we have devised the following specific aims:
Aim 1. To evaluate the role of the PARP1?SIRT1 axis on PGC1? activation during colitis.
Aim 2. To determine if GSK3? tags PGC1? for proteasomal degradation during inflammation. The proposed studies will advance our understanding of the signaling pathways involved in PGC1? deactivation and depletion, which contribute to the subsequent failure in mitochondrial biogenesis seen during IBD. It is our hope that this knowledge will allow us to design novel therapeutic strategies for IBD aimed at improving mitochondrial health in the intestine.
Inflammatory bowel disease (IBD) affects over 1.6 million Americans and is associated with significant lifetime morbidity as well as a heavy financial burden on society. Our current understanding of the factors that initiate and propagate inflammatory changes within the intestine is limited. The current proposal is designed to investigate how abnormalities in mitochondrial function and metabolism within the intestinal epithelium contribute to disease in the hopes of identifying novel therapeutic strategies for IBD aimed at improving mitochondrial health in the intestine.
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