An estimated 3.1 million American are currently diagnosed with Inflammatory Bowel Disease (IBD) and the worldwide incidence of disease is increasing. There is growing appreciation for mitochondrial dysfunction as a cause of and therapeutic target for inflammatory disease, however mitochondrial health has been understudied in the intestine. The broad goal of this proposal is to determine how mitochondrial dysfunction in the intestinal epithelium contributes to IBD pathogenesis and to investigate whether reversing or preventing mitochondrial dysfunction can improve outcomes. We evaluated the intestinal epithelium of patients with IBD for protein levels and expression of Peroxisome Proliferator-activated Receptor-? Coactivator 1-? (PGC1?), the master regulator protein of mitochondrial biogenesis, and found evidence of significant downregulation. Intestinal epithelium-specific PGC1? knockout mice were found to be highly susceptible to an acute intestinal injury model, while pharmacologic restitution of PGC1? levels rescued mice from inflammation. Recently, we found that mitophagy is a key adaptive response to mitochondrial damage in the intestine during IBD. In response to mitochondrial injury, the mitophagy protein Nix is upregulated and moves to the mitochondria where it binds LC3 and initiates degradation of the affected mitochondria. In parallel to these investigations, we contributed to an important multi-institutional study detailing a ?mitochondriopathy? of pediatric-onset UC characterized by downregulation of PGC1? and associated genes governing oxidative phosphorylation and mitochondrial quality control. In fact, this mitochondrial signal was found to be the most significant hallmark of treatment-nave pediatric-onset UC. Although a disruption of mitochondrial dynamics alone likely does not cause IBD, it appears to drive ongoing inflammation within the intestinal epithelium and may serve as important biomarker of disease. Whether a cause or consequence of disease, we postulate that the process of mitochondrial dysfunction offers significant opportunity for therapeutic intervention. Our hypothesis is that the mitochondriopathy of IBD is a signature feature of disease with important functional consequences, and one that is amenable to therapeutic targeting. In order to test this hypothesis, we have devised the following aims:
Aim 1 : To evaluate the cause of mitochondrial dysfunction during IBD.
Aim 2 : To characterize the physiologic response to mitochondrial dysfunction during IBD.
Aim 3 : To target mitochondrial dysfunction therapeutically in murine colitis and characterize the metabolic effects of mitochondrial dysfunction in human IBD. Successful completion of these experiments will frame the causes and consequences of mitochondrial dysfunction during IBD, offering the opportunity to improve disease outcomes by mitigating ongoing inflammation.

Public Health Relevance

Inflammatory bowel disease (IBD) affects 1.6?3.1 million Americans and is associated with significant lifetime morbidity as well as a heavy financial burden to 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 cellular 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK120986-01A1
Application #
9887398
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Greenwel, Patricia
Project Start
2020-01-01
Project End
2024-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213