Inflammatory bowel disease (IBD) represents a spectrum of chronic, relapsing, idiopathic inflammatory disorders of the gastrointestinal tract. Currently, over 1.4 million American are diagnosed with IBD and the incidence is increasing. Studies have demonstrated a decrease in activity of mitochondrial electron transport chain complexes in humans with IBD.10-12 This would suggest a bioenergetic failure within the intestinal mitochondria. It remains unanswered whether this decrease in mitochondrial function primarily drives inflammatory changes in the gut or is a consequence of it. This project will seek to address this gap in our knowledge by exploring the role that abnormal mitochondrial dynamics play in IBD. Mitochondrial biogenesis is the process by which new mitochondria are generated, while mitophagy represents a mechanism for clearance of unhealthy mitochondria. These two processes act to preserve mitochondrial health as a part of normal mitochondrial dynamics. Our data suggest a decrease in the mitochondrial biogenesis protein PGC1? in the setting of murine colitis and human IBD. Further, mice lacking PGC1? in the intestinal epithelium demonstrate a much more severe colitis than their wild-type counterparts. This, combined with changes in mitophagy suggests an overall decline in mitochondrial health. We hypothesize that PGC1? downregulation, subsequent faailure of mitochondrial biogenesis and disorganized mitophagy play key roles in the pathogenesis of colitis, and that the reversal of changes in mitochondrial biogenesis will ameliorate disease. To address this hypothesis, we have devised the following aims: 1) to characterize changes in mitochondrial biogenesis during the pathogenesis of inflammatory bowel disease and assess the protective effects of PGC1? activation in experimental colitis via its effects on mitochondrial biogenesis;2) to define and characterize bioenergetic failure of intestinal mitochondria during the pathogenesis of intestinal inflammation in mice and humans;and 3) to evaluate the role of disorganized mitophagy in mitochondrial failure during the pathogenesis of colitis. Dr. Mollen is a practicing pediatric surgeon who has worked closely with his mentor since becoming full-time faculty. He benefits from a well-established mentor as well as a very supportive research and practice environment. The candidate's immediate goals are to obtain increased knowledge and proficiency in advanced experimental techniques in order to design and carry out increasingly sophisticated experiments to address hypothesis-driven questions. His long-term goals are to become an independent surgeon-scientist who is able to merge his research and clinical interests in IBD into a translational program addressing key questions in the field and potentially offering unique and novel therapies. To achieve these goals, a structured career development plan has been created consisting of: gaining increased experience with advance experimental techniques, specific course work, participation in conferences, frequent meetings with the mentor, and a gradual increase in research independence over the award period.
Inflammatory bowel disease is highly prevalent with a significant lifetime morbidity and financial burden on society. Our current understanding of the factors that initiate and potentiate inflammatory changes within the intestine is limited. A greate understanding of how abnormalities in mitochondrial dynamics and metabolism within the intestinal epithelium contribute to disease will enhance our overall understanding of IBD and may open the door to novel, mitochondrial-based treatment strategies.
|Previte, Dana M; O'Connor, Erin C; Novak, Elizabeth A et al. (2017) Reactive oxygen species are required for driving efficient and sustained aerobic glycolysis during CD4+ T cell activation. PLoS One 12:e0175549|
|Cunningham, Kellie E; Vincent, Garret; Sodhi, Chhinder P et al. (2016) Peroxisome Proliferator-activated Receptor-? Coactivator 1-? (PGC1?) Protects against Experimental Murine Colitis. J Biol Chem 291:10184-200|
|Novak, Elizabeth A; Mollen, Kevin P (2015) Mitochondrial dysfunction in inflammatory bowel disease. Front Cell Dev Biol 3:62|
|Afrazi, Amin; Branca, Maria F; Sodhi, Chhinder P et al. (2014) Toll-like receptor 4-mediated endoplasmic reticulum stress in intestinal crypts induces necrotizing enterocolitis. J Biol Chem 289:9584-99|