The Hunter laboratory studies the pathophysiology of necrotizing enterocolitis (NEC) and other intestinal disorders that affect children such as inflammatory bowel disease (IBD). Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of newborns and affects 5-10% of all infants in the neonatal intensive care unit. Prematurity, formula feeding and abnormal patterns of microbial colonization are established risk factors. Current treatment approaches are limited to bowel rest, antibiotics, and in severe cases surgical resection of necrotic bowel. The nonspecific nature of these therapies reflect the fact that NEC pathogenesis is, essentially, undefined. Delineation of the processes responsible for NEC is, therefore, a high priority and prerequisite to developing meaningful medical interventions to prevent or treat NEC. The main objects of our research are to better understand the complex mechanisms that cause some babies and children to be susceptible to these diseases, and identify potential cures and preventative strategies.
Protein kinase A is an important mediator and is involved in multiple important cellular functions including inflammation and cell death. An increase in intestinal inflammation, injury and epithelial death are characteristic of NEC and IBD. In order to identify key players in the development of disease we use a multi modal approach including cell lines and human tissue samples. We have also engineered 3-dimensional models of infant intestine to work with in the laboratory, allowing us to make key insights into the pathophysiology of human disease. Using these approaches we identified that protein kinase A is activated during human NEC. Excitingly we have demonstrated that blocking the activation of this protein kinase is protective against intestinal injury and NEC in the laboratory demonstrating a potential therapeutic strategy.
Rho kinases (ROCK) are serine/ threonine kinases and are involved in multiple cellular processes including regulating tight junction function, actin cytoskeleton contraction, inflammatory cytokines and cell death. Tight junctions are protein complexes that regulate the connections between cells maintaining normal permeability and intestinal integrity. We have previously demonstrated the importance of these pathways to the pathophysiology of NEC. The objectives of this project are to define mechanisms of ROCK activation, identify molecular pathways targeted by ROCK during experimental NEC and to determine how ROCK inhibition limits NEC progression. The central hypothesis NEC is associated with ROCK activation, resulting in tight junction breakdown that enhances mucosal and systemic inflammation and epithelial cell death. If this hypothesis is correct then ROCK inhibition will be protective against these effects and NEC. These findings will have a significant positive impact on human health by providing a new understanding of the mechanisms governing epithelial intestinal barrier function during NEC.
MicroRNAs (miRNAs) are short non-coding RNAs that are key modulators in various cellular processes at the post-transcriptional level. Aberrant expression of specific miRNAs have been identified in many pathological conditions including cancers, neurodevelopmental disorders, cardiovascular and inflammatory diseases. Unique miRNA expression profiles have been reported in the intestinal epithelial cells of patients with inflammatory bowel disease (IBD) as well as in the peripheral blood of patients with active IBD. The role of miRNAs in NEC has not yet been studied. The objective of this project is to identify miRNAs with aberrant expression in NEC allowing for their use as biomarkers of clinical disease. Successful completion of this project will provide insight into the role of miRNAs in the pathophysiology of NEC. This will be pivotal in the development of diagnostic miRNA biomarkers as well as targeted therapies for the prevention and treatment of NEC.
Doug Wood, BS. Research Technician
Carrie Yuan, BS. Research Technician
Samuel Klonoski, MD. Research Fellow
Emily Winterhalter, Undergraduate Student
John Sincavage, Medical Student
Robin Redline, Research Technician II
Catherine J. Hunter, MD