Denson, LA; Jurickova, I; Karns, R; Shaw, KA; Cutler, DJ; Okou, DT; Dodd, A; Quinn, K; Mondal, K; Aronow, BJ; Haberman, Y; Linn, A; Price, A; Bezold, R; Lake, K; Jackson, K; Walters, TD; Griffiths, A; Baldassano, RN; Noe, JD; Hyams, JS; Crandall, WV; Kirschner, BS; Heyman, MB; Snapper, S; Guthery, SL; Dubinsky, MC; Leleiko, NS; Otley, AR; Xavier, RJ; Stevens, C; Daly, MJ; Zwick, ME; Kugathasan, S. Clinical and Genomic Correlates of Neutrophil Reactive Oxygen Species Production in Pediatric Patients With Crohn's Disease. Gastroenterology. 2018; 154(8):2097-2110.
Crohn’s disease is a form of inflammatory bowel disease (IBD) where the intestinal tract becomes inflamed. Mutations in genes affecting neutrophil reactive oxygen species (ROS) link to clinical phenotypes in children with very early onset of IBD. Dr. Lee Denson and colleagues performed whole-exome sequence analysis in older pediatric patients with Crohn’s disease to identify mutations in neutrophil ROS. They found that the same mutations in genes previously linked to very early onset IBD also play a role in disease severity in older pediatric patients. These data further the understanding of Crohn’s disease pathogenesis and suggests that targeting ROS regulators could serve as a novel therapy for treating IBD.
Ellis, JL; Bove, KE; Schuetz, EG; Leino, D; Valencia, CA; Schuetz, JD; Miethke, A; Yin, C. Zebrafish abcb11b mutant reveals strategies to restore bile excretion impaired by bile salt export pump deficiency. Hepatology. 2018; 67(4):1531-1545.
The canalicular protein, known as bile salt export pump (BSEP), mediates bile salt excretion from hepatocytes. The ABCB11 gene, a liver-specific ABC transporter, encodes the BSEP. Drs. Chunyue Yin and Alexander Miethke lead a team of researchers to use CRISPR/Cas9-based genome editing to knock out the ABCB11 ortholog in zebrafish. They discovered that mutant zebrafish died prematurely and exhibited hepatocyte injury similar to that seen in patients with progressive familial intrahepatic cholestasis type 2. Treatment of mutant zebrafish with rapamycin restored bile acid excretion, decreased hepatocyte damage, and produced an increase in life span of the mutant zebrafish. This study suggests that the use of rapamycin could restore bile salt export when there is a mutation in BSEP.
Lertudomphonwanit, C; Mourya, R; Fei, L; Zhang, Y; Gutta, S; Yang, L; Bove, KE; Shivakumar, P; Bezerra, JA. Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia. Science Translational Medicine. 2017; 9(417).
Biliary atresia is a progressive liver disease that results from complete blockage of the bile ducts. Early detection of biliary atresia is key to the successful outcome however current diagnostic approaches have limited accuracy and are time-consuming. Drs. Jorge Bezerra and Pranav Shivakumar lead the study by using serum proteomics at the time of diagnosis to identify potential biomarkers. They found high circulating concentrations of matrix metalloproteinase-7 (MMP-7), with high discriminatory value between disease and control samples. They also found that the protein is exclusively made in the epithelium of bile ducts and releases upon injury. These results suggest that serum MMP-7 can serve as a diagnostic biomarker for biliary atresia.
Minar, P; Jackson, K; Tsai, YT; Sucharew, H; Rosen, MJ; Denson, LA. Validation of Neutrophil CD64 Blood Biomarkers to Detect Mucosal Inflammation in Pediatric Crohn's Disease. Inflammatory Bowel Diseases. 2018; 24(1):198-208.
Crohn’s disease is a chronic, progressive inflammatory bowel disease (IBD) that over time may result in structural intestinal damage. In search of non-invasive biomarkers of mucosal inflammation, Drs. Phillip Minar, Michael Rosen, and Lee Denson lead the research team to study if the neutrophil CD64 surface marker could serve as a biomarker for mucosal inflammation. They found that neutrophil CD64 index significantly increases during active gastrointestinal inflammation. This study suggests that CD64 could serve as a reliable biomarker to monitor the treatment of intestinal inflammation in pediatric Crohn’s disease.
Trout, AT; Wallihan, DB; Serai, S; Abu-El-Haija, M. Secretin-Enhanced Magnetic Resonance Cholangiopancreatography for Assessing Pancreatic Secretory Function in Children. The Journal of Pediatrics. 2017; 188:186-191.
Exocrine pancreatic insufficiency has negative implications on growth and health. Once identification of the condition occurs, treatment can begin be with pancreatic enzyme replacement therapy and fat-soluble vitamin supplementation. Dr. Maisam Abu-El-Haija and collaborators demonstrated that the use of the noninvasive magnetic resonance pancreatic function testing is feasible to evaluate the severity of pediatric pancreatic disease and the measurement of secreted fluid volumes.