Shang-Jie Xiao1, Xiao-Chun Zhu1, Hua Deng2, Wei-Ping Zhou2, Wen-Yi Yang3, Li-Ke Yuan1, Jiang-Yu Zhang4, Song Tian1, Lu Xu1, Liang Zhang5, Hui-Min Xia6. 1. Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou, China. 2. Translational Medicine Center, Guangdong Women and Children Hospital, Guangzhou, China. 3. Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou, China. 4. Department of Pathology, Guangdong Women and Children Hospital, Guangzhou, China. 5. Translational Medicine Center, Guangdong Women and Children Hospital, Guangzhou, China. Electronic address: zhangliang1999@tsinghua.org.cn. 6. Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. Electronic address: xia-huimin@foxmail.com.
Abstract
BACKGROUND: Hirschsprung disease (HD) is a congenital intestinal anomaly resulting from a failure to form enteric ganglia in the lower bowel. Surgery is the main therapeutic strategy, although neural stem cell transplantation has recently shown promise. However, HD remains a challenging disorder to treat. Our aim was to identify drugs that could counteract the dysregulated pathways in HD and could thus be potential novel therapies. METHODS: We used microarray analysis to identify genes differentially expressed in ganglionic and aganglionic bowel samples from eight children with HD. The signature of differentially expressed genes was then used as a search query to explore the Connectivity Map (cMAP), a transcriptional expression database that catalogs gene signatures elicited by chemical perturbagens. RESULTS: We uncovered several dysregulated signaling pathways, and in particular regulation of neuron development, in HD. The cMAP search identified some compounds with the potential to counteract the effects of the dysregulated molecular signature in this disease. One of these, pepstatin A, was recently shown to rescue the migration defects observed in a mouse model of HD, providing strong support for our findings. CONCLUSIONS: This study advances our understanding of the molecular changes in HD and identifies several potential pharmacological interventions. Further testing of the identified compounds is warranted.
BACKGROUND:Hirschsprung disease (HD) is a congenital intestinal anomaly resulting from a failure to form enteric ganglia in the lower bowel. Surgery is the main therapeutic strategy, although neural stem cell transplantation has recently shown promise. However, HD remains a challenging disorder to treat. Our aim was to identify drugs that could counteract the dysregulated pathways in HD and could thus be potential novel therapies. METHODS: We used microarray analysis to identify genes differentially expressed in ganglionic and aganglionic bowel samples from eight children with HD. The signature of differentially expressed genes was then used as a search query to explore the Connectivity Map (cMAP), a transcriptional expression database that catalogs gene signatures elicited by chemical perturbagens. RESULTS: We uncovered several dysregulated signaling pathways, and in particular regulation of neuron development, in HD. The cMAP search identified some compounds with the potential to counteract the effects of the dysregulated molecular signature in this disease. One of these, pepstatin A, was recently shown to rescue the migration defects observed in a mouse model of HD, providing strong support for our findings. CONCLUSIONS: This study advances our understanding of the molecular changes in HD and identifies several potential pharmacological interventions. Further testing of the identified compounds is warranted.