We were the first to develop a novel animal model of post-pull-through HAEC using the endothelin receptor B targeted-null mouse (Ednrb-/-) by performing a single-stage microsurgical pull-through operation. Our model was the first to show that the mouse developed enterocolitis after pull-through surgery at a rate remarkably similar to humans.
During our characterization of the enterocolitis in Ednrb-/- mice, we observed that Ednrb-/- mice with colonic aganglionosis have small spleens and splenic lymphopenia that most severely affected mature B cells. Further immunological studies with the Ednrb-/- and Endothelin 3 targeted-null mice underway in our lab are shedding new light on the immune phenotype and the molecular mechanisms underlying HAEC.
We founded the HAEC Collaborative Research Group (HCRG), a multicenter study focused on identifying genetic, immunologic and microbiome biomarkers of HAEC in children with Hirschsprung disease. We are currently collaborating with Stephan Targan, MD Laboratory in the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute and Vince Funari, PhD, in the Genomics Core at Cedars-Sinai.
Philip K. Frykman, MD, PhD serves on the Steering Committee of the Hirschsprung Disease Research Collaborative (HDRC), an academic research collaboration involving geneticists, pediatric surgeons, pediatricians and gastroenterologists interested in a global genetic analysis of Hirschsprung disease to answer questions regarding susceptibility genes for aganglionosis and its complications (such as enterocolitis), and how this genetic information can be used for disease prediction, disease management and therapeutic advances.
Using a team-science approach, we continue extend the boundaries of our understanding of the HAEC disease mechanisms, with the aim of identifying risk factors for development of HAEC and developing better prevention and treatment strategies.
Advanced Imaging Innovation in Pediatric Surgery
We are leaders in the innovative use of cutting-edge imaging technology to pediatric surgery. On the diagnostic side, our focus is applying the advanced technique of biomedical spectral imaging to the intraoperative diagnosis of Hirschsprung disease. Our work has shown "proof of concept" that in vivo diagnostics can be performed accurately and in real-time, without the need for time-consuming frozen sections to establish a tissue diagnosis. (See figures below from Frykman et al. 2008) These imaging modalities have wide application to many other fields of surgery where intraoperative tissue diagnosis is the current practice. We are currently collaborating with a group at Cornell University applying multiphoton microscopy to identify ganglion cells in a similar mouse model of HD.
Figure 4. Spectral Detection curves and a spectrally classified image.
|Table 3. Spectral imaging test statistics.|
|Positive predictive value (PPV)||92%|
|Negative predictive value (NPV)||98%|
On the therapeutic side, we study new endoscopic and exoscopic instruments for clinical application to pediatric surgery. These include assessments of a wide range of parameters including image quality, ease of use in specific types of operations, such as neonatal congenital diaphragmatic hernia repair, recurrent tracheoesophageal fistula repair, sacrococcygeal teratoma resection.