Research Interests of Division Faculty
The faculty advisors at Cincinnati Children's Hospital Medical Center include investigators from within the Division of Gastroenterology, Hepatology and Nutrition as well as other divisions within the Children's Hospital Research Foundation and other departments of the University of Cincinnati College of Medicine. Fellows can select a mentor from among the following faculty within the division.
Dorothy M. M. Kersten Professor of Pediatrics
Dr. Balistreri is investigating therapeutic options for children with chronic viral hepatitis B (HBV) and C (HCV). He completed an initial trial of lamivudine treatment of children with HBV to determine viral clearance, seroconversion, and sequence of resistant HBV strains. He is currently involved in two multi-center studies, each of which is a randomized, pla-cebo-controlled trial. The first study is to assess the safety and efficacy of PEG-2α interferon (IFN) combined with ribavirin (compared to PEG-2α IFN alone) in the treatment of children with chronic hepatitis C. The end points of this study are to determine the sustained viral response (SVR) rate, the effects of PEG-2α IFN on body mass index, body composition, and linear growth, and short- and long-term outcomes (health-related quality of life, cognitive, developmental and psychological functioning). The second study is a clinical trial of adefovir in children with chronic hepatitis B. This study examines the safety and efficacy of adefovir vs. placebo in inducing clearance of HBV (loss of HBeAg) in chronically infected children.
Assistant Professor of Pediatrics
Dr. Bates studies intestinal development, with a major focus on how cell-cell interactions are regulated by the Hlx homeobox transcription factor during embryogenesis of the digestive system. Hlx is required for normal growth and development of the intestine and liver in mouse embryos, and the Hlx gene and protein are highly conserved among vertebrate species. Dr. Bates found that Hlx also plays a regulatory role in intestinal development as demonstrated by an abnormal formation of the enteric nervous system and enteric smooth muscle differentiation. The overall hypothesis is that the specific expression of the Hlx protein results in regulation of the development of the intestine (including enteric neurons and intestinal mesenchyme) by directing the expression of genes encoding proteins participating in interactions of mesenchyme with other tissues. Thus, Dr. Bates is working to understand the control of expression of Hlx itself and to identify genes that are in turn regulated by Hlx (downstream targets). Additionally, Bates has participated in a multi-investigator collaborative effort to examine gene expression along the anterior-posterior (proximal-distal) axis and comparing global gene expression in developing and maturing small intestine with that in adaptation of small intestine following partial resection. Finally, Dr. Bates is developing a program to identify genes and environmental factors underlying congenital anorectal malformations in humans. Under his active IRB-approved protocol, he is currently recruiting subjects for candidate gene and association studies.
Professor of Pediatrics; Director, Biliary Atresia Research Center; Associate Director, Digestive Diseases Research Development Center
Dr. Bezerra investigates regulatory mechanisms of liver and biliary injury. One major research focus is translational research on biliary atresia, the most common cause of chronic liver disease in children. He has used large-scale expression arrays and bioinformatics to develop transcriptional maps for human and murine biliary atresia. These maps generated hypotheses regarding pathogenic mechanisms of disease. Testing these hypotheses in the laboratory, Dr. Bezerra began dissecting the molecular basis of neonatal injury and obstruction of extrahepatic bile ducts using unique in vitro and experimental models of disease. He is also applying state-of-the-art approaches to identify the molecular determinants of treatment response in multi-center studies of children with biliary atresia and syndromes of intrahepatic cholestasis. For example, he developed a novel re-sequencing gene chip to identify mutations in five genes causing the most common causes of intrahepatic cholestasis. Bezerra also investigates the control of liver repair by the plasminogen system of proteases. His experiments use several mouse lines genetically engineered to lack or overexpress individual (or combined) members of the plasminogen system to define the molecular networks used by plasminogen to control liver cell plasticity and repair following acute and chronic injuries.
Professor of Pediatrics; Associate Director, Biliary Atresia Research Center
Dr. Bucuvalas' research focuses on improving outcomes for children with liver disease before and after liver transplantation. He is the Steering Committee Chair for the NIH-funded Studies of Pediatric Liver Transplantation Consortium, and he is on the Executive Committee for the NIH-funded Pediatric Acute Liver Failure Consortium. In both cases, his focus has been on outcomes research. He has defined predictors of quality of life, clinical outcome and health care cost using large databases. These observational studies generate hypotheses and form the basis for translational research. More recently, he began collaboration with Dr. Kathy Campbell to study genetic predictors of post transplant calcineurin inhibitor-induced nephrotoxicity. All of these research efforts are aligned with his work in health care delivery and quality improvement and further demonstrate the close integration and interdependency of patient care and research in a population of patients with complex chronic care needs. This work has led to the development of a web-based information portal to provide pediatric liver transplant recipient, their families and health care providers inside and external to Cincinnati Children's timely access to critical clinical data so as to more effectively deliver care across the continuum of disease and over long distances. As part of this effort, he applied a novel statistical process control to increase the proportion of immunosuppressive medication blood levels in target range from 40-80 percent. These initiatives are implemented using an outcomes research platform to advance the field through innovative investigation.
Assistant Professor of Pediatrics
Dr. Campbell is investigating the clinical and genetic determinants of post-transplant renal dysfunction in liver transplant recipients. Her research focuses on the pharmacogenetic factors that affect calcineurin inhibitor metabolism. This line of work constitutes a first step toward individualizing immunosuppression in transplant recipients based on the patient's genetic makeup. Additionally, Dr. Campbell is working with the Renal Function Working Group of the NIH-funded Studies of Pediatric Liver Transplantation Consortium to fully define the clinical factors highly associated with post-transplant renal disease. To incorporate novel biological markers of post-transplant renal dysfunction, she is performing proteomic analysis of urine samples from children at different times following liver transplantation to determine subclinical nephrotoxicity due to acute and chronic exposure to calcineurin inhibitors. This is an extremely important line of research that is becoming a critical medical problem in long-term survivors of liver transplantation.
Professor of Pediatrics; Director, Division of Gastroenterology, Hepatology and Nutrition; Director, Digestive Diseases Research Development Center
Dr. Cohen focuses on host-pathogen interactions and intestinal secretion. His current work is investigating the mechanism of E. coli heat stable enterotoxin and its receptor guanylyl cyclase-C (GC-C). This receptor also binds the endogenous mammalian peptides, guanylin and uroguanylin, that are produced in the intestine. Dr. Cohen has generated two knock out strains of mice, one with a deletion of the guanylin gene and the other with a deletion of the uroguanylin gene. He is using these mice as well as GC-C knock out mice to identify other receptors for these peptides and to test the hypotheses that guanylin and uroguanylin are cytostatic and that removal of these ligands results in increased intestinal epithelial cell proliferation. In addition, he is testing the hypothesis that these peptides form a novel regulatory pathway to allow the intestine to communicate with the kidney to effect salt and water homeostasis.
Assistant Professor of Pediatrics; Director, Fellowship Training Program
The primary focus of Dr. Denson is to determine the mechanisms by which the chronic inflammation associated with inflammatory bowel disease (IBD) inhibits normal childhood growth and mucosal healing. Ongoing studies are investigating cytokine regulation of growth hormone dependent JAK-STAT signaling in the intestinal tract alone, and as a critical component of the growth hormone circuit involving the liver, muscle, and colon. This work has recently led to the identification of mechanisms involving down-regulation of the growth hormone receptor by tumor necrosis factor alpha and up-regulation of a post-receptor inhibitor protein, SOCS-3, by IL-6. These mechanisms may serve as targets for new therapies. Complementary studies have recently identified novel anti-inflammatory effects of growth hormone that promote mucosal healing in colitis. Ongoing studies in children with IBD and in experimental models of colitis will determine the effectiveness of blocking specific cytokines versus administration of growth factors in improving growth and intestinal healing.
Instructor of Pediatrics
The primary focus of Dr. Han's research is to determine the mechanisms by which pediatric Crohn's disease (CD) causes dysfunction of the gut barrier. Ongoing studies are identifying the immune modulation of STAT5b on colonic epithelial cells, macrophages and regulatory T cells in the gut mucosa; moreover, the studies involve the possible therapeutic mechanism of growth hormone (GH) and anti-TNFα in pediatric CD patients. This work has recently indicated that STAT5 may play an anti-inflammatory role in CD by regulating PPARγ inhibition of NFκB activation. Furthermore, both anti-TNFα and GH have improved experimental colitis by up regulating the activity of STAT5b. Taken together, STAT5b may be employed as a novel biologic maker of future therapy and drug development in inflammatory bowel disease; meanwhile, the recognition of these novel STAT5b functions will enrich the classic JAK-STAT pathway in signal transduction.
Professor of Pediatrics; Director, General Clinical Research Center
Dr. Heubi actively pursues a variety of patient-oriented projects that relate to liver disease and nutrition. He is investigating the pathogenesis of inborn errors of bile acid metabolism, including peroxisomal disorders. As new defects have been identified, he actively investigated the development of specific therapies directed toward the underlying abnormalities. He is participating in the Cholestatic Liver Disease Consortium (CLiC) funded by NIH to study rare cholestatic liver diseases in 10 centers throughout the U.S. One current line of investigation focuses on exploring the role of intraluminal contents, such as the composition of bile acids and phospholipid content, on cholesterol absorption and synthetic rate in adults utilizing stable isotope technology. He is also exploring the physiologic basis for variable responses to statins and cholesterol absorption inhibitors as well as exploring the roles of specific intestinal transporters of cholesterol on cholesterol absorption. In another area of research, Dr. Heubi is developing a novel non-invasive method to measure fat excretion in humans, and is pursuing a number of projects related to bone metabolism in health and disease.
Assistant Professor of Pediatrics
Dr. Kohli's primary research focus is to study the pathophysiology of non-alcoholic steatohepatitis (NASH), including the potential role of mitochondria generated mitochondrial reactive oxygen species (mROS). Dr. Kohli recently identified the specific role of the mROS - hydrogen peroxide, as signaling molecule stimulating the Protein Kinase B (PKB) intracellular signaling pathway. He reported that in response to high fat nutritional supplementation, hepato-cytes produce increased mROS which in turn signal through PKB to produce elevated hepatocellular TG levels. He is currently involved in establishing an animal model of surgical weight loss to study its effects on the pathogenesis of NASH in collaboration with investigators at the Obesity Research Center of the University of Cincinnati. He is funded for this project by the Children's Digestive Health and Nutrition Foundation.
The key question for this proposal is the degree to which the beneficial effects of surgical weight loss surgery are associated with less hepatic steatosis and to test several hypotheses about how this change in GI anatomy affects liver function. He is specifically looking to investigate the role of mROS and the PKB cell signaling pathway in this model in-vivo and carry forward his previous work regarding the generation of hepatic steatosis in response to high fat nutritional supplementation in vitro.
Research Instructor of Pediatrics
Dr. Leonis investigates the mechanisms of hepatic tumorigenesis. The long term goal of his research is to define the role of the tyrosine kinase Ron receptor in liver pathophysiology, focusing primarily on the role of Ron receptor gain-of-function in hepatic tumorigenesis. He has previously used the well-characterized lipopolysaccharide-induced murine model of acute liver failure in galactosamine-sensitized mice to show that mice containing a deletion in the tyrosine kinase domain of the Ron receptor have a reduction in the number of liver cells undergoing apoptosis compared to wild-type mice. Currently he is testing the hypothesis that gain-of-function of the Ron receptor leads to hepatic tumorigenesis, possibly via activation of the β-catenin transcriptional cascade. To test this hypothesis both in vitro and in vivo, he has established hepatic cell lines that over-express either the wild type or a constitutively active form of the Ron receptor and generated a transgenic mouse line with liver-specific over-expression of wild type Ron receptor. Dr. Leonis is also developing two lines of translational research. In the first, he has begun investigating human hepatoblastoma tumor specimens for their degree of Ron receptor expression and activation of intracellular signaling pathways relevant to carcinogenesis. In the second, he is the Center Leader in a multi-center prospective study funded by the NIDDK-Pediatric Acute Liver Failure Study investigating the use of N-acetylcysteine in the recovery of children with idiopathic acute liver failure.
Professor of Pediatrics; Medical Director, Schubert-Martin Inflammatory Bowel Disease Center
Dr. Moyer's interests include programmatic development, quality improvement and outcomes measurement. The IBD Center has been selected by Cincinnati Children's to undertake a comprehensive improvement effort using the chronic care model and will join existing teams that have demonstrated success and productivity related to the initiative. The institution has committed financial resources as well as expertise in areas of quality improvement, outcome measures and data analysis. Initial emphasis will be placed on development of clinical guidelines and participation in the Rapid Cycle Improvement Collaborative to identify areas for focused, measurable improvement and to gain expertise in the methodology and use of quality improvement tools. The science and clinical application of quality improvement methods are currently being utilized in a clinical study to address a common pediatric gastrointestinal disorder and this expertise will provide the infrastructure for further quality improvement and outcome projects. The Center is also a site for two collaborative studies:
Multi-site Trial of Azathioprine Dosing in Crohn's Disease, an NIH-supported multicenter study to optimize azathioprine treatment in patients with Crohn's disease
Pediatric IBD Registry and Serologic and Genetic Research Sub-study, a collaborative effort among several pediatric gastroenterology groups to study prospectively the epidemiology and clinical course of pediatric patients diagnosed with IBD
Assistant Professor of Pediatrics
Dr. Rudolph focuses on intestinal crypt cell survival during normal and deranged physiological states. As such, his work relates to molecular pathways that may be involved in the regulation of intestinal failure by modulating the adaptive or regenerative response of the intestine to an injury. Specifically, his work is directed towards the interrogation of the signal transduction pathways in which cAMP inhibits apoptosis using both cell culture and in vivo model systems. In intestinal cells, cAMP accumulation leads to multiple physiological effects, including chloride secretion and the inhibition of apoptosis. Dr. Rudolph has demonstrated that the survival effects of cAMP are through the activation of the ERK1/2 cascade and is dependent upon the action of protein kinase A II (PKAII) but independent of the catalytic subunit. He is dissecting this survival pathway using a cell culture model to explore the divergence of secretion and survival signaling mechanisms. Additionally, he is examining the physiological relevance of this pathway in a mouse model of intestinal epithelial apoptosis. The overall goal is to explore the mechanisms of crypt cell survival and design strategies that specifically protect the intestinal epithelium in times of stress and promotes recovery after an injury.
Assistant Professor of Pediatrics
Dr. Shroyer studies cellular networks that maintain epithelial homeostasis in the intestinal tract. In the intestinal epithelium, the balance between proliferation and apoptosis within the crypts of Lieberkühn maintains villus height and crypt depth; disruption of this balance leads to cancer. Within the crypts, stem cells produce both absorptive and secretory cells. Several genes have been implicated in this process, but delineation of an ordered hierarchy for control of intestinal epithelial differentiation is lacking. One gene in this hierarchy, Math1, is required for secretory lineage development as demonstrated by findings in mice lacking Math1, which produce absorptive enterocytes but none of the secretory lineages. Dr. Shroyer hypothesizes that Math1-dependent secretory lineages are required locally for proliferative homeostasis in the intestine, and that delineation of the genetic pathway for secretory lineage differentiation will clarify the mechanism of intestinal epithelial homeostasis. He is currently characterizing the genetic pathway for intestinal differentiation by microarray-based expression profiling of Math1-/- crypts and crypts null for Gfi1, a putative Math1 target gene also shown to have a role in intestinal epithelial development. Additionally he will develop an in vivo lentiviral-siRNA system to ascertain the phenotype of Notch1 loss in the intestine, and ascertain its position in the hierarchy of intestinal differentiation.
Assistant Professor of Pediatrics
A primary goal of Dr. Steinbrecher is to understand the molecular mechanisms through which gut microflora influences both normal intestinal function as well as inflammatory bowel disease (IBD). In the intestine, the presence of commensal or pathogenic bacteria is sensed by Toll-like receptors (TLR), which initiate a signaling cascade that culminates in specific gene expression patterns that are critical for intestinal homeostasis as well as response to infection and injury. He investigates the role of the nuclear factor (NF)-κB family of transcription factors in this process. Recent data show that specific components of the TLR signal transduction pathway dictate which set of NF-κB-activated, pro- and anti-inflammatory genes are expressed in response to commensal or pathogenic microbiota. Ongoing studies utilize both in vitro molecular studies as well as tissue-specific, gene targeted animal models to investigate the manner in which TLR signaling pathways regulate intestinal gene expression. This approach will then inform complementary studies aimed at determining the effects of blocking specific TLR signaling proteins within the context of animal models of IBD to discover potential therapeutic targets.
Assistant Professor of Pediatrics
Dr. Xanthakos' primary research focus is to identify the biologic determinants of non-alcoholic steatohepatitis (NASH), including potential gene-environment interactions with dietary intake during childhood and adolescence. Dr. Xanthakos recently characterized the histologic spectrum of non-alcoholic fatty liver disease (NAFLD) in morbidly obese adolescents undergoing bariatric surgery at Cincinnati Children's in a collaborative study with Thomas Inge, MD, PhD. These studies revealed that the histologic spectrum of NASH in morbidly obese adolescents differs considerably from the features of NASH described in adults, with more portal inflammation and fibrosis than is seen in adults. The etiology of the difference in histologic pattern between children and adults is not known. Importantly, nearly 20 percent of morbidly obese adolescents do not develop NASH, despite similar degrees of morbid obesity and insulin resistance. Long-term research goals include:
- Determining the biological factors that regulate hepatic susceptibility to inflammation and fibrosis in response to obesity
- Analyzing how genetic polymorphisms in key cytokines and adipokines alter the expression of genes that regulate inflammation and fibrogenesis
- Identifying dietary factors that may predispose genetically-susceptible individuals to develop the NASH
- Developing and applying mechanistically based therapies for NASH in childhood and adolescence
Assistant Professor of Pediatrics
Dr. Yazigi's research interests are inflammatory mechanisms and novel treatment modalities for children with acute liver failure. As a Center P.I. for the NIDDK-funded Multi-Center Group to Study Acute Liver Failure in Children (also known as the Pediatric Acute Liver Failure [PALF] Consortium), Dr. Yazigi is working with other members to define the epidemiology pathogenesis and outcomes of PALF. In addition, as a principal investigator of an ancillary study to the PALF, she is investigating the circulating and hepatic lymphocytes to explore the role of disruption in the perforin signaling pathways in pathogenesis of idiopathic liver failure. In order to optimize outcome of children with liver failure, Dr. Yazigi is working with Mike Leonis, MD, PhD, and members of the PALF Consortium to examine the efficacy of N-acetylcysteine in improving the outcome of children in idiopathic acute liver failure.
