Research Programs of Individual Faculty Members
Dr. Balistreri's current research activities involve a number of clinical trials:
- A phase 3 double-blind, randomized, placebo-controlled study of the safety and efficacy of adefovir dipivoxil in children and adolescents (age 2 to <18) with chronic hepatitis B.
- A multi-center, prospective, controlled trial of long term interferon alfa 2b (IFN) versus IFN and ribavirin in children with chronic hepatitis C, funded by the National Institutes of Health and Hoffman-LaRoche.
- A pilot study to evaluate the bioavailability of Ursocarb versus Actigall in children with chronic cholestasis and in patients with cystic-fibrosis-related liver disease funded through the Food and Drug Administration.
Support:
- A Phase 3 Double-Blind, Randomized, Placebo-Controlled Study of the Safety and Efficacy of Adefovir Dipivoxil in Children and Adolescents (Age 2 to <18) with Chronic Hepatitis B, Gilead Sciences (local PI)
- Pilot Study of Ursocarb vs. Actigall in Chronic Cholestatic Liver Disease and CF-Associated Liver Disease, National Institutes of Health (local PI)
- Pegylated Interferon + / - Ribavirin for Children with HCV, National Institutes of Health, Hoffman-LaRoche (local PI)
The research program of the Bates lab focuses on molecular regulation of digestive system development. The primary research investigates how cell-cell interactions are regulated by the Hlx homeobox transcription factor in development 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. The overall hypothesis is that the specific expression of the Hlx protein results in regulation of the development of the intestine and liver (including enteric neurons and intestinal mesenchyme) by directing the expression of genes encoding proteins participating in interactions of mesenchyme with other tissues. Thus, the lab is working to understand the control of expression of Hlx itself and to identify genes that are in turn regulated by Hlx (downstream targets). They have used DNA microarray technology to identify genes whose expression is altered in cells in the presence or absence of Hlx. They are currently analyzing the expression of a number of interesting genes identified in this comparison. They are also using several approaches to investigate development of enteric neurons and smooth muscle in Hlx knockout mice.
Dr. Bates is also participating in a cross-divisional effort to examine gene expression profiles in a large number of mouse tissues using DNA microarrays, focusing on gene expression along the anterior-posterior (proximal-distal) axis of the GI tract and in development and maturation of the GI tract.
Support:
- Hlx in Enteric Mesenchymal and Neuroral Development, National Institutes of Health (R01 DK61219)
- Role of Hlx in Mouse Gastrointestinal/Liver Development, National Institutes of Health (K08 DK02791)
Dr. Bezerra's research has two areas of studies. In the first, he studies the role of proteases on liver repair. Dr. Bezerra's team has established a synergistic role of plasminogen and plasminogen activators in the reparative response of the liver to an injury. Using mice with unique genetic modifications, he demonstrated that plasminogen plays a central regulatory role in the cellular and matrix remodeling that takes place in the liver undergoing different phases of repair. In addition, he has found that plasminogen also serves as a key regulator in the maintenance of liver cell differentiation following an injury. In the second line of studies, Dr. Bezerra's laboratory combines patient- and laboratory-based experiments to search for the mechanisms regulating pathogenesis of biliary atresia, the most common cause of chronic liver disease in neonate and children. His research team recently identify candidate genes responsible for the biliary injury. In these studies, affected patients were found to have an altered genetic programming for immunoglobulin and cytokine production in the early phases of disease development. Then, using an experimental model of biliary atresia, the research team found that the cytokine interferon-gamma plays a chief role in biliary obstruction. Dr. Bezerra's laboratory is currently dissecting the cellular and molecular pathways of biliary injury and exploring novel therapeutic modalities to stop progression of liver disease in children with biliary atresia.
Support:
- The Plasminogen System and Liver Repair, National Institutes of Health (R01 DK055710)
- Immunologic Dysfunction in Biliary Atresia, National Institutes of Health (R01 DK064008)
- Center for Biliary Atresia: Etiopathogenesis and Clinical Outcome, National Institutes of Health (U01 DK62497)
- Liver-based Biological Systems for Studies of Drug Metabolism, Procter & Gamble Pharmaceuticals<
- Alpha-1-Antitrypsin Gene as a Modifier of Liver Disease, Alpha-1-Foundation/American Liver Foundation
The focus of Dr. Bucuvalas' research effort has been on outcomes of children with liver disease or those who have undergone liver transplantation. Over the last year, he has made significant contributions in the clinical and research arenas towards improving care, enhancing the delivery of care, and optimizing the outcome of children with chronic liver disease and pediatric liver transplant recipients. His most recent work has focused on the quality of life in pediatric liver transplant recipients and renal function in pediatric liver transplant recipients. Dr. Bucuvalas found that psychosocial and physical summary scores of HRQOL for the liver transplant population was decreased compared to the normal population. Physical function from the parents' perspective negatively correlated with the number of hospital admissions, medical complications and with African-American race.
Dr. Bucuvalas serves as the Vice Chair of SPLIT (Studies of Pediatric Liver Transplantation). SPLIT was founded in 1995 and includes the participation of 39 Transplant Centers in the US and Canada. It is designed to characterize and follow trends and indications for transplant, transplantation techniques, and outcomes such as patient and graft survival, rejection incidence, growth parameters, immunosuppressive therapy and complications. He is one of four hepatologists who serve as co-investigators on the SPLIT Grant funded by the National Institutes of Health. Dr. Bucuvalas also serves as the center co-investigators for the NIH funded biliary atresia research network.
In collaboration with Information Services, Dr. Bucuvalas led a team which implemented a web-based health information portal designed to improve the quality of care for our population of pediatric liver transplant recipients, by giving patients, CCHMC health care providers and referring physicians access to critical clinical data 24 hours each day and 7 days each week. The portal is the first of its kind in the region and will begin to address the problem of delivering care to children with chronic medical problems across the traditional boundaries of care. This system will also serve as a prototype for other health information systems for other populations with chronic illness.
Dr. Bucuvalas serves as a co-leader for the Transplant Medication Safety Team. The aim of the team is to ensure that the medication use cycle for recipients of solid organ or blood and marrow transplants is so superbly managed that the readmission rates, rejection rates and 5 year survival rates are 50% better than the national averages and that harm related to the medication use cycle is eliminated. The team has developed methods and tools to manage variation of tacrolimus levels, assess patient confidence and competence with the medication use cycle, provide critical data on the intranet, ensure appropriate timing of dosing and trough blood draw and as mentioned above, develop a web-based health portal for liver transplantation.
Support:
- Multicenter Study of Quality of Liver in Liver Transplant Recipients (Agency for Healthcare Research and Quality) (local PI, with Estella Alonso, MD, Children's Memorial Hospital, Chicago, Ill., PI)
- Multi-Center Study of Biliary Atresia (National Institutes of Health) (co-investigator, with Jorge Bezerra, MD, Cincinnati Children's Hospital Medical Center, PI)
- Studies of Pediatric Liver Transplant Recipients (SPLIT) (National Institutes of Health) (local PI, with Anne Lindblad, PhD, Emmes Corporation, PI)
Dr. Campbell is investigating the clinical and genetic determinants of calcineurin inhibitor induced nephrotoxicity in liver transplant patients. This research, undertaken in collaboration with The Pharmacogenetics Workgroup, aims to identify predictors of post-transplant renal dysfunction, paving the way for clinical trials of individualized immunosuppression regimens in high risk patients. Dr. Campbell is also working with the Renal Function Working Group of the NIH-funded Studies of Pediatric Liver Transplantation multi-center registry, and serves on the Research Oversight Committee of the Cincinnati Children's Hospital Medical Center Pediatric Liver Care Center.
Dr. Cohen's laboratory has continued to investigate mechanisms of intestinal secretion and the pathogenesis of diarrheal disease. They have used a mouse model of osmotic diarrhea to determine the counter-regulatory mechanisms involved in intestinal fluid balance. This model and related tissue culture studies have proved useful in evaluating the response of guanylin to intestinal osmotic stress. Recently, they have developed two mouse lines, one with targeted deletion of the guanylin gene and another with targeted deletion of the uroguanylin gene. These mice will enable them to identify the roles of guanylin and uroguanylin in intestinal secretion. For example, they have identified that uroguanylin has an important regulatory role in salt homeostasis. They will delineate the role and action of these peptides in the intestine, as well as their roles as intestinal hormones in an enteric-renal axis. These studies will lay the groundwork for translational research involving these peptides as therapeutic agents for fluid overload states and for other novel roles for these peptides distinct from their intestinal secretory actions.
Dr. Cohen's clinical research focus is centered on testing and evaluating vaccines for enteric diseases. He is the principal investigator of the Enteric Vaccine Component of the Gamble / Cincinnati Children's Vaccine Testing and Evaluation Unit. This group has recently completed evaluation of two different oral cholera vaccines in randomized, controlled double blind studies. As part of this effort, Dr. Cohen anticipates evaluation of additional cholera vaccines (against O1 and O139 serotypes), a typhoid fever vaccine and vaccines against other enteric pathogens in the next several years.
Support:
- Expression and function of the guanylin ligand family, National Institues of Health (R01 DK47318)
- Evaluation of Control Measures Against Human Infectious Diseases Other Than AIDS, National Institues of Health (N01 AI 25459). Dr. Cohen is PI for Enteric Vaccine Program (Part C).
- Cincinnati DDRDC: Center for Growth and Development (CGD) (R24 DK064403)
- Training Program in Pediatric Gastroenterology and Nutrition [Pediatric Gastroenterology Training Grant], National Institues of Health (T32 DK007727)
The primary focus of Dr. Denson's laboratory is to determine the molecular basis for alterations in growth hormone signaling in inflammatory bowel diseases (IBD).
Normal growth and development are dependent upon the ability of growth hormone to regulate IGF-1 expression. Evidence from studies in children with IBD and mouse models of colitis indicates that inflammatory cytokines which are up regulated in this setting may cause an acquired GH resistance. Consequences may include growth failure, altered body composition and impaired mucosal healing.
We are using complementary experimental and patient-based approaches to investigate regulation of growth hormone signaling in mouse models of colitis and in children with Crohn's disease. These include down regulation of the growth hormone receptor and up regulation of a family of post-receptor inhibitory proteins, the Suppressors of Cytokine Signaling (SOCS). These studies should lead to the development of more effective therapies for children with IBD and other chronic inflammatory conditions.
Support:
- Regulation of the Hepatic Negative Acute Phase Response, National Institutes of Health (K08 DK02700)
- Mechanisms of Growth Hormone Resistance in Colitis, Broad Medical Research Program
- Mechanisms of Growth Failure in Experimental Colitis, Children's Digestive Health and Nutrition Foundation/Nestle Nutrition Young Investigator Award
- Molecular Mechanisms of Growth Hormone Resistance in Chronic Colitis, Crohn's and Colitis Foundation of America First Award
- Cytokine Regulation of Liver Growth Hormone Signaling, National Institutes of Health (R03 DK63956)
- Mechanisms of Bile Secretion and Cholestasis, National Institutes of Health (R01 DK025636), James L. Boyer, MD, Yale University School of Medicine, principal investigator
Dr. Heubi is actively pursuing a variety of patient-oriented projects. In collaboration with Kenneth Setchell, PhD (Mass Spectrometry Laboratory), he is investigating the pathogenesis of inborn errors of bile acid metabolism. As new defects have been identified, specific therapy directed toward the underlying abnormality has been devised.
In collaboration with Patrick Tso, PhD, Laura Woollett, PhD, and David Hui, PhD, at the University of Cincinnati, and Peter Jones, PhD, at McGill University, Dr. Heubi is investigating the effects of the impact of variations of the intestinal environment on cholesterol absorption and synthetic rate in adults utilizing stable isotope technology. They are also pursuing studies examining the impact of intestinal transporters on cholesterol absorption in adults as well as examining the biologicvariability of response to statins and ezetimibe (a recently approved drug that inhibits cholesterol absorption).
Dr. Heubi is actively pursuing projects related to bone disease in childhood and has organized and initiated a trial of a bisphosphonate for the treatment of bone disease in children and adults with neuromuscular disease.
Dr. Heubi is the director of the General Clinical Research Center of Children's Hospital Medical Center and the University of Cincinnati.
Support:
- Investigations in the Pathogenesis of Liver Disease in Inborn Errors of Bile Acid Metabolism and Peroxisomal Disease, General Clinical Research Center (with Kenneth Setchell, PhD, Mass Spectrometry Laboratory)
- The Effect of Fat Ingestion on Serum Apolipoprotein A-IV Levels in Healthy Human Subjects, General Clinical Research Center (with Corrina Alper, PhD, and Patrick Tso, PhD, University of Cincinnati Department of Pathology and Laboratory Medicine)
- General Clinical Research Center, National Center for Research Resources/National Institutes of Health (M01 RR 008084) (with Thomas F. Boat, MD)
- Regulation of Plasma Cholesterol Levels by Cholesterol Absorption, Synthesis and LDL-Receptors, National Institutes of Health (P01 DK54504)/General Clinical Research Center
- Bone Mineral Density Study: Clinical Center, National Institutes of Health Contract/General Clinical Research Center (with Heidi Kalkwarf, PhD, RD, Division of General & Community Pediatrics)
- Antiresorptive Therapy for Osteopenia Associated with Chronically Immobilized Children and Adults with Neuromuscular Disease, Industry/Gastroenterology Training Grant/General Clinical Research Center (with Valeria Cohran, MD, Children's Memorial Hospital, Chicago, Illinois)
- Pharmacokinetics of the Supplement Secoisolariciresinol-Diglycoside, a Lignan from Flaxseeds, Industry/General Clinical Research Center (with Kenneth Setchell, PhD, Mass Spectrometry Laboratory)
- Behavioral Treatment and Nutrition in Pediatric Crohn Disease, National Institutes of Health (K24 DK 059492)/General Clinical Research Center (with Lori Stark, PhD, Division of Psychology)
Liver tumors cause significant suffering and death in adults and children worldwide. The long-term goal of this investigator's research program is to understand how human liver tumors develop, with the hope of designing medicines or treatments specifically targeted to the way these types of tumors grow.
Our laboratory studies the biology of the Ron receptor tyrosine kinase. This receptor belongs to a class of proteins which, when malfunctioning, causes a variety of human tumors. Overactive Ron receptor is associated with human cancers of the breast and colon, and causes cells in the laboratory to acquire important tumor-forming properties. Our preliminary data shows that Ron receptor is over-produced in a specific pediatric liver tumor (i.e., hepatoblastoma). Therefore, the overall hypothesis of our research program is that increased activity of the Ron receptor leads to liver tumor formation.
Understanding the way that malfunctioning Ron receptor can cause tumors to form is important in order to alter the way tumors behave in the future. Therefore, we have initiated experiments to determine which signaling pathway within liver cells is necessary for Ron receptor tumor-causing properties, with initial focus on the beta-catenin signaling pathway.
Support:
Dr. Putnam is investigating methods of evaluation and management of eosinophilic esophagitis.
Support:
- Analysis of Eosinophil-associated Gastrointestinal Inflammation, Burroughs Wellcome Fund (with Marc E. Rothenberg, MD, PhD, Division of Allergy and Clinical Immunology)
Dr. Rudolph's current investigative strategy is derived from the hypothesis that the guanylin family of peptide ligands may be involved in the control of intestinal cell turnover. Specifically, his studies explore the role of cyclic nucleotides in enterocyte proliferation and apoptosis. cGMP and cAMP have been implicated in the processes of cellular proliferation and apoptosis in a number of non-intestinal cell lines, although their role is highly cell-specific. He is currently using a cell culture model that has been used to characterize GC-C mediated chloride secretion, to determine the effects and to delineate the signal transduction pathways that utilize cGMP production in the processes of cell turnover. He has also studied the effect of guanylin on apoptosis using a cell free assay of caspase 3 activation in Xenopus laevis oocytes. In the immediate future, he will use a unique mouse line that carries a targeted inactivation of the guanylin gene to study these effects in vivo.
As a second but related independent line of research, Dr. Rudolph is investigating the role of cAMP in the process of proliferation and apoptosis in intestinal epithelial cell culture. Preliminary evidence has shown that staurosporine-mediated apoptosis is inhibited when cells are preincubated with cholera toxin, a potent activator of cAMP. These cell survival mechanisms appear to be dependent on cAMP dependent activation of the mitogen-activated protein kinases. He is currently gathering preliminary data regarding the endpoints of MAPK activation on intestinal cell function, and plans to delineate the signal transduction pathways that lead to MAPK activation and cell survival signals.
Support:
- Cyclic-AMP Induced Crypt Cell Survival in the Intestine (K08 DK066297)
Dr. Yazigi is participating in the Acute Liver Failure Study Group, a multi-center data collection on acute liver failure in children and adults. Epidemiologic and outcomes studies are in progress. Ancillary studies looking into the pathophysiology of acute liver failure and treatment options are being developed.
Support:
- A Multi-Center Therapy Trial for Acute Liver Failure (local PI, with William M. Lee, MD, University of Texas Southwestern Medical Center, Dallas, Texas; and Robert Squires, MD, University of Pittsburgh, Pittsburgh, Pennsylvania), National Institutes of Health (R01 DK058369)
