Research Opportunities Outside the Division
The faculty advisors for GI fellows include investigators from within the Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children's Hospital Medical Center and other divisions within the Children's Hospital Research Foundation and the University of Cincinnati College of Medicine.Fellows can select a mentor from among the these faculty members:
John Cuppoletti, PhD, Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine
Dr. Cuppoletti's research is focused on ion channels, transport proteins, and transport processes of the gastrointestinal tract and the lung. In recent years, potassium and chloride channel regulation, pharmacology, and molecular engineering have become increasingly important as tools to study the mechanisms by which these proteins function. More recently, as the X-ray crystal structures of these proteins have become available, Dr. Cuppoletti combined these types of studies with animal models and computational chemistry approaches in attempts to understand the fundamental processes of protein gating that underlie function and gating of these channels. In addition, he has undertaken studies wherein these transport proteins are placed in synthetic membranes in order to obtain more detailed information regarding function of these proteins that cannot be obtained from purely biological membranes.
David A. D'Alessio, MD, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Cincinnati College of Medicine
The regulation of insulin secretion following nutrient ingestion is complex and critical to the maintenance of normal glucose homeostasis. Signals from the gastrointestinal tract play a key role in postprandial insulin secretion and considerable effort has been focused on intestinal hormones to mediate these effects. Glucagon-like peptide 1 (GLP-1) is released from specialized intestinal mucosal endocrine cells following meal ingestion. GLP-1 binds to specific receptors on pancreatic β-cells and augments glucose-stimulated insulin secretion. However, Dr. D'Alessio's work and that of other groups suggests that GLP-1 may have a broader role on glucose tolerance by regulating other processes such as gastric function, food intake and hepatic glucose production. Dr. D'Alessio also participates in the University of Cincinnati Obesity Center studying the effects of dietary fat on body weight regulation, metabolism and islet cell function using a rat model of diet induced obesity. He has completed two clinical trials comparing low-fat versus low-carbohydrate diets on body weight and cardiovascular risk factors in humans. He is now midway through a trial comparing low-fat and high monounsaturated fat diets on glycemic control, lipids and body weight in persons with type 2 diabetes.
Jay L. Degen, PhD, Division of Developmental Biology
The long-term goal of Dr. Degen's research program is to understand the roles of both soluble and cell-associated hemostatic factors in development, hemostasis, wound healing, inflammatory response, and disease pathobiology. Since a detailed understanding of these processes can only be achieved in an easily-manipulated in vivo experimental setting, a major focus of his research effort has been the generation and characterization of mice with specific deficits in key hemostatic factors, including fibrinogen, prothrombin, tissue factor, plasminogen, plasminogen activators, and plasminogen activator receptor. Although the mid-gestation lethality of tissue factor- and prothrombin-deficient mice argues that thrombin-mediated proteolysis is important for development, the viability of fibrinogen- and plasminogen-deficient mice illustrates that dramatic swings in the hemostatic balance in either direction are compatible with development to term and growth to adulthood. A primary research focus of the laboratory is to take viable mice with selected deficiencies in coagulation, platelet, and fibrinolytic factors and to rigorously test the hypothesis that hemostatic factors play a crucial role in disease pathogenesis. Further, the laboratory is employing genetic approaches to define the specific mechanism(s) by which key hemostatic factors alter disease pathophysiology. Recent studies have shown that that the loss of fibrinogen or plasminogen can have a profound influence on the pathobiology of a variety of common diseases, including vessel wall disease, cancer, kidney disease, lung disease, and gastrointestinal disease/repair. Understanding the mechanisms by which hemostatic factors alter disease progression may suggest novel therapeutic strategies for treating a wide spectrum of diseases, including inflammatory bowel disease and other disorders of the gastrointestinal tract.
Gregory A. Grabowski, MD, Division of Human Genetics
Dr. Grabowski investigates the pathogenesis of selected lysosomal storage diseases. Studies range from gene transfer, purification and characterization of recombinantly produced selectively mutated enzymes, knock-in and knock-out mouse generation, and genome wide studies of transcriptomes and proteomes. These studies use high-density microarrays and bioinformatics to identify molecular signatures of lysosome-based biological processes, and integrative morphology to define the cellular basis of molecular signatures and the phenotype of organs of the digestive system in gene-targeted mice. The overall goal of his research program is to define the nature of the signature pathways in disease pathogenesis, and the evolution of the disease phenotypes in mouse models that have been developed as prototypes for selected human diseases. By combining biochemistry/molecular genetics, high-throughput functional genomics, and histopathologic approaches, new strategies will be developed for effective therapeutic interventions and their evaluation by novel biomarkers. Particular emphasis relates to the regulatory role of macrophages or the tissue-specific injury of the liver, spleen and intestine, and the molecular signals controlling the process.
Simon P. Hogan, PhD, Division of Allergy and Immunology
Dr. Hogan's research is focused on cellular and molecular networks that underlie the development of gastrointestinal inflammation and associated dysfunction in gastrointestinal disorders. Current projects focus on the role of individual Th2 cytokines and eosinophils in disease pathogenesis and characterization of the downstream signaling pathways employed by these molecules and cells to induce disease. Dr. Hogan's experimental approach is integrative, employing state-of-the-art molecular genetic techniques in association with model systems to identify the role of inflammatory cells and molecules in the events that underpin disease.
David Y. Hui, PhD, Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine
Dr. Hui investigates the role of pancreatic lipolytic enzymes in dietary lipid absorption, metabolism, and impact on metabolic diseases including obesity, diabetes, and atherosclerosis. He uses gene targeting approach to produce mice with defective expression of each of the pancreatic lipolytic enzymes, namely carboxyl ester lipase (CEL), pancreatic phospholipase A2 (PLA2), and pancreatic triglyceride lipase (PTL), and then test their efficiency in lipid absorption and transport. Results indicate that the CEL plays an important role in chylomicron assembly and secretion. Mice lacking this enzyme absorb lipid and cholesterol efficiently, but intestinal lipoproteins produced from the CEL-null mice are smaller in size than the normal chylomicrons. In contrast, mice lacking PTL displayed reduced cholesterol absorption efficiency and delayed fat absorption and metabolism, whereas the PLA2-defective mice have normal lipid absorption and transport mechanisms but are resistant to diet-induced obesity and diabetes. Current research is being undertaken to determine the mechanism by which CEL influences chylomicron production, the mechanism by which PTL affects cholesterol absorption, and the mechanism by which observation of the PLA2 lipolytic product lysophosphatidylcholine directly suppresses insulin signaling and thereby contributing to postprandial hyperlipidemia and hyperglycemia. Dr. Hui has also initiated a project to identify the role of the putative cholesterol transporter NPC1-L1 in cholesterol transport and absorption and impact on lipoprotein metabolism. Specific attention is paid to the mechanism by which the cholesterol absorption inhibitor ezetimibe influences intracellular cholesterol trafficking as well as its systemic effect on lipoprotein metabolism.
Thomas H. Inge, MD, PhD, Division of Pediatric and Thoracic Surgery
Overweight and obesity are among the most common metabolic/nutritional disorders affecting the U.S. population, with 31% of adults and 16% of adolescents now meeting Centers for Disease Control criteria for these conditions. As the obesity epidemic has unfolded, so too has the increase in prevalence of abnormalities of carbohydrate metabolism. The single most effective treatment for type 2 diabetes in severely obese adults may be gastrointestinal diversionary surgery (e.g., gastric by-pass) to effect weight loss via a durable state of hypocaloric intake. While it is clear that rapid and profound weight loss can significantly improve carbohydrate metabolism in adults, it is not clear to what degree diabetes is reversible in these patients. The pathophysiology of type 2 diabetes in adolescents and children is not well understood and no studies have yet examined the effect of surgical weight loss on insulin resistance, insulin secretion, or glucose tolerance in severely obese young people. Understanding the relative benefits of surgically induced weight reduction on carbohydrate metabolism in adolescents compared to older subjects is important for determining optimal timing of this intervention. Dr. Inge will test the hypothesis that bariatric surgical intervention will more effectively improve insulin resistance, β-cell dysfunction, and glucose tolerance in adolescents compared to adults. He will also assess the nutritional and metabolic complications of this procedure.
Xi (Jason) Jiang, PhD, Division of Infectious Diseases
Dr. Jiang's research focuses on the interaction of norovirus (NV) with human histo-blood group antigen receptors. He has characterized the receptor binding patterns of fourteen strains of NVs using recombinant virus-like particles (VLPs) generated from baculovirus-infected insect cells and identified eight receptor binding patterns defined by the ABO, Lewis, and secretory blood types of saliva donors. The eight binding patterns are classified into two binding groups: the A/B binding group and the Lewis binding group. A genetic relatedness has been found among strains with similar binding patterns. The molecular basis of the pathogen/receptor interaction has been further elucidated, including mapping of the binding domain and characterization of the binding interface. Based on these data, Dr. Jiang has proposed a model of the receptor/ligand interaction.
Christopher L. Karp, MD, Division of Molecular Immunology
Dr. Karp's research program focuses on understanding the molecular mechanisms underlying regulation and dysregulation of inflammatory responses in infectious, autoimmune and genetic diseases in humans. Interrelated, ongoing areas of study include (1) the molecular mechanisms underlying dysregulation of pulmonary inflammatory responses in cystic fibrosis; (2) the molecular mechanisms underlying regulation and dysregulation of IL-12 regulation and dysregulation in infectious and autoimmune diseases; (3) the molecular mechanisms of control of Toll-like receptor-driven signaling pathways in health and disease; (4) regulatory T cell immunogenetics and function; and (5) Ebola virus pathogenesis and therapy.
Shelley Kirk, PhD, RD, LD, Center for Epidemiology and Biostatistics
The treatment of pediatric obesity supported by the medical community is a moderate restriction in calories by modifying intake of fat and simple sugars, along with an increase in energy expenditure through more physical activity. However, this approach is associated with only limited success. As a result, overweight children and adolescents are seeking alternative approaches to weight management, such as diets that modify the type and amount of carbohydrates. However, there are limited data on the safety and efficacy of these diets, particularly with younger children. The focus of Dr. Kirk's research is to compare the safety and efficacy of low carbohydrate and reduced glycemic load diets to a more standard dietary inter-vention for the management of pediatric obesity (i.e., portion-controlled, moderate fat, high carbohydrate diet). The currently funded clinical trial will involve 150 overweight children (ages 7-12) who will be randomly assigned to one of the three diet groups for 12 months. The effects of each diet will be determined by measuring changes in anthropometric measures (body weight, height, body mass index, waist circumference, body composition), other cardiovascular risk factors (blood pressure, fasting lipid profile, fasting glucose and insulin, and inflammatory markers of cardiovascular disease), and measures of psychological well-being and mental status. The results of this study will provide information in the quest for safe, effective, and health-promoting weight management strategies for obese children.
Uma Kotagal, MD, Center for Health Policy & Clinical Effectiveness
The Division of Health Policy and Clinical Effectiveness serves as research and development function for the health care delivery system. The primary purpose of the program is to develop, implement and study interventions focused on improving the health of the children. Dr. Kotagal directs a program focused on health services research, health systems research, cost-effectiveness analysis, and outcomes research.
Alex B. Lentsch, PhD, Department of Surgery, University of Cincinnati College of Medicine
Dr. Lentsch's work investigates the intricate roles of various soluble mediators in the initiation and regulation of the acute inflammatory response to hepatic ischemia/reperfusion. His work also examines age-related mechanisms of liver injury in this setting. He has recently shown that there are significant alterations in the inflammatory response and the injury response in young versus adult mice. The different responses among age groups appear to relate to altered regulation of a number of cellular and molecular aspects of this injury. For example, his laboratory has observed that adult mice have a much higher resident population of CD4+ lymphocytes in the liver compared to young mice. Parallel studies have shown that these cells play an intricate function in the dynamics of both the inflammatory response and direct hepatocellular injury. Furthermore, Dr. Lentsch's work has shown that some key cytoprotective proteins, such as the heat shock protein-70 (HSP70) is induced to a much lesser extent after ischemia/reperfusion in the livers of adult mice compared to young mice. Such divergence in the injury response due to age may relate to selective, age-dependent activation of specific genes that may lead to therapeutic targets for a number of liver diseases.
James Lessard, PhD, Division of Developmental Biology
The Lessard laboratory is interested in the development and function of visceral smooth muscle and is applying transgenic strategies in mice to address these issues. To study development, they have generated transgenic mice that express EGFP or EYFP under the control of an enteric smooth muscle actin promoter or vascular smooth muscle promoter, respectively. The mice are being used to visualize the developing smooth muscle within the gastrointestinal tract and elsewhere. Additionally, they are isolating highly enriched smooth muscle cell populations from gastrointestinal tissues using laser capture micro-dissection to define the patterns of gene expression in developing normal and aberrant models. This information is likely to provide clues regarding the molecular mechanisms involved in the development, maturation, and phenotypic modulation in these cells as well as ultimately leading to the discovery of novel genes that are selectively expressed in gastrointestinal smooth muscle cells. To study function, they have ablated the enteric smooth muscle actin gene in mice. While animals lacking this protein are minimally affected, mice lacking both smooth muscle actins show major gastrointestinal deficits and die as neonates. In addition, mice lacking enteric smooth muscle actin and one of the vascular actin genes development megacolon. The Lessard laboratory hopes to make use of these animal models to develop a better understanding of similar motility disorders in humans.
Min Liu, PhD, Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine
Dr. Liu is currently studying the role of hypothalamic apolipoprotein AIV (apo AIV) in the development of obesity and how it can be modulated for preventive and therapeutic purposes. Apo AIV is a circulating signal released from intestinal cells in response to lipid feeding, and it contributes to the anorexic effect of a lipid meal. He has demonstrated that apo AIV is also synthesized in the hypothalamus, and that hypothalamic apo AIV gene and protein expression is regulated physiologically. Current work focuses on the following goals: 1) to determine hypothalamic apo AIV gene expression and protein levels and the responsiveness of hypothalamic apo AIV to dietary lipids in several strains of obese and lean animals. He will also determine the response to chronic high-fat feeding in apo AIV knockout mice, 2) to characterize the transport of apo AIV from blood into the central nervous system and to assess the areas in the brain that are activated by apo AIV administered either centrally or intravenously, and 3) to determine the interaction of apo AIV with other regulatory peptides within the hypothalamus. The new knowledge may lead to novel targets for preventive and therapeutic interventions for obesity.
John N. Lorenz, PhD, Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine
Dr. Lorenz focuses on the study of integrative physiology in a wide variety of transgenic mice with selectively induced genetic mutations, to evaluate the biological interplay among various ion transporters in the gastrointestinal-renal-cardiovascular axis. Using molecular techniques to produce mice lacking various GI and kidney-specific transporters, he is studying the contribution of these transporters to overall fluid and electrolyte homeostasis. Presently, he is pursuing the phenotypic analysis of several knockout strains of mice including the uroguanylin, guanylin, Na+/H+ exchanger 3, Na+/H+ exchanger 2, renal outer-medullary K+ channel, colonic H-K-ATPase, and Na-K-Cl cotransporter 1 knockouts. Using sophisticated techniques such as in vivo renal micropuncture and microperfusion, Dr. Lorenz hopes to gain a more thorough understanding of the salt and fluid homeostatic mechanisms within the kidney. Ultimately, these studies investigating hemodynamics and fluid and electrolyte balance will provide insights to genetic basis of disease states such as hypertension.
Lisa J. Martin, PhD, Center for Epidemiology and Biostatistics
Obesity has reached epidemic proportions in children, such that obesity related diseases typically seen in adults now occur in children. Several studies have reported an association between feeding human milk and reduced obesity later in life. The mechanisms by which human milk could provide protection against obesity are unclear but bioactive factors in human milk provide a promising explanation. One such factor is adiponectin. Serum adiponectin improves insulin sensitivity and fatty acid metabolism; low levels are associated with obesity, type 2 diabetes, dyslipidemia, and cardiovascular disease. A major goal of Dr. Martin's work is to determine the impact of human milk adiponectin on the metabolic development of the infant. Dr. Martin is now characterizing the longitudinal changes in human milk adiponectin throughout lactation, to determine if mother's adiposity influences human milk adiponectin, defining the impact of specific factors in human milk on later development of obesity and metabolic traits, and identifying the structures of adiponectin in human milk and their biologic activity and outcomes in breastfeeding infants. Studies of adiponectin will form the basis for developing a novel approach to prevent obesity and co-morbidities with onset in childhood.
Anil Mishra, PhD, Division of Allergy and Immunology
Dr. Mishra has demonstrated the feasibility of using DNA chips to examine mRNA transcript profiles in esophageal tissue of mouse model of eosinophilic esophagitis (EE). He has tested the hypothesis that microarray analysis of RNA transcripts expressed in the esophagus of experimental EE will provide critical insight into disease characteristics including diagnosis, pathogenesis, and treatment. His analysis indicated a total of 211 genes that were upregulated and 44 downregulated genes by more than 2 fold. This study showed that esophageal tissue from mouse model of EE would have a unique expression profile compared with healthy states. His studies will provide fundamental information concerning the pathogenesis of EE.
Marshall H. (Chip) Montrose, PhD, Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine
Dr. Montrose studies ion transport regulation in stomach and large intestine. He is testing the hypotheses that regulation of the extracellular pH directly above the gastric epithelium is mediated by cyclooxygenase-1, and is integral to the ability of the tissue to recover from limited damage to the epithelium. He is using two-photon light absorption to produce micro-lesions (1-4 cells) targeted at the gastric surface epithelium, and monitoring the tissue recovery in real time (60 min) using two-photon and confocal microscopy. Additionally, Dr. Montrose is studying the regulation and function of NHE2 and NHE3 (Na+/H+ exchangers) in the large intestine. These two Na+/H+ exchanger isoforms contribute to sodium and water absorption, but their relative contributions remain uncertain. He is testing several hypotheses about the differential responsiveness of these two isoforms to extracellular and intracellular pH microdomains near the membranes. Experiments use cells transfected with fusion proteins combining NHE and fluorescent proteins so that they can investigate whether pH near the mouth of the transporter is altered (pH-sensitive fluorescent proteins) or if translocation of NHE to the membrane occurs in response to altered ionic conditions (pH-insensitive fluorescent proteins). He is also using live tissue confocal microscopy to ask if Na+/H+ exchange function is present in the base of colonic crypts (long believed to be an exclusively secretory structure) of NHE1 and NHE2 knockout mice.
Ardythe L. Morrow, PhD, Center for Epidemiology and Biostatistics
Dr. Morrow's research focuses on the epidemiology of breastfeeding and human milk factors in relation to child health outcomes. The human milk program project is designed to understand the role of innate immune factors in human milk in relation to protection against obesity and diarrheal diseases in childhood. Current work is evaluating the role of human milk adiponectin in metabolic development. She has previously been able to show that human milk oligosaccharide moieties, which are synthesized by fucosyltransferases encoded by the Lewis-Secretor genes, inhibit the binding of certain enteric pathogens (noroviruses, Campylobacter, stable toxin of E. coli, and V. cholerae) to host cell receptors and thereby preventing diarrhea in breastfed infants. Dr. Morrow is testing the hypothesis that these specific human milk oligosaccharides can be isolated, characterized, synthesized, and administered to prevent diarrheal disease.
Steven Potter, PhD, Division of Developmental Biology
Dr. Potter's research focuses on kidney development, and he also works collaboratively with investigators studying intestinal organogenesis in his role as director of the Gene Expression and Sequence Core. His overall research strategy investigates the genetic pathways that drive organogenesis, with particular interest in genes that occupy upper level positions in the genetic hierarchy of development. Among these are the Hox genes, dispersed homeobox genes, zinc finger transcription factors, and other transcription factor genes, as well as growth factors and their signal transduction pathways. He has generated targeted mice with mutations in Hoxa 11, Gsh-1, Gsh-2, c-myb, Sp4, Sp8, Lhx4, PygI, PygII, LRD, Prx1, and Npas3 and studied the resulting developmental defects. He also uses microarrays to define downstream targets of transcription factors, to provide a global analysis of mutant phenotypes, and to create an atlas of normal gene expression states during organogenesis.
Scott W. Powers, PhD, Division of Behavioral Medicine and Clinical Psychology
Dr. Powers' research program is in the area of dietary adherence in young children with chronic illnesses, particularly cystic fibrosis, children at risk of obesity, and type 1 diabetes. Current studies in child behavior and nutrition focus on testing behavioral and nutrition interventions to improve dietary adherence, health outcomes and quality of life for toddlers and preschoolers with cystic fibrosis; investigating barriers to dietary adherence in young children (under age 7) with type 1 diabetes using behavioral assessment techniques; and investigating challenges to implementing nutrition and physical activity interventions for prevention and treatment of obesity in young children at risk (under age 5, with a focus on African American families) who participate in the Supplemental Program for low income Women, Infants, and Children (WIC). A major focus of Dr. Powers is to translate behavioral science into efficacious and effective interventions that improve nutritional and health outcomes for children.
Marc E. Rothenberg, MD, PhD, Division of Allegy and Immunology
Dr. Rothenberg's investigates the mechanisms of allergic responses especially in mucosal tissues with a primary focus on the gastrointestinal tract. The goal of the research is to develop the best treatment strategy for allergic disorders (especially eosinophilic gastrointestinal disorders (EGIDs) based on mechanism-driven research. He uses multiple approaches involving analysis of the cellular and molecular processes in vitro and in vivo, often utilizing genetically engineered mice. In addition, several novel models of antigen-driven allergic gastrointestinal disorders have been developed and these provide the experimental framework for identifying mechanisms of disease. Furthermore, translational research involving several aspects of patient-based research including innovative drug intervention clinical trials, genome wide expression profiling of intestinal tissue, and genetic analysis using candidate gene approaches are underway. For example, early results with humanized anti-IL-5 therapy in patients with EGIDS have revealed a promising role for this new biological modifier, prompting an ongoing placebo-controlled clinical trial.
Randall R. Sakai, PhD, Department of Psychiatry, University of Cincinnati College of Medicine
Dr. Sakai's research examines the role of the renin-angiotensin system and adrenal steroids in mediating thirst and sodium appetite. The expression of sodium appetite in the rat is controlled by a multitude of hormonal mechanisms evoked when the animal is sodium depleted. Previous studies have shown that it is not the sodium deficiency itself but rather the syner-gistic action of angiotensin and aldosterone, hormones that are released in response to the sodium depletion, which generate the appetite for salt and have long-term effects that enhance subsequent salt intake. Dr. Sakai is examining the genomic and non-genomic effects of steroids on sodium intake. Additionally, he has a unique animal model to study social stress. This model is used to determine how social hierarchies influence the regulation of food intake and body weight and to identify the neuroendocrine mechanisms that underlie social influences on body weight. Understanding the mechanisms underlying the regulation of the stress response as well as the long-term consequences of stress may enhance rational clinical therapies for treatment of affective disorders such as depression and post-traumatic stress disorder. Both programs of research utilizes an interdisciplinary approach to examine behavioral and physiological phenomena at multiple levels and includes behavioral observations, in vivo manipulations such as antisense oligodeoxynucleotide technology, and molecular biological assays.
Randy J. Seeley, PhD, Department of Psychiatry, University of Cincinnati College of Medicine
Under normal circumstances, caloric intake is precisely matched to caloric expenditure such that the amount of stored calories in the form of body fat remains stable. The evidence suggests that this is accomplished via a hormone (leptin) that is produced directly in fat cells that circulates back and has potent effects on the central nervous system (CNS). Dr. Seeley's research group focuses on understanding the effects leptin has on behavior and the CNS in service of regulating food intake. Specifically, they have been interested in hypothalamic neuropeptide systems (NPY, CRH and melanocortins) that might mediate the effects of leptin. Additionally, they have been exploring how these neuroendocrine systems are altered in a number of obesity models. Dr. Seeley's work has two major areas of clinical relevance. The first and most obvious is obesity. A deeper appreciation of the way in which leptin acts in the CNS to produce weight loss should provide a number of new targets for the development of pharmaceutical interventions for obesity. Dr. Seeley has an active collaboration with Procter & Gamble to help leverage the discoveries into new treatment options for the obese population. The second area of clinical relevance is wasting which accompanies AIDS and some tumors. Weight loss is a major contributor to the mortality associated with these conditions. Both the length and quality of patients' lives could be substantially increased by effective treatments for wasting. They have developed a model of tumor anorexia that they are using to measure changes in neuroendocrine systems and attempting to reverse the anorexia with a variety of agonists and antagonists for identified receptors.
Sulaiman Sheriff, MD, Department of Surgery, University of Cincinnati College of Medicine
Neuropeptide Y (NPY) is a 36 amino acid peptide present in high concentration in mammalian brain. Injection of NPY into hypothalamic regions elicits a powerful feeding response in rats, and NPY has been strongly implicated in diabetes and obesity. The peripheral satiety factor, leptin, has been shown to exert satiety stimuli in mice and rats by inhibiting the synthesis and release of NPY in hypothalamic sites that are known to regulate eating behavior. Most importantly, PYY 3-36, a peripheral homologue of NPY released from the L-cells of the gut into the circulation after a meal, is reported to act as a satiety signal. Administration of PYY 3-36 in humans significantly decreased appetite and attenuated food intake by 33 percent for up to 24 hours. In an attempt to understand the causes of eating disorders and obesity, Dr. Sheriff is investigating the molecular mechanisms regulating NPY-induced feeding in the hypothalamus. Activation of Y1 and Y5 receptors of NPY in the hypothalamic PVN by NPY trigger the hunger signal by inhibiting cAMP accumulation and mobilizing intracellular Ca++. These two prominent second messengers activate a transcription factor, CREB, the activation of which regulates many CREB-dependent genes. These biochemical events translate into a hunger signal. PYY 3-36 activates hypothalamic Y2 receptors to turn off the hunger stimuli. Dr. Sheriff's overall goal is to investigate the signal transduction cascade and the regulatory genes involved in maintaining energy homeostasis.
Kenneth E. Sherman, MD, PhD, Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine
Dr. Sherman's research focuses on the interactions of hepatotropic viruses in immunosuppressed hosts. In particular, his laboratory investigates the relationship between hepatitis C virus (HCV) and immunodeficiency virus infection. He uses state of the art molecular techniques that include viral kinetic modeling in different stages of disease progression and the emergence and molecular genotypes of HCV quasi-species analysis in the context of well-defined clinical settings. To explore the underlying mechanisms of host response to a viral insult, he studies cellular and immune correlates of viral evolution. He is also actively involved in translational research utilizing antiviral and immunomodulatory therapies for patients with viral hepatitis.
Gary E. Shull, PhD, Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine
Ion transport proteins are important in homeostatic processes that are disturbed in a number of human diseases, including those of the gastrointestinal tract, heart, kidney, and skin. To understand the physiological functions of these ion transporters, Dr. Shull is developing mouse models in which their genes have been disrupted, and analyzing them using molecular, physiological, and bioinformatics techniques. This work has revealed a diversity of phenotypes, including systemic acid-base disorders of the gastrointestinal tract, mouse models of congenital diarrheal disease, impaired cardiac performance, reduced blood pressure, profound hearing loss, male infertility, systemic acid-base disorders, and perturbations of transepithelial ion transport in the kidney. Many of the ion transporters for which they have developed knockout mouse models are known to be involved in human diseases. These studies have provided important insights about the physiological functions of these ion transporters in vivo.
Lori J. Stark, PhD, Division of Behavioral Medicine and Clinical Psychology
Dr. Stark has longstanding interest in examining behavioral and environmental factors that contribute to nutritional health and eating disorders. She has had funding from the NIH to examine barriers and interventions to improve adherence to dietary treatment in cystic fibrosis (CF), and to improve calcium intake in order to improve bone mass. Her studies in CF have found that achieving the dietary recommendations for optimal nutritional status is challenging as children with CF must exceed the recommended energy intake for same age children. In trying to achieve these dietary goals parents often resort to ineffective parenting strategies that not only do not work but have a negative effect on family functioning. She had designed effective behavioral interventions to increase caloric intake and reduce parent-child distress during meals. She has also applied this methodology to other nutritional problems such as improved calcium intake and examined the effect on bone mass in children with juvenile rheumatoid disease and Crohn's disease.
Gregory M. Tiao, MD, Division of Pediatric and Thoracic Surgery
Dr. Tiao's research is focused on biliary atresia, which is the most common cause of persistent neonatal cholestasis. Surgical reconstruction of the extra-hepatic biliary tract is beneficial in a subset of patients, but most patients progress to end-stage liver disease despite surgery, requiring liver transplantation for long-term survival. As a result, biliary atresia is the number one indication for pediatric liver transplantation. His primary studies address the molecular basis of virus-induced biliary injury in an experimental murine model of biliary atresia. His ongoing studies demonstrate that the viral tropism to the epithelium of extrahepatic bile ducts depends, at least in part, on the virus-specific rotavirus strain and on the expression of specific integrins by cholangiocytes. Logical extension of these studies is being pursued, in which he is dissecting the intracellular signals that regulate the host response following rotavirus infection.
Matthias H. Tschöp, MD, Department of Psychiatry, University of Cincinnati College of Medicine
The communication between afferent signals, specific central nervous system circuitry and efferent pathways plays a major role in the regulation of food intake, energy balance and body weight. Dr. Tschöp focuses on the crosstalk between neuroendocrine signals of these pathways as a possible target for the treatment of obesity, anorexia and cachexia. He first described the novel hormone ghrelin as not only an important regulator of energy balance, but also as the only circulating orexigenic agent known. He also found that human body weight changes influence ghrelin levels and that mutations in the ghrelin gene are associated with symptoms of the metabolic syndrome. Recent data indicates that ghrelin action in the brain is mainly mediated by hypothalamic neurons, but also targets other brain areas such as the ventral tegmental area. Dr. Tschöp is currently dissecting ghrelin induced energy balance changes in food intake, respiratory quotient and locomotor activity as well as metabolic changes due to modulation of the thyroid and hypothalamic-pituitary-adrenal axis. To decipher the multiple mechanisms involved in ghrelin action and regulation, they are using novel tools such as ghrelin neutralizing RNA Spiegelmers (biostable RNA-based compounds), several ghrelin receptor antagonists and a variety of transgenic models.
Patrick Tso, PhD, Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine
Dr. Tso studies the mechanisms and factors regulating the assembly and secretion of chylomicrons and very low-density lipoproteins by the small intestine. Recently, he demonstrated that the secretion of apolipoprotein B into lymph by the small intestine was unaltered by acute feeding of triglyceride. Since each triglyceride-rich lipoprotein contains one copy of apolipoprotein B, it would imply that the number of triglyceride-rich lipoproteins made by the small intestine is not altered during active lipid absorption. Rather, the triglyceride-rich lipoproteins simply enlarge to accommodate the excess triglycerides. He also demonstrated that the reason why the gut makes a smaller version of apolipoprotein B (B-48 instead of B-100 in the liver) is because it is more efficient in facilitating the transport of triglyceride as chylomicrons by the enterocytes. Additionally, he demonstrated that increased apolipoprotein A-IV in chylous lymph is an important factor involved in anorexia after fat feeding. This finding demonstrates for the first time a physiological function of apolipoprotein A-IV that is not shared by apolipoprotein A-I. He is actively pursuing both the site of action of apolipoprotein A-IV and the active site of the apolipoprotein A-IV molecule.
Susan E. Waltz, PhD, Department of Surgery, University of Cincinnati College of Medicine
Dr. Waltz is defining the in vivo role of the receptor tyrosine kinase Ron in liver pathophysiology. She generated mice with a targeted ablation of the tyrosine kinase (TK) domain of Ron (TK-/-). These mice display marked protection compared to control mice in a well-characterized model of endotoxin (lipopolysaccharide, LPS) induced acute liver failure in galactosamine (GalN)-sensitized mice. In response to LPS/GalN, control mice exhibit profound hepatocellular injury evaluated by increases in serum aminotransferase levels and hemorrhagic necrosis of the liver. In contrast, the TK-/- mice have mild aminotransferase levels and relatively normal liver histology. The TK-/- mice also display a significant reduction in hepatocyte apoptosis compared to controls. Initial data have also shown that LPS/GalN treatment of TK-/- mice results in diminished levels of IFNγ, an essential mediator of this injury model, as well as reduced amounts of select chemokines. The reduction in cytokine and chemokine production is associated with a decrease in the number of infiltrating neutrophils into the liver. Based on preliminary data, Dr. Waltz's future goal is to the determine if Ron receptor signaling promotes the progression of acute liver failure by augmenting IFNγ and select chemokine production, leading to an increase in neutrophil recruitment, hepatocyte apoptosis and acute liver failure.
Ning Wang, PhD, Division of Allergy and Immunology
Dr. Wang's research focus on statistical genetics, specifically on identifying genetic components contributing to human complex disorders, such as childhood asthma and Eosinophilic Esophagitis (EE) using candidate gene or genome-wide scan approaches. The major goals of her R21 project are: 1) Test the association of the eotaxin-3 gene with EE; and 2) Test the association of cadherin-like-26 gene with EE, and examine the gene-gene interaction between eotaxin-3 and cadherin-like 26 underlying susceptibility to EE. The analyses will be stratified by age of onset, atopic status, and disease severity to elucidate the genotype-phenotype link. In addition, the case-control association result is likely to be confounded by population stratification problem, i.e. the cases and controls groups may have different genetic background, thus lead to false positive results. Another area of research is how to detect and adjust for population stratification differences.
Alison Weiss, PhD, Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine
Dr. Weiss focuses on host pathogen interactions with regard to infectious diarrhea caused by E. coli O157:H7. Disease caused by E. coli O157:H7 is characterized by diarrhea, hemorrhagic colitis, and the potentially fatal complication, hemolytic uremic syndrome (HUS). Shiga toxin (Stx) is a major virulence factor of E. coli O157:H7. Two major antigenic variants of Shiga toxin, Stx1 and Stx2, share 55% amino acid homology. Strains of O157:H7 can produce Stx1, Stx2, or both; however, the ability to produce Stx2 has been associated with progression to severe disease, including HUS. The importance of Stx2 in life-threatening disease has been definitively established in recent studies demonstrating that administration of purified Stx2 led to the development of HUS in experimental models, while an equivalent dose of Stx1 did not. While it is clear that Stx2 can induce cellular death, it is also not clear that cellular death is required for development of HUS. Neutrophil recruitment and activation may play a role in development of HUS. Sublethal doses of Stx2 have been shown to induce endothelial cells to produce an aberrant cytokine cascade that is believed to recruit and retain neutrophils. Currently, she is examining the differences between Stx1 and Stx2 and the relationship to host toxicity.
James M. Wells, PhD, Division of Developmental Biology
Dr. Wells' research focuses on intestinal development. Dr. Wells has found that fibroblast growth factor 4 (FGF4)-mediated signaling is necessary and sufficient for establishing midgut and hindgut domains in vivo. He has also identified that a secreted FGF binding protein (FGFbp1) regulates FGF4 activity. Dr. Wells is also studying the mammalian transcription factor Sox17. He has shown that Sox17 promotes the degradation of β-catenin and T-cell specific transcription factors in a non-canonical fashion. He has found that Sox17 is expressed in crypt cells of the gut and by basal cells of the conducting airway in the lung. Currently Dr. Wells is investigating if Sox17 is involved in stem/progenitor cell activity in the gut and the lung using a tetracycline-inducible Sox17 transgenic line that he has generated. Additionally, Dr. Wells is trying to promote endodermal differentiation of embryonic stem cells by using a tetracycline inducible approach to express Sox17. He is presently analyzing these cell lines for their ability to differentiate into endoderm and its derivatives in vitro. Ultimately, he plans to study the therapeutic potential of embryonic stem cell-derived gastrointestinal cells in animal models of gastrointestinal disease.
Dan A. Wiginton, PhD, Division of Developmental Biology
Research in the Wiginton lab focuses on in vivo mechanisms of gene regulation controlling development of the small intestine and cell differentiation along the crypt-villus axis of the small intestinal epithelium. It is proposed that a discrete network of regulatory factors control these processes. The Wiginton lab is attempting to understand the role of GATA factors (GATA-4/5/6) in the network that controls epithelial cell differentiation from stem cells into four major functional cell types (enterocytes, goblet cells, Paneth cells, and enteroendocrine cells). In addition, Dr. Wiginton's lab is investigating the genetic pro-grams that regulate profiles of gene expression along the various physical and temporal axes of the small intestine. Significant variations in gene expression are observed along the cephalocaudal (horizontal) axis of the intestine within a particular cell type. These functional variations are established and maintained in the adult even though the intestinal epithelium undergoes a constant, continuous renewal. Changes in gene expression are also observed along the intestinal crypt-villus axis, related to cell differentiation status and cell migration. There are also very significant temporal changes in gene expression during fetal and early post-natal stages of intestinal development. Little is understood about how these temporal changes are orchestrated and regulated. The adenosine deaminase (ADA) gene is currently being used as a model in Dr. Wiginton's lab to understand the interrelated network of transcription factors and cis-acting elements that regulate gene expression along the various physical and temporal axes of the small intestine in humans and mice. An intestinal-specific enhancer and a novel temporal control element located in the ADA gene's second intron are under investigation, as part of these studies.
David P. Witte, MD, Division of Pathology and Laboratory Medicine
In addition to his role as Director of the Integrative Morphology Core, Dr. Witte is a co-investigator in several projects studying gene regulation of development and characterizing animal models of liver and intestinal disease. Dr. Witte's background includes more than fifteen years of combined anatomic pathology training and professional pathology experience utilizing morphologic based methodology including anatomic dissection and macroscopic observation, light and electron microscopy, specialized histochemical staining techniques, immunohistochemistry, and characterizing gene expression patterns by in situ hybridization. Dr. Witte has been involved with the detailed characterization of the expression pattern of more than 25 developmentally regulated genes in the mouse embryo including homeobox containing transcription factor genes and other critical developmentally regulated genes necessary for implantation or normal organ morphogenesis and the detailed mapping of gene regulatory elements.
Stephen C. Woods, PhD, Department of Psychiatry, University of Cincinnati College of Medicine
Dr. Woods is examining the role of gastrointestinal hormones in influencing food intake and body weight. Specifically, considerable evidence suggests that two kinds of peripheral signals influence eating. Some signals, represented by cholecystokinin, are peptides secreted in response to meals. Besides contributing to digestion, some of these peptides additionally signal the central nervous system (CNS) to contribute to sensations that lead to satiety ("fullness"). Other signals, represented by insulin and leptin, circulate to the CNS in direct proportion to adiposity. Within the brain, they interact with meal-generated satiety signals to determine food intake and ultimately body weight. Working with animal models (rats and mice), Dr. Woods' research considers all aspects of these systems including secretion and interactions of the signals, their ability to influence peripheral and central neural circuits and the CNS systems that control food intake and energy homeostasis. Dr. Woods is typically able to obtain behavioral, physiological, hormonal, anatomic and molecular biological data from the same animals.
Margaret H. Zeller, PhD, Division of Behavioral Medicine and Clinical Psychology
Dr. Zeller's research aims to identify potentially modifiable individual, parent, and family factors that are associated with excessive weight gain in youth and that serve as barriers to successful pediatric weight management, both behavioral and surgical. Dr. Zeller has recently completed a study that examined the social, emotional, and family functioning of treatment-seeking obese youth as compared to demographically matched non-overweight controls. A longitudinal follow-up of these youth, who are now adolescents, is planned. Dr. Zeller also has focused on instrument development, specifically in the area of weight-specific health related quality of life. Most recently, Dr. Zeller has expanded her research to include psychosocial predictors of successful bariatric surgical outcomes when performed in adolescents. Dr. Zeller also is a collaborator on a multi-site study to examine the benefits and define complications to be expected when bariatric surgery is performed in adolescence compared to the standard approach of performing bariatric surgery in adulthood. Adolescents will be recruited from several high volume adolescent bariatric centers and a comparison cohort from adult bariatric centers participating in the Longitudinal Assessment of Bariatric Surgery (LABS).
Aaron M. Zorn, PhD, Division of Developmental Biology
Dr. Zorn's long-term research goal is to understand the molecular mechanisms controlling the development of the liver, pancreas and gastrointestinal tract, which are derived from the embryonic endoderm. He uses frog embryos as a model system to investigate the genetic pathways underlying this poorly understood process of organogenesis. He is applying a combination of molecular and embryological techniques, including microarray technology and transgenics, to uncover the molecular and cellular events responsible for early liver development. Current investigations examine how transcription factors integrate signals from different growth factors to specify endoderm and embryonic liver. Dr. Zorn is also conducting a number of screens to find novel genes involved in liver development. This research will help uncover the molecular basis of congenital diseases in these organ systems, organ failure, and the ability to direct the development of stem cells to make therapeutically useful tissue.
Stephen D. Zucker, MD, Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine
The focus of Dr. Zucker's research is on elucidating the physiological functions of unconjugated bilirubin. Current work specifically examines the role of bilirubin both as an endogenous anti-inflammatory agent and in the chemoprevention of colorectal cancer. His studies have shown that bilirubin attenuates lipopolysaccharide hepatotoxicity, suppresses carrageenan-induced hindpaw inflammation, and ameliorates ovalbumin-stimulated asthma. Ongoing experiments employ both in vivo and in vitro methodologies to systematically elucidate the mechanism(s) by which bilirubin exerts these effects. Dr. Zucker has further demonstrated that bilirubin decreases the viability of colon cancer cells in vitro through the induction of apoptosis, and that this effect is mediated through activation of the mitochondrial pathway. Bilirubin treatment is well tolerated in vivo, and is associated with a marked reduction in tumor number in animal models. It is anticipated that his ongoing studies will provide new insight into the role that bilirubin plays in the regulation of inflammation and in the modulation of intestinal tumorigenesis.
