Meet the Faculty of the Pediatrics Student Research Program
1) Steven H. Abman, MD (Pulmonary)
Dr. Abman is the Director of the Pediatric Heart Lung Center (PHLC), which is a multidisciplinary group of collaborators who promote the translation of research to clinical care for newborns, infants and children with severe cardiopulmonary diseases. Ongoing studies explore mechanisms that regulate pulmonary vascular tone, structure and growth in the developing lung. Current work examines the roles of nitric oxide (NO) in the pathobiology and treatment of neonatal pulmonary hypertension. In addition, we study lung development in the fetus, newborn and infant, and mechanisms that contribute to chronic abnormalities of lung structure and function in premature infants (known as bronchopulmonary dysplasia; BPD). We utilize diverse methods and experimental models, including whole animal studies with fetal and neonatal sheep, rats and mice; endothelial, alveolar type II cells, smooth muscle and endothelial progenitor cell studies in vitro; fetal lung explants; and diverse molecular and biochemical assays. Students would work on their own project along with members of the PHLC team, attend regular laboratory meetings and participate in related research activities.
2) Bruce Appel, PhD (Stem Cell Biology)
We investigate how the nervous system forms during embryonic development, with the hope that that such information will help us repair nervous systems damaged by disease or injury. We use zebrafish embryos as a model system because they are transparent and develop outside the mother, permitting us to use time-lapse microscopy to watch neural cells as they migrate and differentiate into neurons and glia. We also study the effects of mutations that disrupt neural development in zebrafish, with the expectation that they will help us understand the basis of genetic diseases that cause neurological disorders in humans. Finally, we using zebrafish to learn how to promote regeneration of neural cells that are lost as a consequence of birth defects.
3) Vivek Balasubramaniam, MD (Pulmonary)
Dr. Balasubramaniam is Head of the Pediatric Heart Lung Center Laboratory. His work focuses on the roles of endothelial progenitor cells (EPCs) and related progenitor cells during lung development and their potential roles for treating children with pulmonary hypertension and chronic lung disease.
4) Tim Benke, MD, PhD (Neurology/Neuroscience)
The Benke lab studies the long-term consequences of early life seizures on the developing brain. These changes may not necessarily result in epilepsy, but are known to lead to cognitive and behavioral impairments. Understanding the molecular mechanisms leading to cognitive and behavioral impairments is meant to segue into new and novel treatments for all causes of intellectual disability and even autism. Students working in the Benke lab will use animal models of early life seizures to probe these underlying molecular mechanisms. Techniques that will be used include electrical recordings in living rat brain slices, stereotactic injection of interesting antisense viral vectors, electroencephalogram (EEG) and video monitoring in freely moving rats, western blotting and immunohistochemistry.
5) Richard KP Benninger, PhD (Bioengineering/Barbara Davis Center)
The islets of Langerhans are multi-cellular micro organs located in the pancreas which play a central role in maintaining blood glucose homeostasis through secretion of hormones insulin and glucagon. We study the regulation of insulin and glucagon secretion and specifically how different cellular populations within the islet interact to enhance the overall regulation of hormone secretions. We follow an approach whereby precise perturbations in signalling activity are introduced into a well-defined population of cells in the islet, utilizing transgenic mouse models, microfluidics and optogenetics. Quantitative confocal and two-photon microscopy, together with biochemical and physiological approaches, are applied to measure the effect of these perturbations across the islet and how they manifest in the overall islet dynamical response. Predictive mathematical models are then used to describe these results. We are applying this approach to understand several aspects of how islet connectivity is important for glucose homeostasis and how it is disrupted during the development of diabetes. The overall goal is to be able to manipulate cell-cell communication within the islet to improve the regulation of insulin and glucagon secretion and to optimize islet transplantation approaches to treat and cure diabetes.
6) Amy Brooks-Kayal, MD (Neurology/Neuroscience)
The Brooks-Kayal lab studies the changes in the brain that occur after a brain injury that lead to the development of acquired epilepsy. These cellular and molecular changes are then used as targets for development of new treatments to prevent and/or treat epilepsy. Students working in the Brooks-Kayal lab will use animal models of acquired epilepsy to test potential new treatments to see if they reduce occurrence of seizures after brain insults. Techniques that will be used include electroencephalogram (EEG) and video monitoring in rodents, western blotting and immunohistochemistry.
7) Jorge DiPaola, MD (Hematology/Oncology)
The DiPaola lab is interested in studying the genetics and physiology of blood clotting (also known as hemostasis). The process of platelet binding and aggregation is highly regulated such that the platelets rapidly stem the flow of blood at the site of vessel injury while not causing vessel occlusion. In addition, upon binding and activation, platelets release granule contents that include clotting proteins and numerous growth factors that are involved in tissue growth and wound healing. Thus platelets play a central role in blood vessel repair and have both physical and biochemical properties that are essential for normal hemostasis. We are also interested in Von Willebrand Factor (VWF), which is multimeric protein present in platelets and endothelial cells. Our current studies of VWF mutations are primarily focused on identifying genetic factors that give rise to the clinical variability seen in the patients with von Willebrand Disease (VWD) and to develop assays to better characterize and understand this bleeding disorder. Association and linkage analysis, along with next generation sequence strategies, are being used to study families with VWD and other congenital bleeding disorders. Also, in collaboration with the Neeves lab at the Colorado School of Mines, we are testing a state of the art microscopy system to further examine platelet function under different flow rates and to characterize the effects of shear on platelet binding and aggregation in normal individuals and those with bleeding disorders. By applying both genetic and biochemical approaches we hope to expand our scope of understanding of platelet development and function, and to be better able to diagnose and treat related bleeding disorders.
8) Lenny Dragone, MD, PhD (Rheumatology/Immunology)
Dr. Dragone is interested in developing strategies to manipulate lymphocyte-signaling pathways to treat autoimmune disease. He is defining how alterations in ubiquitinylation as well as NEDDylation alter signaling through the T-cell receptor complex in mouse models of inflammatory arthritis and systemic lupus erythematosus (SLE) to determine their role in autoimmune pathogenesis. In addition, he is defining the mechanism of pregnancy-induced arthritis amelioration as a means of identifying new signaling pathways that may be targeted to treat autoimmune disease.
9) Nick Foreman, MD (Hematology/Oncology)
The goal of the Foreman laboratory is to better understand the biology of pediatric brain tumors. In particular, we are interested in identification of biological characteristics of these tumors that have clinical relevance, such as drug sensitivity, diagnosis and prognosis. To identify novel clinically relevant factors, we screen patient surgical samples using gene expression microarray tools. Gene expression microarray technology allows us to simultaneously measure tens of thousands of genes in a tiny sample of tumor, an extremely powerful and efficient approach that provides huge amounts of novel data. Analysis of this microarray data is performed by our laboratory, and students working in the Foreman lab would be encouraged to be involved with this. Students would then further explore the results of microarray analyses using protein expression analyses including flow cytometry, Western blot and immunohistochemistry.
10) Jed Friedman, PhD (Biochemistry/Molecular Genetics/Reproductive Sciences)
The prevalence of obesity has been increasing dramatically in the United States over the past decades and obesity is now present at increasingly younger ages, indicating that risk factors for this condition start operating very early in life. Fetal life is considered one of the critical (or sensitive) periods when an exposure may have lifelong effects on the structure or function of organs, tissues, and body systems through biological programming. We are interested in investigating the metabolic and genetic causes and consequences of nutrition on the early developmental origins of childhood obesity. This involves novel animal models (mice, non-human primate) together with invasive clinical investigation of human pregnancy. In humans we routinely obtain skeletal muscle and adipose tissue biopsies obtained from obese women with and without GDM during pregnancy along with post-partum follow-up of the mothers and their offspring. These studies focus on measurements of body composition, gene expression, and cell culture studies of mitochondrial function and inflammatory status. Our studies in mice and Non Human Primates in conjunction with the Oregon National Primate Research Center are currently focused on the role of dietary fatty acids and inflammation as early markers of fetal liver steatosis and insulin resistance in liver, fat, and skeletal muscle through a combination of genetic and epigenetic pathways. These studies combined with in-vitro studies of cell lines (hepatocytes, adipocytes, and dendritic cells) emphasize the importance of genes and metabolic pathways important for control of body weight.
11) Doug Graham, MD PhD (Hematology/Oncology)
The Graham lab investigates two receptor tyrosine kinases, Mer and Axl, which help promote cancer cell survival in pediatric leukemia. These receptors are abnormally expressed in pediatric leukemia patient samples and cell cells and help promote resistance to commonly used chemotherapy drugs. When the expression or activation of these receptors is inhibited, the cancer cells become more sensitive to chemotherapy. Thus, these receptor tyrosine kinases are attractive new drug targets for the treatment of pediatric leukemia, and the Graham lab is actively involved in developing and testing antibodies and small molecule inhibitors against Mer and Axl. A future goal is to transition some of these new targeted drugs into pediatric leukemia clinical trials.
12) Eva Grayck, MD (Critical Care/Developmental Lung Biology)
The overall mission of the Grayck lab is to understand the role of oxidative stress in the development of pulmonary arterial hypertension in the immature lung. Our work focuses on an important antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), which is highly expressed in the lung and vessels under normal conditions and is impaired in vascular and lung diseases, leading to inflammation and fibrosis. We utilize a number of genetically engineered mouse strains with alterations in EC-SOD expression along with cell culture systems to test how EC-SOD modulates pulmonary vascular remodeling and inflammation in models of pulmonary hypertension. Ultimately our long-term goal is to provide a foundation for the development of novel cell-targeted antioxidant therapies to treat pediatric pulmonary arterial hypertension.
13) Research at the Perinatal Research Center (PRC)
William W. Hay, Jr. MD (Scientific Director of the PRC)
Stephanie Thorn PhD
Paul Rozance MD
Laura Brown MD
Dr. Hay's research group (Drs. Thorn, Brown, and Rozance) focuses on the mechanisms by which maternal nutrition and diseases (such as diabetes) that produce different plasma nutrient substrate and hormone concentrations regulate placental uptake, metabolism, and transfer to the fetus of essential nutrients (principally glucose and amino acids), and in turn, how these processes are interrelated to fetal nutrition, metabolism of nutrient substrates, hormone balance, and growth rate. A major effort over the years has been a focus on intrauterine growth restriction (IUGR) and how this condition results in metabolic and developmental adaptations which set up an individual for long term health problems including hypertension, cardiovascular disease, pulmonary disease, obesity, and diabetes; this is known as the Fetal Origins of Adult Disease Hypothesis. Basic work is conducted in the pregnant sheep model involving fetal surgery and in vivo metabolic experiments. Cell and molecular studies focus on a variety of fetal organs including the liver (Dr. Thorn), skeletal muscle (Dr. Brown), and pancreatic beta cells (Dr. Rozance), as well as adipose tissue, heart, lungs, brain, and placenta. Through this research, it is hoped that there will be a better understanding of how to provide nutrition to the pregnant and lactating mother in order to better nourish the fetus and neonate, in order to correct or prevent acute and long-term adverse consequences of abnormal fetal nutrition.
14) Paul Jedlicka, MD, PhD (Pathology)
The Jedlicka laboratory is interested in identifying and understanding novel pathways controlling the pathogenesis of Ewing Sarcoma, an aggressive cancer of bone and soft tissues affecting children and young adults. The current focus is on microRNAs, which are important, novel regulators of gene expression in health and disease, with therapeutic potential. At present, most of our efforts are directed at understanding microRNAs controlled by the EWS/Fli1 fusion oncoprotein, the main oncogenic driver in Ewing Sarcoma. Specifically, we are working to understand: (1) how these microRNAs contribute to Ewing Sarcoma pathogenesis; (2) how their expression is regulated by the EWS/FLi1 oncoprotein; and (3) how these findings could be harnessed for novel therapies for this aggressive disease.
15) Amy Keating, MD (Hematology/Oncology)
The Keating laboratory focuses on pediatric brain tumor investigations, specifically a type called astrocytoma. We are working on understanding how these astrocytoma cells grow, survive following chemotherapy and radiation treatment, and migrate throughout the brain. By recognizing and characterizing how astrocytoma cells accomplish these processes, we can work toward our goal of developing new therapies that work better and are safer for our young patients. Students working in the Keating lab would be exposed to molecular and cellular biology techniques, including cell culture, cell growth analysis, basic microscopy, immunoblotting for protein analysis, and basic biostatistics used for medical and scientific investigations.
16) Megan Kelsey, MD (Endocrinology)
Dr. Megan Kelsey is a pediatric endocrinologist interested in relationships among puberty, obesity, insulin resistance and gonadal function. Specifically, she is doing clinical research to study metabolic changes during puberty that may cause certain at-risk children to develop type 2 diabetes early. She is also interested in effects of obesity on pubertal development itself and sex differences in these effects. Dr. Kelsey is conducting a longitudinal clinical trial of metformin during puberty to learn more about these relationships. Dr. Kelsey’s lab performs studies in the Clinical Translational Research Center at the Children’s Hospital, including IV glucose tolerance testing to measure insulin sensitivity and β-cell function, dual x-ray absorptiometry to measure body composition, MRI technique to measure liver and visceral fat, and specialized techniques for measuring sex steroids and gonadotropins in urine. Dr. Kelsey’s research also involves a large, national trial to better understand type 2 diabetes in youth (TODAY), a study evaluating complications related to insulin resistance in type 1 and type 2 diabetes, several clinical treatment trials for type 2 diabetes, and a continuous glucose monitoring study in obese adolescents. Students would gain insight into underlying pathophysiology of type 2 diabetes in youth and measurement techniques involved in metabolic research and would have the opportunity to work closely with other research teams in pediatric endocrinology.
17) Nancy Krebs, MD, MS (Pediatric Nutrition)
The focus of our research program is primarily on mineral nutrition, especially zinc and iron, with both studies in international and local settings. Our interventions seek to refine nutrient requirements in women and children in health and disease; to examine effects of dietary and supplemental constituents on bioavailability; and determine effects of nutritional intake on the intestinal microbiome. Laboratory-based methodologies include stable isotopes; ELISA's for biomarkers of Fe & Zn status; and various elemental analyses. Additional area of focus for of our research program includes community and clinical-based investigations in childhood obesity prevention and treatment.
18) Katherine Lee, PhD (Infectious Diseases)
The Lee lab is interested in better understanding the interactions of varicella-zoster virus (VZV) with human cells. In particular, we would like to identify host factors important to VZV infection and pathogenesis. We have developed novel tools, such as genetic libraries and in vitro model based on induced pluripotent stem cells, to address questions concerning VZV latency and reactivation.
19) Cara Mack, MD (Gastroenterology)
Biliary atresia is a devastating disease that leads to liver transplant in the majority of children. The etiology of biliary atresia is not known and the Mack lab investigates the role that the immune system plays in the bile duct damage. The overall hypothesis is that the bile duct injury is initiated by a virus infection, followed by an autoimmune inflammatory process targeting bile ducts. The Mack lab investigates the pathways of the adaptive immune response (cellular- T cell and humoral- B cell) in order to determine the key players involved in bile duct destruction. The majority of studies utilize a mouse model of biliary atresia and limited research on human liver tissue is performed as well. The Mack lab is affiliated with both the Department of Pediatrics, Division of Pediatric GI, Hepatology & Nutrition and the Department of Medicine, Division of Allergy & Immunology.
20) Shelley Miyamoto, MD (Cardiology)
Pediatric Cardiovascular Research Laboratory (PCRL:
Shelley Miyamoto, MD
Brian Stauffer, MD
Kika Sucharov, PhD
The mission of this multidisciplinary research group is to perform translational and molecular research focused on children with heart disease. Expertise within the laboratory spans the cardiovascular field from pediatric to adult disease and from basic molecular biology to cardiovascular physiology and clinical translation. Our research utilizes a pediatric and adult heart tissue bank as well as animal models. Our current projects include study of: (1) the beta-adrenergic system and downstream signaling pathways; (2) regulation of phosphodiesterase expression and activity; (3) tissue and circulating microRNA profiling; and (4) the role of histone deacytelases in hypoplastic left heart syndrome. Currently, treatment of pediatric heart failure is largely extrapolated from the results of trials performed in adults with heart failure. Our results demonstrate that children with heart failure have a unique molecular adaptive response that warrants specific targeted therapy. Students working in our laboratory would be exposed to a variety of molecular biology techniques including RT-PCR, Western blotting, various activity assays and basic biostatistics.
21) Kristen Nadeau, MD, MS
Dr. Kristen Nadeau is a pediatric endocrinologist who performs clinical-translational research on reducing long-term complications of pediatric type 1 and type 2 diabetes and polycystic ovarian syndrome. The focus of her group’s work is better understanding early contributors to cardiovascular disease (CVD), including mechanisms of insulin resistance, cardiovascular and muscle dysfunction. Dr. Nadeau’s lab performs studies including intravenous hyperinsulinemic clamps with multiple isotopes, hyperglycemic clamps and glucose tolerance tests to measure insulin sensitivity and pancreatic beta-cell function; subcutaneous continuous glucose monitoring; assessment of liver, visceral and muscle fat deposition with MRI/MRS techniques; heart function with resting and exercise-stress echocardiography; vascular function with carotid artery ultrasound, brachial artery ultrasound, and measures of arterial stiffness; exercise function via VO2max testing by bicycle and metabolic cart; and muscle mitochondrial function via MRI/MRI with exercise. Dr. Nadeau’s research also includes several large trials, including medication studies to improve diabetes control in youth with type 2 diabetes (TODAY), a medication trial to improve pancreatic beta cell function in youth and adults with early type 2 diabetes (RISE), a study of pubertal hormones and insulin resistance, and a medication trial to reduce cardiovascular disease in youth with type 1 diabetes. Finally, Dr. Nadeau’s work includes a study of periodontal disease in American Indian youth with obesity and type 2 diabetes. Thus students would have a rich exposure to clinical/translational research in youth with obesity and diabetes.
22) Lee Niswander, PhD (Developmental Biology)
Dr. Niswander is the head of the Section in Developmental Biology, whose researchers use different model organisms to better understand the mechanisms that underlie birth defects and childhood disease. The Niswander lab uses the mouse embryo to determine the genes that regulate the early development of the brain and spinal cord. Mutations in these genes can lead to birth defects such as spina bifida and microcephaly. Our goal is to elucidate the function of these genes using developmental, molecular and biochemical approaches as well as time-lapse imaging to visualize the cell movements and cell behaviors that drive the formation of the central nervous system. We are also studying how environmental influences alter the risk of these birth defects.
23) Christopher Porter, MD (Hematology/Oncology)
The Porter lab uses functional genomics studies to identify gene products which, when inhibited, sensitize acute myeloid leukemia cells to conventional and targeted chemotherapeutics. Targets are then validated in petri dishes and in animal models of leukemia. Students working in the Porter lab will be involved in target validation using RNA interference. The students will be exposed to various molecular biology techniques, likely to include tissue culture, western blotting, and real-time, reverse transcription PCR.
24) Tamim Shaikh, PhD (Human Genetics and Genomics)
The Shaikh lab investigates the genetic basis of neurodevelopmental and neuropsychiatric disorders. Their main focus is on identifying the genetic mutations that underlie multiple congenital anomaly syndromes (MCAS), which includes phenotypes like global developmental delay, intellectual disabilities and deficits, other neurological phenotypes such as seizure disorders, behavioral issues, etc., cranio-facial differences, cardiac defects and/or defects in other tissues and organs. Dr. Shaikh’s group uses high resolution genomic technologies including microarrays and high-throughput sequencing to identify genetic mutations in these patient samples. They have identified novel, pathogenic mutations in several candidate genes and are now beginning to analyze the effect of mutations in these genes using functional genomics approaches and animal models (mainly zebrafish).
25) Kurt R. Stenmark, MD (Pediatric Critical Care)
Pulmonary arterial hypertension (PAH) is a syndrome in which pulmonary arterial obstruction increases pulmonary vascular resistance, which leads to right ventricular (RV) failure and a 15% annual mortality rate. The Stenmark laboratory is interested in determining the cellular and molecular mechanisms that contribute to structural remodeling and resultant obstruction of the pulmonary vasculature and to right heart failure in the setting of pulmonary hypertension. Most work in this field has focused on changes in the behavior or resident vascular cells believing that these cells alone are the primary determinants of the vascular remodeling. However, several years ago, we were among the first to report that cells expressing progenitor cell markers appeared in the remodeled pulmonary hypertensive vessel wall along with a variety of other cells of hematopoietic origin (monocytes, macrophages, lymphocytes), in a variety of experimental models of pulmonary hypertension. We are thus extremely interested in determining the mechanisms that are involved in the recruitment of progenitor cells to the vessel wall and the right ventricle, their differentiation potential and fate, and ultimately their specific roles in vascular stiffening and remodeling and right heart failure.
26) Johan Van Hove, MD, PhD (Medical Genetics and Metabolism)
The field of medical genetics is rapidly advancing with the advent of whole exome sequencing. My laboratory examines disorders that affect the mitochondrion. The mitochondrion contains about 1000 proteins, and performs a very large number of biochemical reactions. We examine patients with genetic disorders of mitochondrial enzymes with an emphasis on either disorders of energy generation or disorders of neurochemistry such as infantile seizures. We identify new genetic causes of disease, we then examine the way in which the gene leads to the symptoms, and develop new treatments focused on the specific cause. Get more information about Denver Genetic Laboratories.
27) Rajeev Vibhakar, MD, PhD (Hematology/Oncology)
The Vibhakar lab is interested in studying the Biology of childhood brain tumors. We have several projects underway. One line of research understands the role of microRNAs in regulating tumor cell growth and control of brain tumor stem cells. Another major line of research involves identifying new molecular targets for potential therapy.
28) Karen Wilson, MD, MPH (Hospital Medicine)
Dr. Wilson’s research involves children’s exposure to secondhand tobacco smoke, and in particular the effect of secondhand smoke on children hospitalized for respiratory illness, and using the hospital stay to help smoking parents quit. We are currently developing an inpatient intervention for parents, and will be testing this over the summer. In addition, Dr. Wilson is working with other members of the Section on Hospital Medicine on projects that help to improve the quality and delivery of care to hospitalized children. Our research is more clinical and health services oriented, and involves recruiting and interviewing patients and their families, reviewing medical charts, and following quality measures.
29) Clyde Wright, MD (Neonatology)
Dr. Wright’s lab investigates the effects of Bronchopulmonary dysplasia (BPD) in very low birthweight infants. BPD affects 25% of the very low birthweight infants and leads to significant long term morbidity. BPD results in part from multiple inflammatory and oxidant insults encountered in the perinatal period. Exposure to hyperoxia is thought to contribute to the pathogenesis of BPD. The major focus of our research is to further define how the neonatal lung responds to toxic exposures of oxygen. Over 100 genes orchestrating the cellular response to these insults are regulated by the transcription factor NF-κB. Clinical studies have correlated NF-κB activation in the preterm lung to an increased risk of developing BPD. Our lab is working to define how NF-κB activation modulates hyperoxic injury in the newborn lung.
Learn more about the Student Research Program.