The Research Affinity Group structure at Children’s Hospital reflects the increasingly interdisciplinary and multidisciplinary nature of many key research questions. This approach aligns with the emerging national consensus that multidisciplinary centers are essential to advancing the nation's research agenda.
The Institute designed the Research Affinity Group structure to build on areas of existing strength, identify new and important research areas, and explore important, broad and interdisciplinary scientific questions that may have an impact on the health of children. Our investigators now collaborate across disciplines more easily to address issues of central importance to children's health. This collaboration has the potential to link multi-talented investigators with common research interests who are widely dispersed through the Institute.
Here are our current Research Affinity Groups:
Fetal Biology and Therapy
Center Leader: Alan Flake, MD
The convergence of technologies in modern medicine suggests that, within the next decade, essentially all anatomic and genetic diseases could be diagnosed early in gestation. Early diagnosis could enable physicians to not only treat fetal disease, but also to anticipate childhood and adult disease.
The Fetal Therapy Research Affinity Group investigates the possibilities for treating many disorders during fetal development, which may provide a therapeutic “window of opportunity” for treatment.
As part of its mission, the affinity group facilitates interaction between a diverse group of Children's Hospital investigators interested in fetal biology and therapy. Investigators focus on fetal diagnosis and treatment, maternal aspects of fetal therapy, new methods of minimally invasive surgical or fetoscopic intervention, treatment of anatomic malformations and fetal stem cell or gene therapy.
Fetal therapy research is focused on a number of common fetal anatomic malformations, most notably prenatal surgical closure of myelomeningocele (MMC), a condition in which the backbone and spinal canal do not close before birth. Children's Hospital is one of three surgical centers in an ongoing federally sponsored clinical trial designed to compare prenatal surgical closure of MMC with standard postnatal treatment.
As part of this research endeavor, the affinity group recently developed an experimental MMC model that closely parallels the human form of the disease. This model is expected to allow for a more in-depth study of MMC and perhaps lead to new treatment strategies.
Other areas of research focus the affinity group centers on are congenital diaphragmatic hernia, a defect in the diaphragm that allows the abdominal organs to enter the chest cavity and the potential for using fetal tracheal occlusion as a treatment for lung hypoplasia, as well as pharmacological and gene therapy approaches to pulmonary vascular hypertension. To this end, fetal therapy investigators are developing models of congenital lung malformation and abdominal wall defects.
In collaboration with the Hospital's Center for Fetal Diagnosis and Treatment and the Fetal Heart Program, the Fetal Therapy Affinity Group is developing techniques for fetal cardiac intervention, specifically to open ventricular outflow tract obstructions to allow cardiac remodeling and prevent underdevelopment of the heart. Further investigations into experimental models of human anatomic defects may provide new insights into the pathophysiology of these disorders and allow for the development of new therapeutic approaches.
Hospital researchers are also investigating stem cell and gene therapy in utero. With the clinical goal of treating sickle cell disease and other hematologic disorders, investigators are aggressively pursuing strategies to increase engraftment of hematopoietic stem cells in the fetus and are making substantial progress toward improving donor cell homing to and engrafting in the fetal liver. Part of the stem cell research project involves strategies of highly selective myeloablation of the fetus using innovative reagents that specifically target hematopoietic stem cells and progenitors.
In utero gene therapy studies also involve investigations of early gestational injection methods using a high-resolution ultrasound system that allows microinjection into the amniotic space. This results in high efficiency transduction of epithelial stem cells in experimental models.
Genes, Genomics, and Pediatric Disease
Center Leaders: Nancy Spinner, PhD and John Maris, MD
Genetics is a discipline with unique implications for pediatric medicine and the field impacts all aspects of childhood healthcare. As new technologies have allowed for increasingly precise probing of the genome, the field has undergone tremendous growth in recent years. The completion of the Human Genome Project provided the essential roadmap for these studies, and the creation of robust methods for defining the entire genetic and epigenetic architecture of an organism or even an individual cell has catalyzed discoveries that are shaping modern pediatric clinical care.
Genetics and genomic research at Children’s Hospital is multifaceted and spans many divisions. These research efforts are conducted in the Genes, Genomes, and Pediatric Disease Research Affinity Group, which is led by Nancy B. Spinner, PhD and John M. Maris, MD The affinity group houses an outstanding program focused on the molecular genetic basis of human disease. Major recent advances include discovering the genetic basis of many human conditions, application of molecular diagnostics in the everyday clinical setting, discovery of the mechanisms by which genetic alterations lead to disease, and a translational genomics program that has led to new therapies in pediatric cancers and other conditions.
Because genomic medicine is by definition multidisciplinary, the GGPD research affinity group further enables ongoing collaborative research efforts at Children’s Hospital. The affinity group has a successful monthly chalk talk series for CHOP investigators, and a monthly seminar series that draws international experts from around the country. These activities provide a forum for establishing or extending collaborations with colleagues at CHOP, the University of Pennsylvania and at leading institutions worldwide.
Health and Behavior
Center leaders: Stephen Leff, PhD and Joel Fein, MD, MPH
Advances in neurosciences and the behavioral and social sciences have created new opportunities toward devising effective treatments and preventative approaches to reduce morbidity and enhance well-being. However, behavioral research faces unique challenges surrounding the essential components of research, and researchers cannot always easily find clear answers for their questions.
The Health and Behavior Research Affinity Group (RAG) serves as a forum for multidisciplinary research investigators to collaborate and gain a better understanding of the direct and indirect effects of behavior health on children. Behavioral outcomes, such as quality of life, functional impairments, and cognitive difficulties can be effective targets for intervention.
The goals of the Health and Behavior RAG are to strengthen the community of researchers in health and behavior research, enhance multidisciplinary and translational activities and initiatives, and provide leadership and support to the Children's Hospital community for research questions and activities related to behavior and child health.
Through a monthly seminar series and a yearly retreat, the Health and Behavior RAG brings together nationally-prominent investigators from highly-specialized disciplines to provide opportunities for mentoring and development, facilitate research accomplishments, and ultimately enhance the effectiveness of pediatric care for children and their families.
HB-RAG Feature: The Researcher
Laura A. Prosser, PT, PhD is a Research Scientist in the Center for Rehabilitation at CHOP. She earned a PhD at Temple University and completed post-doctoral research training at the National Institutes of Health (NIH) prior to joining CHOP in 2011. She also provides consultative physical therapy services in the Cerebral Palsy and Neonatal Follow-up Clinics. Dr. Prosser’s research focuses on optimizing neurorehabilitation treatments and learning how rehabilitation can induce helpful structural brain changes (neuropplasticity) in children with neurological injury. This includes investigating the developmental trajectories of impaired movement in children with early brain injuries, developing and testing the efficacy of novel interventions, and investigating the interaction between neuromaturation and rehabilitation-induced neuroplasticity.
During pilot work at the NIH, she demonstrated that a novel intervention based on principles of neuroplasticity and typical infant motor learning has potential to alter the trajectory of motor development in infants and toddlers with cerebral palsy, which may lead to greater function throughout the lifespan. She plans to open a clinical trial at CHOP in 2013 to expand this work. Cerebral palsy is the most common cause of pediatric physical disability and her past work has included biomechanical investigations of early walking patterns and the efficacy of interventions targeted at improving muscle performance and walking function in this population. She is also currently studying the motor and neuroplastic responses to a novel asymmetrical gait training program in children with hemiplegia from prior stroke. This work is in collaboration with investigators in Neurology and uses transcranial magnetic stimulation to understand rehabilitation-induced changes in the cortical control of muscles. This work will also establish a genetic repository to begin to investigate genetic factors that mediate response to rehabilitation in children with neurological injury.
Dr. Prosser’s work has been recognized by the American Academy of Cerebral Palsy and Developmental Medicine, the NIH Intramural program, and Temple University’s College of Health Professions. Since joining CHOP, she has established local and national collaborators, actively peer-reviews manuscripts for various journals, and serves on grant review panels for the American Academy of Cerebral Palsy and Developmental Medicine, the American Physical Therapy Association and the National Institute for Disability and Rehabilitation Research.
Dr. Prosser can be contacted at prosserl@email.chop.edu.
An archive of past featured researchers is also available.
Metabolism, Nutrition, and Physical Development
Center Leaders: Babette Zemel, PhD and Rebecca Simmons, MD
Disorders of nutrition and metabolism affect the majority of patient populations cared for at Children's Hospital. Failure-to-thrive, obesity and bone deficits are common complications in a wide variety of chronic conditions. Malabsorption, inflammation, reduced physical activity, altered dietary intake and medical treatments often have a profound effect on nutrient metabolism, growth, body composition, and health and disease outcomes. In addition, many of the major chronic diseases of adulthood, such as diabetes, hypertension, osteoporosis, cardiovascular disease and some cancers are nutrition-related and have antecedents in childhood.
The goal of the Metabolism, Nutrition and Development Affinity Group is to identify the causes and consequences of metabolic and nutritional disorders of childhood and to identify effective strategies for disease prevention and treatment. An additional goal is the prevention of obesity and nutrition related diseases in adulthood that have their origins in infancy and childhood.
The group boasts many multidisciplinary research projects across a wide range including gastroenterology, hepatology and nutrition, endocrinology, psychiatry, cardiology, hematology, nephrology, rheumatology, pulmonology, neurology, nursing, child development and neonatology. Obesity is a common theme across many of the specific areas of research. The obesity epidemic is a growing concern, and is increasingly becoming a problem in the pediatric patient population. Major research efforts include evaluation of behavioral and medical treatments for obese adolescents, practice-based obesity prevention and treatment, effect of obesity on bone strength, early life determinants of obesity and diabetes, prevention and treatment of diabetes, and the effect of obesity on sleep apnea, asthma and other pulmonary complications.
The State Tobacco Resettlement Act funded the project titled Risk Factors for the Pediatric Metabolic Syndrome to evaluate the contribution of obesity, obstructive sleep apnea, fasting insulin levels and family history of diabetes to overall glucose tolerance, insulin sensitivity, and lipid and blood pressure abnormalities. This study has shown relationships between disordered sleep, insulin resistance and other abnormalities associated with the metabolic syndrome such as lower adiponectin and HDL, and higher HbA1C and waist circumference. The State Tobacco Resettlement Act funds also support a new multi-center study of obesity led by Robert Berkowitz, MD, that provides office based obesity treatment in both urban and rural settings.
The research program led by Rebecca Simmons, PhD, is focused on elucidating the underlying molecular mechanisms that link the abnormal milieu of diabetic or obese pregnancies to the development of obesity and type 2 diabetes in offspring. Having developed a number of models of diabetes and/or obesity in pregnancy, Dr. Simmons' research has determined that this abnormal metabolic environment induces epigenetic modifications in key genes that regulate β-cell and adipocyte development. One study of newborns whose mothers had diabetes during pregnancy was conducted to determine whether diabetes in pregnancy alters genomic DNA methylation in genes important for regulating glucose homeostasis, and whether these epigenetic changes permanently alter gene expression, resulting in an adverse phenotype. To test this hypothesis investigators are using a novel technology to compare genome-wide cytosine methylation in amniocytes and in a single population of CD34+ cells derived from the cord blood of newborns of mothers who have diabetes.
Abnormalities of growth and body composition in children with chronic diseases are another major research theme in the Metabolism, Nutrition and Development Affinity Group. Various research projects are underway to describe the timing, magnitude, causes and consequences of growth failure and altered body composition in children with sickle cell disease, cystic fibrosis, Crohn disease, renal insufficiency, juvenile rheumatoid arthritis, Down syndrome, intractable epilepsy, liver disease, lupus erythymatosis and cardiac malformations. As part of a current ongoing collaboration, Barbara Medoff-Cooper, PhD, RN; Virginia Stallings, MD; and Babette Zemel, PhD, have identified patterns of growth failure in infants after cardiac surgery, demonstrating the need to develop nutritional care intervention strategies for these at-risk infants. Another set of collaborative studies, directed by Dr. Stallings and conducted over the past 15 years, have identified numerous nutritional deficiencies and potential treatment strategies for children with sickle cell disease. This series of studies has identified increased energy requirements, poor growth and delayed maturation, and deficiencies of zinc, vitamin D and vitamin A. A study on zinc supplementation demonstrated the benefits of this important nutrient for improved growth. Investigators are now studying vitamin A supplementation to determine the effect of improved vitamin A status on frequency of hospitalizations and sickle cell-related illness episodes.
Another major research focus is skeletal development and the effects of nutrition, inflammation and obesity on bone density, the attainment of peak bone mass and fractures. Mary Leonard, MD, MSCE; Sandy Burnham, MD; and Meena Thayu, MD, are conducting studies of children with renal, rheumatologic and gastrointestinal disorders to examine the effects of medication use, disease effects and physical activity on bone density and strength. Nicolas Stettler, MD, MSCE, has recently initiated a study of the effects of weight loss treatment on bone accrual in obese adolescents. Dr. Zemel has several studies of bone development in healthy children to improve our understanding of the normal patterns of development of the skeleton.
Another major focus of the RAG is to foster career development of junior investigators. We established the Pilot and Feasibility program, which is intended to provide support for both junior and established investigators to collect preliminary data sufficient to support a federal RO1 grant application for independent research support. We solicited submission of applications for support to perform pilot and feasibility studies in nutritional sciences, obesity and related disorders. To date, we have funded three projects. The first is a collaboration led by Myles Faith, PhD, Dr. Medoff-Cooper and other members of the affinity group to examine the genetics of feeding style and body composition in twin infants. Two new investigators, Andrea Kelly, MD, and Jon Burnham, MD, were recently awarded pilot grants.
These projects focused on determining whether vitamin D supplementation improves bone health in children with lupus and the effects of vitamin D supplementation on body composition and markers of inflammation in children with cystic fibrosis. The RAG has also provided funds for a study of vitamin D status in children with perinatally acquired HIV infection.
In addition, researchers in the affinity group investigate biliary atresia and bile duct development through the Fred and Suzanne Biesecker Center for Pediatric Liver Disease. Bringing together experts across hospital disciplines, such as gastroenterology, human genetics and pathology, the affinity group also partners with the adult liver program at the University of Pennsylvania.
Affinity group members participate in several seminar series to promote interdisciplinary interactions and generation of innovative lines of research. At Children's Hospital these include the Nutrition Center Seminar Series and the Seminars of the Division of Pediatric Endocrinology. At the University of Pennsylvania RAG members attend the seminar series held by the Institute for Diabetes, Obesity and Metabolism, the Penn Center for Musculoskeletal Disorders, and the Center for Clinical Epidemiology and Biostatistics.
Mitochondria
Center Leader: Marni Falk, MD
The Mitochondrial Research Affinity Group has been created to address the needs of the diverse community of researcher engaged in mitochondria-focused research. Due to the importance of mitochondrial biology in many forms of disease, the clinical backgrounds of these investigators are wide-ranging and include clinical genetics, metabolism, endocrinology, anesthesiology, hematology, oncology, gastroenterology, neonatology, immunology, neurology, pathology, and ophthalmology. The basic science affiliations of these investigators are equally wide-ranging and include pathology, biochemistry and biophysics, biology, genetics, metabolism, animal biology and anthropology.
The goals of the Mitochondrial Research Affinity Group include improved collaborations in mitochondrial research, enhanced interaction between graduate students and faculty, and increased familiarity with research programs involving mitochondria at the University of Pennsylvania and beyond. Our activities will include a regular schedule of talks by group members, special events with invited experts, and a grant program for the purpose of furthering mitochondrial investigations.
Mitochondria are experiencing a scientific and medical renaissance. It was recognized in 1988 that mitochondrial DNA mutations can contribute to human disease. At that time it was thought that the function of these cellular organelles was generally understood. However, mitochondria are increasingly being recognized as having a complex and widespread role in contributing to many common disorders.
Mitochondrial function has been found to play a role in disorders such as non-insulin dependent diabetes mellitus, Parkinson's disease, Alzheimer's disease, Huntington disease, hearing loss, stroke, liver disease, renal disease and cancer. In addition, a mitochondrial basis is increasingly becoming clear for rare pathologies that cross all ages and many medical specialties. Specific examples include Leigh syndrome, rhabdomyolysis, cardiomyopathy and conduction defects, ophthalmologic problems including optic neuropathy and ophthalmoplegia, and the hereditary spastic paraplegias.
The mitochondrial respiratory chain has been implicated, to varying extents, in the pathophysiology of volatile anesthetic metabolism, aging, free radical generation and scavenging, calcium homeostasis, and programmed cell death. Recognition of the importance of mitochondrial function to human health has expanded so significantly that a Roadmap Initiative in Mitochondrial Disease is now under consideration at the National Institutes of Health.
From a pediatric perspective, mitochondrial disorders of energy generation collectively comprise the most common group of inherited metabolic disease, with a minimum lifetime prevalence of one in 5,000. The current diagnostic evaluation of suspected mitochondrial disease is invasive, costly, and unfortunately, has less than a 50 percent likelihood of identifying a clear etiology. As mitochondrial dysfunction impacts pediatric health across all specialties, it is imperative that research efforts be directed at clinical questions to improve diagnostic approaches and therapies, and basic questions to better understand the biological role of mitochondria in disease.
Dozens of faculty members at The Children's Hospital of Philadelphia are pursuing mitochondria-focused research. Due to the importance of mitochondrial biology in many forms of disease, the clinical backgrounds of these investigators are wide-ranging and include clinical genetics, metabolism, endocrinology, anesthesiology, hematology, oncology, gastroenterology, neonatology, immunology, neurology, pathology, and ophthalmology. The basic science affiliations of these investigators are equally wide-ranging and include pathology, biochemistry and biophysics, biology, genetics, metabolism, animal biology and anthropology.
The Mitochondrial Research Affinity Group has been created to address the needs of this diverse community. Our goals include improved collaborations in mitochondrial research, enhanced interaction between graduate students and faculty, and increased familiarity with research programs involving mitochondria at the University of Pennsylvania and beyond. Our activities will include a regular schedule of talks by group members, special events with invited experts, and a grant program for the purpose of furthering mitochondrial investigations.
Neuroscience
Center Leader: Michael Robinson, PhD
A startling number of children are afflicted with diseases of the nervous system. These disorders include epilepsy, stroke, head trauma, autism and attention-deficit hyperactivity disorder. In addition, many genetic disorders, such as inborn errors of metabolism, manifest with primary brain dysfunction. Concern for pediatric health related to these disorders has heightened because of evidence that some have had an increased incidence over the past three decades.
Although some of these disorders, like stroke, have been traditionally associated with the elderly, recent studies suggest that children are also at risk. Additionally, the incidence of autism and seizures are troubling. These disorders collectively place a significant strain not only on children and their families but also on society.
Children's Hospital follows the largest and most diverse population of children with neurologic, psychiatric and developmental disabilities in the country. Outstanding clinical and basic researchers complement the clinical care programs throughout the Hospital. The Neuroscience Research Affinity Group facilitates the development of targeted investigation and fosters the interactions necessary to rapidly translate research into best clinical practices. The affinity group targets four areas of research priorities: neuroprotection, epilepsy, stress biology and autism/complex neurobehavioral disorders.
Neuroscience investigators are currently conducting a pediatric stroke program and a multi-site study of the incidence and outcomes of stroke in children and adolescents. Researchers are also investigating the changes in neurons that lead to epilepsy and to understanding how a ketogenic diet – high in fat, low in carbohydrates and protein – reduces seizure frequency. Autism research is conducted with the support of the Regional Autism Center (RAC), which provides assessment and management for research in children and adolescents with autistic spectrum disorders.
In addition, affinity group members are actively involved with the Intellectual and Developmental Disabilities Research Center (IDDRC), which has been active for the past 15 years. This center strives to coordinate and enhance mental retardation research at Children's Hospital and the University of Pennsylvania. It provides services to more than 90 NIH funded projects with an aggregate value of more than $12 million.
Children's Hospital researchers also benefit from the Center for Dynamic Imaging and attention-deficit hyperactivity disorder primary care center. By creating clinical centers that focus on specific disease groups, investigators can develop disease-based research models that may be used to produce targeted treatment approaches for a variety of conditions.
The neuroscience research community is strengthened by the Neurodevelopmental Disabilities training grant that supports postdoctoral fellows, the Leadership Development through Interdisciplinary Training – commonly known as LEND – and yearly fellows' poster day, where post-doctoral trainees present their research to the community. The group also organizes seminar series and meetings to attract esteemed scientists from around the world.
Normal and Malignant Hematopoiesis
Center Leader: Carolyn Felix, MD
Gene and protein networks that signal blood cell maturation from primitive bone marrow progenitor cells, as well as networks that regulate the balance of cell growth and cell death, are especially relevant to hematopoiesis. Research at Children's Hospital into this field focuses on networks that regulate the development of specific blood cell elements in normal and diseased states. The Normal and Malignant Hematopoeisis Research Affinity Group aims to address problems in these networks to develop targeted prevention and more effective treatments for disordered hematopoiesis, leukemia and lymphoproliferative diseases in children.
The progenitor cells in the hematopoietic system give rise to heterogeneous cell populations – red and white blood cells, as well as platelets – that execute specific functions. Technologies like gene expression profiling and proteomics have revealed global pictures of the networks that distinguish specific blood cell elements in normal and malignant states. Current research in the affinity group involves deciphering which elements in these networks can be targeted for new treatments and, ultimately, for preventing diseases of the hematopoietic system.
The Normal and Malignant Hematopoeisis Research Affinity Group brings together investigators engaged in clinical, translational and basic research who are skilled in oncology, hematology, stem cell transplantation, cytogenetics, biochemistry, epidemiology, pharmacology, pathology, immunology, cell biology and bioinformatics. Linking new technologies and knowledge integration hold promise for better diagnosing, treating and preventing pediatric diseases of the hematopoietic system.
Recent hematopoesis research at Children's Hospital is focused on leukemia, the most common childhood cancer, and its two major subtypes: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Whereas most children diagnosed with ALL can be cured, the prognosis remains poor for the 20 percent of patients diagnosed with AML.
Hospital researchers are focused on synergistic studies with the long-term goal of developing preventative strategies and leukemia-specific treatments for various forms of pediatric AML. A form of AML, which occurs as a complication of anticancer chemotherapy, has an especially poor prognosis. One project examines how disruption of the cellular protein called topoisomerase II causes chromosomal breakage that leads to AML. A mechanistic understanding of the cause of this form of AML could lead to safer chemotherapy regimens and protective compounds.
Another focus of hematopoesis research in the affinity group is GATA-1, a critical transcription factor protein that programs the expression of genes in blood cell development. Patients with Down syndrome are especially susceptible to AML, and the GATA-1 transcription factors is abnormal in the form of AML associated with Down syndrome.
Investigators in this affinity group are also pursuing a strategy to reduce the complications and mortality from infections associated with intensive AML treatment regimens by determining individual genetic variations that underlie infection risk.
Other affinity group research is focused on dissecting signaling pathways in immune cells called NKT cells to determine their role in the immune response, which may prove relevant to the development of immunity against tumors.
These interdisciplinary projects ultimately have potential to advance the current knowledge on normal and malignant hematopoiesis as well as to translate knowledge on the science of hematopoiesis to reduce morbidity and mortality in heterogeneous forms of leukemia in children.
Activities of the research affinity group, including a rich seminar series and annual retreat, facilitate the progress of an ever-expanding web of researchers with a common interest in broad areas of hematopoiesis within the CHOP Research Institute, the Children's Hospital campus and beyond. This avenue to combining expertise in specific areas from new interchanges beyond the clinic and the individual laboratory will speed the Hospital's advances in promoting bench-to-bedside research.
Proteins
Center Leader: Yair Argon, PhD
Most diseases are caused by malfunctions of a protein. A defective receptor may preclude proper function of pancreatic cells; an altered protein may lead to malignant transformation, or the inability of a hormone to be secreted may lead to abnormal organ development. Understanding the changes in the expression or function of proteins is therefore key to developing therapies.
Gaining such understanding, however, is no small feat because each of the 30,000 genes in human DNA can encode more than one form of a protein, increasing the complexity of the information contained in DNA. In addition, not every pathologic change is due to a single gene mutation. In many diseases, the alteration is in an atypical realignment of interacting proteins.
Research conducted in the Proteins and Disease Research Affinity Group focuses on this problem by investigating how proteins function, how they interact, and how they differ between normal and diseased tissues. Several investigators in the affinity group measure how receptors on the surface of cells transmit information that leads to growth and differentiation of the endocrine or the immune systems. Their work interfaces with that of another group of investigators who are interested in viral infections, since viruses often “highjack” normal cellular proteins.
Another critical area of the affinity group's investigation lies with markers of disease, or protein patterns that are expressed differently in people with a particular disease. Some investigators are relating modifications common to many proteins, such as additions of phosphate or nitrate, to alterations in the functions of key metabolic enzymes in normal and defective neonatal development.
Yet a third focus is the question of how proteins misfold, lose their proper structure and therefore become dysfunctional. Three research groups are studying how a special set of cellular proteins, called molecular chaperones, either protect other proteins from misfolding or correct the defect, in the context of cystic fibrosis, systemic amyloidosis and thalassemia.
A new focus of the group is proteomics, cataloging all the proteins present in a given tissue at a particular stage of pathological state. Knowing these protein patterns will greatly enhance the current wealth of genetic information about a variety of diseases.
A new technique developed by the affinity group separates complex protein mixtures by multi-dimensional chromatography into hundreds of discrete fractions, and has already improved upon the enumeration of proteins that are present in diseased and normal tissues. Being able to identify rare proteins may uncover those that play important roles in an individual disease.
These research advances hold the promise of discovering signature patterns – proteins that are found consistently in patients with a specific disease – that will become diagnostic tools.
The Proteins and Disease Affinity Group provides a forum for investigators from a variety of divisions to work together, improving the effectiveness of their research. Shared instruments in the Protein Core Facility, a seminar series featuring outside speakers, a monthly in-house lab meeting and a multi-investigator seed project all allow group members to interact and gain feedback on ongoing research.
Vaccines and Immunotherapies
Center Leader: Terri Finkel, MD, PhD; Co-leaders: Steven Douglas, MD; with Paul Offit, MD
Researchers harnessed the protective powers of the immune system for medicinal purposes with the development of modern vaccines more than a half-century ago. Nevertheless, infectious diseases remain the leading cause of death for children around the world, and researchers are exploring new ways to use vaccine technology to eliminate this threat.
The immune system sometimes continues its attack long after it eliminates the invading disease. Immune system dysfunction is involved in autoimmune disorders as varied as asthma, inflammatory bowel disease and rheumatoid arthritis. While autoimmune disorders often develop during childhood, they are debilitating chronic illnesses that last a lifetime. As discoveries in the laboratory shed light on the healing potential of the immune system, vaccines will be developed to correct autoimmune disorders by halting the immune system's mistaken attack on the body itself.
New vaccines also are being developed to help the immune system recognize and eliminate cancer. Unlike infectious diseases against which the immune system is prepared to defend, cancer evades detection. Unfortunately, traditional treatments designed to kill cancer also destroy healthy cells, leaving the immune system weak and the body defenseless.
Because numerous diseases involve a component of immune system dysfunction, the Vaccines and Immunotherapies Affinity Group – including researchers from such different fields as cancer research, gene therapy, immunology, infectious disease, rheumatology and vaccine development – is applying shared knowledge toward a better understanding of the immune system and its powers to protect and heal.
Infectious disease research at the Hospital is focused on developing a safe and effective vaccine against rotavirus, the most common cause of diarrhea and dehydration in children. One product of this research is a newly developed oral vaccine delivery system that could one day eliminate the need for needles, making vaccines easier and more cost effective to administer, especially in the developing world.
In 2006, the U.S. Food and Drug Administration approved RotaTeq®, the rotavirus vaccine developed at Children's Hospital and The Wistar Institute and further developed by Merck & Co. The federal government's Advisory Committee on Immunization Practices now recommends that the vaccine become part of the routine infant immunization schedule.
Another infectious disease with global impact is HIV. Standard vaccines for HIV have so far proven ineffective because the virus has evolved to include sophisticated methods for evading detection by the immune system. Hospital researchers are working to understand how HIV invades cells and evades detection by the immune system and designing compounds and delivery systems that target the cells that HIV invades.
For example, investigators are supported by NIH-funded program project, translational research, and biotechnology grants to develop new therapeutics and vaccines against HIV. Clinical trials of pediatric AIDS treatments in development are conducted through the Philadelphia International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Unit, located collaboratively at the Children's Hospital and the Hospital of the University of Pennsylvania.
Refining treatments for neuroblastoma, the most common and deadly form of solid-tumor cancer in children, is another focus of this research affinity group. Until recently, the standard of care for children with neuroblastoma – a combination of surgery, chemotherapy and stem cell transplantation – achieved survival rates of only 35 percent. Investigators are focused on new ways to boost the natural immune response of patients during recovery from stem cell transplantation, a time when patients are extremely vulnerable to life-threatening infections or relapse of cancer.
In addition, Children's Hospital researchers are developing a better understanding of autoimmune disorders, the role of genetics and the ways in which infectious diseases alter immune system functioning. Investigators are working to develop immune therapies for juvenile rheumatoid arthritis, dermatomyositis and lupus using an immune therapy designed for treating lymphoma. Researchers are also investigating the high vaccine failure in children with certain genetic disorders causing immunodeficiency and autoimmunity, and are developing strategies for enhancing vaccine delivery.