The George and Jean Brumley , Jr.
Neonatal-Perinatal Research Institute
Division of Neonatology, Department of Pediatrics
Duke University School of Medicine
Intoduction:
The Neonatal-Perinatal Research Institute (NPRI) was created in 1996 as a multidisciplinary platform to address health problems of the newborn child through translational research programs and to train the next generation of physician-scientists to continue addressing these problems in the most productive manner.
The research mission of the NPRI includes basic research into the etiology and pathogenesis of birth defects, and prenatal and neonatal injury in a variety of animal models; clinical research focuses on the causes of neonatal brain and lung injury and their sequellae in later childhood; and finally, research in health policy, health economics and medical informatics aims to surmount barriers to appropriate medical care for affected patients and their families.
The educational mission of the NPRI is directed towards creating academic leaders in research and translational medicine directed specifically to neonatal well-being.
Background:
According to the March of Dimes, about 150,000 babies are born with birth defects each year in the United States . The American College of Obstetricians and Gynecologists (ACOG) reports that for every 100 babies born in the United States , three will have some kind of major birth defect. In North Carolina between 3,000 and 4,000 infants are born with serious birth defects, of which about 200 die before their first birthday. Birth defects are defined as abnormalities of structure, function, or body metabolism that are present at birth. These abnormalities lead to mental or physical disabilities or are fatal. The causes for most birth defects are unknown but they are currently thought to be the result of genetic, environmental, or unknown factors.
In addition to birth defects, low birth weight is a major factor in neonatal health. In the United States over 250,000 low birth weight infants are born each year. These infants often have a constellation of problems that affect their successful adaptation to extrauterine life. This may result in both acute and chronic problems that often exist beyond infancy. In North Carolina , low birth weight rates have risen from 7% to 9% in the past 10 years; and in 2001 the state was ranked 42 nd with regard to high infant death rate. The impact of infant morbidity extends far beyond the hospital delivery rooms and nurseries and into society at large. For the afflicted child, a serious neonatal/perinatal problem can result in life-long physical and psychological suffering. This human tragedy coupled with an economic burden exceeding $2 billion per annum, demand that effective solutions be found.
The Neonatal-Perinatal Research Institute was created to provide a dedicated environment wherein investigators from different fields could participate in collaborative multidisciplinary research aimed at understanding the basis of key problems suffered by neonates and to train the next generation of physician- scientists.
The NPRI was founded in 1996 by Dr. Ronald Goldberg , present Division Chief, with the support of the late Dr. George Brumley , Jr. , past Division Chief of the Duke Neonatal-Perinatal Program. The mission of the NPRI is three fold - to discover the bases for birth defects and neonatal injury of the brain and lungs and translate the findings into clinical practice; to address issues of health policy as they affect newborn care; and to educate the next generation of physician- scientists to this endeavor. Since it was founded, the NPRI has grown to a successful, multimillion dollar endeavor affiliated with 70 senior investigators supported by a variety of external funding agencies. Since 1999, these faculty have trained 15 clinician-scientists.
Research Focus:
The NPRI hosts a wide range of research initiatives by investigators with primary appointments in traditional departments including Cell Biology, Neurobiology, Nursing, Immunology, Pharmacology, Cardiology, Neonatology, Neurology, Pediatrics, Psychology, Maternal-Fetal Medicine, Anesthesiology, Pediatric Critical Care, Medical Ethics, Medical Genetics, The Pratt School of Engineering, Biomedical Engineering, Medical Informatics and Optics, Institute for Genome Sciences and Policy, Center for Human Genetics, Fuqua School of Business and the Duke Clinical Research Institute.
Topics under investigation fall under three major groups: basic, clinical, and public policy research. Basic research includes major initiatives in the causes of birth defects that particularly affect the cardio-craniofacial field and left-right cardiac axis determination, and the perinatal mechanisms of disrupted development and post- natal injury with special emphasis on lung, brain, and heart. Clinical research addresses the problems of low birth weight infants, morbidity and mortality, perinatal asphyxia, ventilatory management, growth and development of high risk infants and the role of genomics in neonatal morbidity. Finally public research has led to new techniques to improve financial management necessary for the care of our patients.
1) Birth Defects:
Birth defects are the result of multifactorial causative agents however, in recent years many congenital defects have been linked to genetic mutations. Research by NPRI investigators focuses on the role of genetic and cellular etiologies of birth defects that are the leading causes of infant mortality in the United States . Congenital malformations of the heart and neural tube are the most common serious birth defects, and are the subject of intense investigation in the NPRI.
2) Neonatal Brain and Lung Injury:
A major interest of the NPRI is to elucidate basic mechanisms underlying the stereotypic features of inflammation, injury and repair that disrupt normal perinatal and neonatal development. The NPRI encourages skilled investigators with expertise in brain, lung and cardiovascular injury to cooperate in the development and use of clinically relevant animal models, incorporating perinatal inflammation, oxidative and ischemic injury, and premature labor.
3) Translational/Clinical Research:
Clinical projects conducted under NPRI auspices include co-sponsoring of NICHD Neonatal Network research studies as well as Division of Neonatology research projects. The NPRI's success in clinical research was highlighted by the awarding of the very first Duke Translational Medicine Award to NPRI investigators. Specific areas of interest include neonatal pulmonary hypertension, pulmonary injury and lung function and the role of genomics in neonatal inflammatory infection and brain injury.
The Division has played a major role in developing the NICHD-Neonatal Research Network DNA repository which is housed at Duke. NPRI-sponsored support for projects in Health Policy and Health Economics has provided monetary resources for six Master degree candidates as well as initial seed support of the research projects of 22 fellows and 23 NPRI faculty.
C. NICHD-Sponsored Fellowship Training:
The second major initiative of the NPRI is to train the next generation of clinical-scientists. Our goal is to have an impact on the health of neonates by training leaders in scientific investigation (clinical as well as basic) in developmental and biology problems of neonates. This is assured by the exceptionally talented basic and clinical mentors available to our trainees and the linking of the Duke Masters Programs in Genomics and Clinical Research, Bioinformatics and Health Policy to specific scientific research opportunities. The quality of the training program is reflected in the quality of its graduates and NICHD Fellowship Training Grant awarded in 2005.
D. Funding
Intramural funding for the NPRI was originally from the Division of Neonatology and the Duke University Medical Center who provided $1 million in start-up support for service provided by the Division.
Extramural support comes from various sources including private donors. The NPRI secured substantial philanthropic research funding from outside the University such that its total current endowment is in excess of $2.7 million, ensuring ongoing stability of the program. Using these funds, the NPRI awards research and educational grants to fellows and junior faculty members to support multidisciplinary collaborations (see NPRI Grants for Small Projects).
NPRI funding is from individual investigators in the NPRI is through the National Institutes of Health, Zeist Foundation, pharmaceutical companies, The Duke Endowment and other private philanthropic organizations. The majority of this funding is the result of NPRI sponsored research programs. Investigators in the NPRI and Division of Neonatology alone have over $16 million in NIH funding during the current year with another $3 million from other sources.
E. Scientific Endowment
Recently, the Zeist Foundation has endowed the George and Jean Brumley, Jr. Neonatal-Perinatal Research Institute, providing two endowed chairs for basic scientists and additional programmatic support. The NPRI has been designated as a key program in the Dean 's 10 year strategic research development plan.
F. Laboratory Resources
NPRI lab space totals approximately 7,000 and is located in the Bell , Sands and Cell Biology in the GSRB II building.
G. NPRI Affiliated Programs at Duke
H. DUMC Mycology Research Unit (DUMRU)
The DUMRU and the Duke Antimicrobial Trials Unit (ATU)
, which engages in translational research at the interface between basic science and clinical interventions. The ATU has collectively participated in over 20 clinical trials with antifungal agents in the past three years. These include pivotal trials and newer antifungal agents in adults and children. In addition, Duke has several outstanding clinician-scientists engaged in molecular fungal research including Gary M. Cox , M.D. , and Aimee Zaas, M.D. Drs. William Steinbach , Daniel Benjamin and Brian Smith , a Neonatology fellow, perform translational research in invasive mycoses in the pediatric and neonatal patient populations, respectively. DUMRU is supported by an NIH program grant to continue an interdisciplinary research approach to increase out understanding of the pathobiology of medically important fungi. Initially this group received NPRI funding and subsequently has also recently received an NIH program award to further develop nanotechnology approaches to diagnosis of fungal sepsis and bacterial pneumonia with a focus on candidemia.I. Metabolomics/Biomarker Core
The Sarah W. Stedman Nutrition and Metabolism Center at Duke has developed a research-dedicated metabolomics.biomarker laboratory. This laboratory was created by Dr. C. Newgard and Dr. D. Millington . Currently the Stedman Center laboratory employs gas chromatography GC/MS and tandem MS to measure 100 "targeted" intermediary metabolites of known identity in 4 classes: a) free fatty acids, b) acyl carnitines, c) organic acids and d) amino acids. The Stedman Center is in the process of expanding the capabilities of this targeted platform to include other analyte "modules," including phospholipids, sphingolipids, and a larger array of glucose-derived metabolites with an ultimate goal of creating a platform that provided targeted analysis of 300-400 individual metabolites. When complemented with the aability to measure key hormones of energy balance and metabolic hemostasis, pro- and anti-inflammatory cytokines and physiologic variables, this platform has the capacity to provide metabolic profiles that may allow insight into the broad impact of various intervention strategies.
J. Duke Clinical Research Institute (DCRI)
The DCRI, directed by Dr. Robert Califf , is the largest Academic Research Organization (ARO) in the world. The DCRI has received worldwide recognition for performing some of the largest and most influential clinical trials and outcome studies in medicine. The DCRI has over 800 employees, over 100 faculty and 40 Ph.D. and Masters level quantitative experts. This provides the DCRI with a significant ability to conduct research. At present, 97 randomized clinical trials are being performed by faculty and staff of the DCRI. The DCRI has a long history of cardiovascular research ranging from large scale claims database analysis to clinical database analysis to large clinical trials. This effort is now being broadened to include multiple clinical disciplines. A main objective of the DCRI is organizing collaborative clinical investigation and developing partnerships among centers, among disciplines and among investigators to provide a more efficient methodology for performance and dissemination of research. Current large-scale trials involve more than 2,000 hospitals and practices in over 30 countries. The DCRI has played an important role in translation of the collaborative basic research of Dr. Stamler and members of the Division of Neonatology, specifically Dr. Ron Goldberg and Dr. Martin Moya, a former fellow, to trial.
K. Duke Center for Human Genetics (CHG))
The Duke Center for Human Genetics has teamed with Neonatology faculty to develop the NRN's Anonymized DNA Bank and development of the genomic approach to neonatal disease. The CHG and its faculty are committed to the success of the NRN's efforts in Genomics. The CHG organizes its resources into two research cores: the Family Studies and Bioinformatics Core and the Genomics Resource Laboratory Core. CHG core-generated data is stored, integrated and analyzed using PEDIGENE ® , an internationally acclaimed CHG-designed computer data management system. As one of the largest and oldest academic DNA banks in the United States , the CHG DNA Bank and Tissue Repository is a cornerstone of our genomic research effort providing rapid, low cost, high quality DNA extraction and associated services to human genome researchers. Genotyping information from samples stored in the NRN bank will be directly entered into the NRN Coordinating Center 's linked database. The Family Studies and Bioinformatics Core is headed by CHG Director Margaret Pericak-Vance , Ph.D. This core centralizes essential aspects of gene identification including Genetic Epidemiology, Family Ascertainment and Bioinformatics. The Genomics Resource Laboratory Core is headed by Jeffrey Vance , M.D. , Ph.D. The Genomic Laboratory houses the CHG molecular biology unit. These molecular biologists apply the latest genetic laboratory techniques to identify disease genes. The Genomics Research Laboratory posses the technical and physical resources that support CHG research projects. These resources include 1) high-throughput genotyping, 2) mutation and polymorphism detection, 3) physical mapping and 4) sequencing and gene expression analysis. With its well-equipped and highly automated screening technology, this core conducts rapid sample isolation and analysis. The resulting data are managed and stored via the PEDIGENE ® system. The Genomics Research Laboratory is home to the CHG DNA Bank and Tissue Repository which contains over 100,000 DNA samples from patients and families.
L. Duke Institute for Genome Sciences and Policy
The IGSP consists of a multidisciplinary network of Centers and programs that together form an integrated approach to advancing the Genome Revolution and addressing its implications for health and society. Each of the following Centers provides core competencies and areas of scholarship that comprise the comprehensive scope of the IGSP's mission: 1) Center for Applied Genomics and Technology, 2) Center for Genome Ethics, Law and Policy, 3) Center for Genomic Medicine, 4) Center for Bioinformatics and Computational Biology, 5) Center for Models of Human Disease, 6) Center for Population Genomics and Pharmacogenetics, and 7) Center for Evolutionary Genomics. While the IGSP is the major focal point on campus for the study of genome sciences and policy, it collaborates with other multidisciplinary research units at Duke doing related work in genomics. Duke Neonatology clinical research faculty have had its most direct interactions with the Center for Genomic Medicine and its Director, Geoffrey Ginsburg , M.D. , Ph.D. The Center's mission is to identify unique characteristics in both biospecimens and in the individual risk assessments that may define individual prognostic models and indicators of appropriate therapeutic interventions. It is dedicated to the development of clinico-genomic information that can be used for making medical decisions.
M. Microdigital Fluidics
The overall objective of this collaboration is to explore microfluidics for clinical blood reduction strategies. The Pratt School of Engineering and Advanced Liquid Logic Inc. are currently exploring the feasibility of an integrated microfluidic lab on-a-chip for fully automated clinical diagnostics on nanoliters of physiological samples. We will mainly focus on developing protocols and strategies for performing clinical chemistry and molecular diagnostics for point of care applications. Current diagnostic instruments are incapable of handling nanoliter sample volumes and are also unfit for performing the analysis in the field. Our long-term goal is to develop a portable, automated, and inexpensive platform for clinical diagnostics.
Ask for the neonatologist on call at: 1-800-MED-DUKE (1-800-633-3853) or dial the pager directly at: (919) 970-1714. Phone (919) 668-1592 Fax (919) 681-6065 |
