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Professor of Pediatrics
Office Phone: 202-476-5291
- B.S., Vanderbilt University, 1981
- MD, University of Tennessee, 1985
I have worked on the interface between molecular genetic bench research and clinical medicine since my earliest days in genetics. After my Pediatrics Residency at Vanderbilt (1985-88), I completed a fellowship in Research and Clinical Genetics with Dr. John Phillips (1988-90). During this period I developed the early gene linkage maps of human chromosomes 20 and 17 and after fellowship served as the Editor for human chromosome 2 for the Human Genome Project. My clinical work in inborn errors of metabolism led me to examine first the genetic location of many of these genes but then into molecular defects in these important biochemical pathways. Initially I focused on the rare and severe genetic forms of these diseases but transitioned into examining the effects of common functional genetic changes in biochemical pathways in common clinical diseases. Combining environmental severity with genetic diversity, has led my research into bringing the lessons learned from rare diseases into clinical trials. This has led to work in treating patients undergoing cardiac surgery and premature infants at risk for lung disease. During this time (1998-2010) I also served as director of the DNA cores at Vanderbilt University building a University wide resource for DNA isolation and characterization and developing the Vanderbilt biobank (BioVU) which currently houses over 100,000 samples from the Vanderbilt Clinics. Going forward at Children’s National Medical Center, my laboratory will continue to focus on using biochemical intermediates to treat conditions in critical care medicine and other environmentally stressful situations. Besides the satisfaction of working on affecting patient outcomes, this work has led to collaborations in a number of disparate fields including bioarchaeology.
Vanderbilt Children’s Hospital 1985-88 Pediatrics Residency
Vanderbilt Children’s Hospital 1988-1990 Medical & Biochemical Genetics Fellow
- Neill MA, Aschner J, Barr F, Summar ML. Quantitative RT-PCR comparison of the urea and nitric oxide cycle gene transcripts in adult human tissues. Mol Genet Metab 2009; 97(2):121-127.
- Mitchell S, Ellingson C, Coyne T et al. Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Hum Mutat 2009; 30(1):56-60.
- Eeds AM, Hall LD, Yadav M et al. The frequent observation of evidence for nonsense-mediated decay in RNA from patients with carbamyl phosphate synthetase I deficiency. Mol Genet Metab 2006; 89(1-2):80-86.
- Summar ML, Hall L, Christman B et al. Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I. Mol Genet Metab 2004; 81 Suppl 1:S12-S19.
- Pearson DL, Dawling S, Walsh WF et al. Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med 2001; 344(24):1832-1838.
- Canter JA, Summar ML, Smith HB et al. Genetic variation in the mitochondrial enzyme carbamyl-phosphate synthetase I predisposes children to increased pulmonary artery pressure following surgical repair of congenital heart defects: a validated genetic association study. Mitochondrion 2007; 7(3):204-210.
- Barr FE, Beverley H, VanHook K et al. Effect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery. J Pediatr 2003; 142(1):26-30.
- Barr FE, Tirona RG, Taylor MB et al. Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: potential therapy for postoperative pulmonary hypertension. J Thorac Cardiovasc Surg 2007; 134(2):319-326.
- Smith HA, Canter JA, Christian KG et al. Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline. J Thorac Cardiovasc Surg 2006; 132(1):58-65.
- Kemp BM, Tung TA, Summar ML. Genetic continuity after the collapse of the Wari empire: Mitochondrial DNA profiles from Wari and post-Wari populations in the ancient Andes. Am J Phys Anthropol 2009.
Inborn Errors of Metabolism: Our laboratory works on genetic defects in patients with urea cycle disorders. We have been engaged with this work at both the molecular and clinical level for the last 20 years. This work started with carbamyl phosphate synthetase I (CPSI), which controls flow through the hepatic urea cycle. We have found changes in this enzyme which affect the availability of downstream products such as citrulline and arginine. Much of our work in this area involves the characterization of the functional effects of these changes. We have developed Bacterial Artificial Chromosome Systems for testing these. Clinically we are a founding member of the NIH sponsored Urea Cycle Disorders Consortium of the Rare Disease Clinical Research Centers.1-3
Variations in Common Metabolic Genes and Effects on Health: We focus on variation in common housekeeping biochemical pathways and how these hold up under stress. Using the EDGE concept (Environmentally Determined Genetic Expression, see attached paper) we determine the factors involved in the interplay between the clinical situation (environment) and genetic factors that determine when a particular phenotype manifests. Using this information we work to develop both predictive tools and targeted treatments that take advantage of knowledge about the biochemical pathways involved. Working with clinician scientists (Dr. Rick Barr and Dr. Paul Moore among others) we have been able to maintain a balance of both bench and clinical projects looking at variation. We are currently working on pathways involving4-7 :
- Urea Cycle Metabolism
- Nitric Oxide Metabolism
- Glutathione Metabolism
- Fatty Acid Oxidation Metabolism
- Heavy Metal Transport System
Clinical Systems using common metabolic variants include:
- Pulmonary Hypertension
- Sub-arachnoid hemorrhage related vasospasm
- Post-cardiac surgery related pulmonary hypertension
- Bronchopulmonary dysplasia
- Asthma and Bronchiolitis
- Alzheimer's Disease
- Autism and Vaccines
Down Syndrome as a model of Gene Overexpression: With Dr. Aaron Bowman, we are developing a new vector system for the production of induced pleurpotent stem cells. We will use these to examine the effects of a variety of molecular changes (including trisomy 21) on cell behavior and development. We are also looking at baseline and stress condition markers of oxidant injury in patients with Down syndrome. Our primary model for this is the overexpression of hydrogen peroxide (trisomy 21 contains the superoxide dismutase gene) in cells and resultant oxidant injury. Our clinical studies include pulmonary hypertension in patients with DS and homocysteine metabolism. The theme is the effect of overexpression of genes in clinical disease.
Use of Metabolic Precursor Molecules in Treating Disease: In these studies we are using information from our common pathway variation studies to target the use of metabolic intermediate molecules on clinical situations. In collaboration with Dr. Rick Barr, pediatric critical care, we are examining the role of introducing nitric oxide precursor (citrulline) into pediatric cardiac surgery patients to modify the incidence of post-surgical pulmonary hypertension. With the neonatology group we are planning a project to examine the role of nitric oxide precursor (citrulline) in infants with persistent pulmonary hypertension of the newborn and those at risk for bronchopulmonary dysplasia. With our collaborator Dr. Brian Christman, we are conducting an intervention trial with patients undergoing bone marrow transplantation to offset the treatment related complications using biochemical intermediates. We are also examining the effects of the glutathione precursor gamma-glutamylcysteine on neuronal and other cells in offsetting oxidant injury.8, 9
Bioarchaeology: In our bioarchaeology lab we are exploring best methods to isolate and study DNA from ancient remains. We are working with the anthropology department to determine the genetic origins of ancient samples and the rates of genetic change from the 1400's to modern samples. We are working with the physics department on the use of lasers in cleaning the surface of the ancient samples from modern contamination.10
- Clinical and Translational Research
Industry Relationships and Collaborations
This faculty member (or a member of their immediate family) has reported a financial interest with the health care related companies listed below. These relations have been reported to the University and, when appropriate, management plans are in place to address potential conflicts.