Jonathan D. Gitlin, M.D.
Helene B. Roberson Professor
Pediatrics
Genetics
Director, Children's Discovery Institute
Molecular Genetics and Genomics Program
Developmental Biology Program
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Office Phone: 314-286-2764
Lab Phone: 314-286-2836
Other Phone:
FAX: 314-286-2893
Box: 8208
Lab Address: 7110 McDonnell Pediatric Research Building
Email: gitlin@wustl.edu
Website: http://peds.wustl.edu/faculty/Gitlin_Jonathan_D/
Keywords: genetics; biochemistry; development; zebrafish
Short Research Description: Molecular genetic mechanisms of human nutrition. |
Research Abstract:
Our laboratory is interested in fundamental aspects of human nutrition. Copper is an essential nutrient that plays a critical role in the biochemistry of all aerobic organisms. Proteins exploit the unique redox nature of copper to undertake a series of facile electron transfer reactions required for cellular respiration, iron homeostasis, pigment formation, neurotransmitter production, peptide biogenesis, connective tissue biosynthesis and antioxidant defense. The reactivity of copper in biological systems also accounts for the potential toxicity of this metal when cellular copper homeostasis is disturbed. For this reason, specific pathways have evolved for the trafficking and compartmentalization of copper within cells.
One goal of our studies is to understand the pathways of nutrient trafficking and metabolism at the cellular and molecular level. As a starting point, we have focused on the inherited disorders of copper metabolism in humans, defining the molecular genetics including two copper-transporting P-type ATPases and a novel family of proteins termed copper chaperones that deliver copper to specific targets within the cell. Elucidation of the structure and function of these proteins reveals a remarkable evolutionary conservation of the mechanisms of copper metabolism and provides a useful heuristic paradigm for understanding cellular nutrient metabolism.
Another goal is to understand the role of nutrition in early human development. The human disorder Menkes disease reveals a critical role for copper in early central nervous system devlopment, and mice with a genetic deletion of the copper chaperone atox1 demonstrate an essential role for copper in perintal development. Utilizing zebrafish as a model vertebrate organism and taking advantage of the tools of chemical genomics, we have developed pharamacologic methods to perturb copper homeostasis in the yolk sac and thus dissect the precise role of copper in vertebrate development and organogenesis. We are now placing these observations in a broader biological context through a critical analysis of many nutrients in early embryonic development and organogenesis in the zebrafish embryo. |
Selected Publications:
Gansner JM, Mendelsohn BA, Hultman KA, Johnson SL, Gitlin JD. Essential role of lysyl oxidases in notochord development. Dev Biol 2007 307:202-213.
Madsen E, Gitlin JD. Copper and Iron Disorders of the Brain. Annual Review Neurosci 2007 30:317-337.
Gitlin JD. Distributing Nutrition. Science 2006 314:1252-1253.
Mendelsohn BA, Yin C, Johnson SL, Wilm T, Solnica-Krezel L, Gitlin JD. Atp7a determines a hierarchy of copper metabolism essential for notochord development. Cell Metabolism 2006 4:155-162.
Schlief ML, West T, Craig AM, Holtzman DM, Gitlin JD. Role of the Menkes copper transporting atpase in NMDA receptor-mediated neuronal toxicity. Proc Natl Acad Sci USA 2006 103:14919-14924. |