U.S. Department of Health and Human Services
Caroline Philpott
 

 Contact Info

 
Tel: 301-435-4018
Email: carolinep@intra.niddk.nih.gov
 

 Select Experience

 
  • Clinical Associate in GeneticsNICHD, NIH1995–1998
  • Postdoctoral FellowNICHD, NIH1990–1995
  • Resident in Internal MedicineJohns Hopkins Hospital1987–1990
  • M.D.Duke University1987
  • B.A.Duke University1983
 

 Related Links

 

    Caroline C. Philpott, M.D.

    Chief, Liver Diseases BranchGenetics and Metabolism Section
    Specialties
    • Cell Biology/Cell Signaling
    • Genetics/Genomics
    • Molecular Biology/Biochemistry
    • Systems Biology

    Research Summary

    Current Research

    Iron is an essential nutrient for almost every organism. It is required by every cell in the human body, yet it can also be a potent cellular toxin. Iron is essential because enzymes that require iron cofactors (namely, heme, iron-sulfur clusters, mononuclear, and diiron centers) are involved in virtually every major metabolic process in the cell. Iron deficiency continues to be the most common nutritional deficiency in the world, especially among children and women of childbearing age, where it causes anemia and impairs neurological development and function. Although the pathogenesis of anemia in iron deficiency is well understood, other manifestations of iron deficiency are not understood at the cellular or metabolic levels. Iron overload is a feature of an increasing number of human diseases, including genetic disorders such as hereditary hemochromatosis, thalassemias, and Friedreich’s ataxia, as well as chronic inflammatory diseases of the liver, such as hepatitis C. Our laboratory focuses on the genetics and cell biology of iron uptake and utilization in eukaryotes. Previously, we identified and characterized systems of iron transport in baker’s yeast, Saccharomyces cerevisiae. More recently, we have used the genetic tractability of yeast to focus on the intracellular trafficking and distribution of iron cofactors in yeast and mammalian cells.

    Mammalian cells express hundreds of metalloproteins. Most contain the abundant metals iron and zinc, while others contain various trace metals such as copper, manganese, molybdenum, and cobalt. Although incorporation of the appropriate metal ion(s) into cellular metalloproteins is a critical and essential process, the mechanism by which most metalloproteins receive their specific cofactor is unknown. Some proteins rely on metallochaperones—proteins that specifically bind metal ions and deliver them to target enzymes and transporters through direct protein-protein interactions.

    We identified poly (rC) binding protein 1 (PCBP1) as a cytosolic iron chaperone that delivers iron to ferritin. In mammals, ferritin is an iron storage protein consisting of 24 subunits of heavy (H) and light (L) peptides that assemble into a hollow sphere into which iron is deposited. PCBP1 binds both Fe(II) and ferritin and facilitates the incorporation of iron into ferritin. Studies are underway to identify other iron enzymes that require PCBP1 for the insertion of iron cofactors and to further characterize the cell biology and biochemistry of iron chaperones in mammals.

    The final step of heme biosynthesis occurs within the mitochondria, yet heme proteins are located in virtually every compartment of the cell. Thus heme, a hydrophobic molecule, must be transferred to the cytosol and to other membrane-bound organelles for insertion into newly synthesized heme proteins. Soluble heme-binding proteins have been identified in plants and mammals, but their roles in cellular heme metabolism or transport are unclear. We are conducting studies to identify and characterize the proteins involved in intracellular heme trafficking.

    Our research program couples the power of yeast genetics, mammalian cell biology, and murine models to understand the biology of iron utilization in human health and disease.

    Need for Further Study

    We identified poly (rC) binding protein 1 (PCBP1) as a cytosolic iron chaperone that delivers iron to ferritin. In mammals, ferritin is an iron storage protein consisting of 24 subunits of heavy (H) and light (L) peptides that assemble into a hollow sphere into which iron is deposited. PCBP1 binds both Fe(II) and ferritin and facilitates the incorporation of iron into ferritin. Studies are underway to identify other iron enzymes that require PCBP1 for the insertion of iron cofactors and to further characterize the cell biology and biochemistry of iron chaperones in mammals.

    Soluble heme-binding proteins have been identified in plants and mammals, but their roles in cellular heme metabolism or transport are unclear. We are conducting studies to identify and characterize the proteins involved in intracellular heme trafficking.