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Diane McVey Ward

Research Associate Professor of Microbiology and Immunology

Diane Ward Photo

B.S. Brigham Young University

Ph.D. University of Utah

Research

References

diane.mcveyward@path.utah.edu

Diane Ward's Lab Page

Diane Ward's PubMed Literature Search

Molecular Biology Program

Membrane Trafficking and Iron Metabolism

Research

My research has focused on two major areas.  First, I study membrane trafficking specifically looking at vesicle formation and molecules involved in endocytic/secretory vesicle homeostasis.  My lab, in collaboration with Dr. Ryan O’Connell (Pathology), has focused on identifying the mechanisms that regulate exosome formation, release and delivery in vivo and in vitro and how exosomes modulate immune response.  I have also focused my efforts on biochemically and genetically dissecting the mechanisms of vesicle fusion with lysosomes, specifically examining how the loss of the protein Lyst (mutant in Chediak Higashi Syndrome) affects lysosome size.   We have utilized yeast, mammalian cells and mouse models to understand lysosome biology and membrane trafficking.  Understanding lysosome biology has led to the study of how iron is stored in lysosomes and how it is transported out of lysosomes upon iron demand.  This research connects my membrane trafficking research and the second focus in my lab.

The second area of research I have focused on is iron metabolism. Iron is an element required by virtually all organisms. The transport of iron into cells and within cells requires appropriate membrane trafficking. Our studies on iron metabolism have focused primarily on the mechanisms that regulate iron import/export in the model organism Saccharomyces cerevisiae with the goal of identifying homologues in higher eukaryotes. Malregulation of iron metabolism in humans leads to anemia when iron uptake into the body is inadequate and iron overload disease when iron transport cannot be regulated. Work in the lab has led to a mechanistic understanding of both iron overload and the anemia of chronic disease. Mammalian iron metabolism is regulated by a hormone, termed hepcidin, which is secreted by the liver in response to inflammation and iron. We discovered that this hormone binds to the iron exporter Ferroportin and induces the internalization and degradation of Ferroportin resulting in retention of iron in cells. We have identified mitochondrial iron transporters Mitoferrin1 and Mitoferrin2 and partner proteins Abcb10 involved in mitochondrial iron homeostasis. We have generated conditional knockout mice for Mitoferrin1 and Mitoferrin2 and are determining their role in development, red blood cell formation and organ physiology. 

References

  1. Seguin, A, Jia, X, Wallace, JA, Qiu, A Bradley, T, Shrestha, R, Li, L, Hockin, M, Titen S, Warner, D, Dowdle, PT, Wohlfahrt, ME, Hillas, E, Firpo, M, Phillips, JD, Paw, BH, Barasch, J, Kaplan, J, Ward, DM.  (2018). Targeted deletion of mouse Slc25a28 (Mitoferrin2) reveals Mitoferrin1 and Mitoferrin2 are necessary for cell proliferation.  Submitted.
  2. Meznarich, JA, Draper, L, Christensen, RD, Yaish, HM, Luem, ND, Perkins, SL, Pysher, TJ, Jung, G, Nemeth, E, Ganz, T, Ward, DM.  (2018). Fetal Presentation of Congenital Dyserythropoietic Anemia Type 1 with Novel Compound Heterozygous CDAN1 Mutations. Blood Cells Mol Dis 71:63-66. PMID:29599085.
  3. Yien, YY, Shi, J, Chen C, Cheung, JTM, Grillo, AS, Shrestha, R, Li, L, Chung, J, Kafina, MD, Kingsley, PD, King, MJ, Ablain, J, Zon, LI, Palis, J, Burke, MD, Bauer, DE, Orkin, SH, Koehler, CM, Phillips, JD, Kaplan, J, Ward, DM, Lodish, HF, Paw, BH.  (2018) Erythropoietin regulates terminal erythropoiesis via Fam210b-mediated mitochondrial iron import. J. Biol. Chem. in press.
  4. Ward, DM, Chen, OS, Li, L, Kaplan, J, Bhuiyan, SA, Natarajan, SK, Bard, M, Cox, JE. (2018) Altered sterol metabolism in budding yeast affects mitochondrial iron-sulfur(Fe-S) cluster synthesis. J. Biol. Chem. 293:10782-10795 PMID:29773647. PMCID: PMC6036212.
  5.   Zhu, W, Shi, DS, Winter, JM, Rich, BE, Tong, Z, Sorensen, LK, Zhao, H, Huang, Y, Tai, Z, Mleynek, TM, Yoo, JH, Dunn, C, Ling, J, Bergquist, JA, Richards, JR, Jiang, A, Hartnett, ME, Ward, DM, Mueller, AL, Ostanin, K, Thomas, KR, Odelberg, SJ and Li, DY.  (2017).  ARF6 is an actionable node that controls VEGFR2 trafficking and signaling in Diabetic Retinopathy.  J.Clin. Invest. 127: 4569-4582. PMID:29058688. PMCID:PMC5707163
  6. Alexander, M, Ramstead, A, Bauer, K, Runtsch, MC, Wallace, J, Huffaker, TB, Larsen, DK, Tolmachova, T, Seabra, MC, Round, JL, Ward, DM and O’Connell, RM.  (2017).  Rab27-dependent exosome production inhibits chronic inflammation and enables acute responses to inflammatory stimuli.  J. Immunology.  199: 3559-3570. PMID:28978688. PMCID:PMC5821227
  7. Feldkamp, ML, Ward, DM, Pysher, TJ and Chambers, CT. (2017).  Chlamydia trachomatis is responsible for lipid vacuolation in the amniotic epithelium of fetal gastroschisis.  Birth Defects Res. 109:1003-1010. PMID:28635162
  8. Seguin, A, Takahashi-Makise, N, Yien, YY, Huston, NC, Whitman, JC, Musso, G, Wallace, JA, Bradley, T, Bergonia, H, Kafina, MD, Matsumoto, M, Igarashi, K, Phillips, JD, Paw, BH, Kaplan, J and Ward, DM.  (2017).  Reductions in the mitochondrial ABC transporter Abcb10 affect the transcriptional profile of heme biosynthesis genes.  J. Biol. Chem. 292:16284-16299. PMID: 28808058 PMCID:PMC5625058

  9. Li, L, Kaplan, J and Ward, DM.  (2017).  The glucose sensor Snf1 and the transcription factors Msn2 and Msn4 regulate transcription of the vacuolar iron importer gene CCC1 and iron resistance in yeast.  J. Biol. Chem. 292:15577-15586. PMID:28760824. PMCID:PMC5602413

  10. Feldkamp, ML, Ward, DM, Pysher, TJ and Chambers, CT. (2017).  Chlamydia trachomatis is responsible for lipid vacuolation in the amniotic epithelium of fetal gastroschisis.  Birth Defects Res. (in press).

  11. Yaish HM, Farrell CP, Christensen RD, MacQueen BC, Jackson LK, Trochez-Enciso J, Kaplan J, Ward DM, Salah WK, Phillips JD.  (2017)  Two novel mutations in TMPRSS6 associated with iron-refractory iron deficiency anemia in a mother and child. Blood Cells Mol Dis. 65:38-40. PMID:28460265

  12. MacQueen, BC, Christensen, RD, Ward, DM, Yaish, HM, Bennett, ST, O’Brien, EA, Sheffield, MJ, Baer, VL, Now, GL, Weaver Lewis, K, Fleming, RE and Kaplan, J.  (2017).  The iron status at birth of neonates who are “at risk” for developing iron deficiency; a pilot study.  J. of Perinatology. 1-5.  PMID:27977019.

  13. Shrestha, R, Kaplan, J and Ward, DM.  (2016). Conventional and Secretory Lysosomes: Encyclopedia of Cell Biology. Vol.2:225-234.

  14. Alexander, M, Hu, R, Runtsch, MC, Kaegle, DA, Round, JL, Ward, DM and O’Connell, R. (2015). Exosome-delivered microRNAs reprogram the inflammatory response to endotoxin. Nature Comm. 6:7321. PMID:26084661
  15. Kaplan, J and Ward, DM. (2015). Muscle specific iron deficiency has systemic consequences.  EBioMedicine 11:1582-1583. PMID:26870775. PMCID:4740307.
  16. Yien, YY Robledo, RF, Schultz, IJ, Takahashi-Makise, N, Gwynn, B, Bauer DE, Dass, A, Yi, G, Li, L, Hildick-Smith, GJ, Cooney, JD, Pierce, EL, Mohler, K, Dailey, TA, Miyata, N, Kingsley, PD, Garone, C, Hattangadi, SM, Huang, H, Chen, W, Keenan, EM, Shah, DI, Schlaeger, TM, DiMauro, S, Orkin, SH, Cantor, AB, Palis, J, Koehler, CM, Lodish, HF, Kaplan, J, Ward, DM, Dailey, HA, Phillips, JD, Peters, LL, Paw, BH.  (2014) TMEM14C is required for erythroid mitochondrial heme metabolism.  J. Clin. Inv.  124:4294-4304. PMID:25157825.
  17. Ben-Othman, R, Flannery, A, Miguel, Ward, DM, Kaplan, J and Andrews, NW. (2014). Leishmania-mediated inhibition of iron export promotes parasite replication in macrophages. PLOS Pathogens. 10:1-13. PMID:24497831
  18. Chung, J, Anderson, SA, Gwynn, B, Deck, KM, Chen, MJ, Langer, NB, Shaw, GC, Huston, NC, Boyer, LA, Datta, S, Paradkar, PN, Li, L, Wei, Z, Lambert, AJ, Sahr, K, Wittig, JG, Chen, W, Lu, W, Galy, B, Schlaeger, TM, Hentze, MW, Ward, DM, Kaplan, J, Eisenstein, RS, Peters, LL and Paw, BH. (2014). Iron Regulatory Protein-1 protects against mitoferrin1-deficient Porphyria. J. Biol. Chem. 289:7835-7843. PMID:24509859
  19. Li, l, Miao, R, Jia, X, Ward, DM and Kaplan, J.  (2014). Expression of the yeast cation diffusion facilitators Mmt1 and Mmt2 affects mitochondrial and cellular iron homeostasis: evidence for mitochondrial iron export. J. Biol. Chem. 289:7835-7843. PMID:24798331
  20. Kaplan, J and Ward, DM. (2013). The essential nature of iron usage and regulation: variations on a theme. Curr. Biol. 15:R642-6. PMID:23928078
  21. Kaplan, J and Ward, DM. (2013). Molecular Genetics of Chediak-Higashi Syndrome. Invited review. eLS. September DOI: 10.1002/9780470015902.a0024308
  22. Chen, C, Garcia-Santos, D, Ishikawa, Y, Seguin, A, Li, L, Fegan, KH, Hildick-Smith, GJ, Shah, DI, Cooney, JD, Chen, W, King, MJ, Yien, YY, Schultz, IJ, Anderson, H, Dalton, AJ, Freedman, ML, Kingsley, PD, Palis, J, Hattangadi, SM, Lodish, HF, Ward, DM, Kaplan, J, Maeda, T, Ponka, P and Paw, BH. (2013). Snx3 regulates recycling of the transferrin receptor and iron assimilation. Cell Metab. 17(3):343-52. PMID:23416069
  23. White, C, Yuan, X, Schmidt, P, Bresciani, E, Campagna, D, Hall, C, Ward, DM, Liu, P, Fleming, M and Hamza, I. (2013). HRG-1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab. 17:261-270. PMID:23395172
  24. Bagley, DC, Paradkar, PN, Durchfort, N, Kaplan, J and Ward, DM. (2012). Mon1a protein acts in trafficking through the secretory apparatus. J. Biol. Chem. 287:25577-25588. PMID:22665492
  25. Durchfort, N, Verhoef, S, Vaughn, MB, Shrestha, R, Adam, D, Kaplan, J and Ward, DM. (2012). The enlarged lysosomes in beige cells result from decreased lysosome fission and not increased lysosome fusion. Traffic. 13:108-119. PMID:21985285
  26. Li, l, Miao, R, Bertram, S, Jia, X, Ward, DM and Kaplan, J. (2012). A role for iron-sulfur clusters in the regulation of Yap5-dependent high iron transcriptional responses in yeast. J. Biol. Chem. 287:35709-35721. PMID:22915593
  27. Shah, DI, Takahashi-Makise, N, Cooney, JD, Seguin, A, Li, L, Schultz, IJ, Pierce, EL, Narla, A, Hattangadi, SM, Langer, NB, Chen W, Dailey, TA, Medlock, AE, Hurst, SN, Faccenda, D, Wiwczar, JM, Vogin, G, Brugnara, C, Zhou, Y, Ward, DM, Ebert BL, Campanella, M, Danial, NN, Dailey, HA, Kaplan, J and Paw, BH. (2012). Mitochondrial Atpif1 regultes heme synthesis in developing erythroblasts. Nature. 491:608-612. PMID:23135403

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Last Updated: 12/7/18