Cats viremic with feline leukemia virus, subgroup C (FeLV-C) develop pure red cell aplasia (PRCA). This results from a block in BFU-E to CFU-E maturation. Although granulocytic and erythroid progenitors are infected, only erythroid differentiation is impaired. Thirty amino acids of variable region 1 (VR1) of the surface unit protein of the FeLV-C envelope are the genetic determinants of host cell infection, of retroviral interference, and of PRCA. We hypothesized that FeLV- C inhibits the cell surface expression (or function) of its receptor (via envelope-mediated interference), leading to PRCA. As a corollary, the receptor must have a critical role in normal erythropoiesis, but be redundant or non-essential for granulocytic differentiation. Using a retroviral vector cDNA library generated from cat (3201B) T cells, we have cloned the cDNA for the FeLV-C receptor (termed FLVCR). The predicted protein is comprised of 567 amino acids, has 12 membrane-spanning domains, and is likely a member of the major facilitator superfamily (MFS) of transporter proteins. There is significant homology with D-glucarate transporters in bacteria and C. elegans. The goals of this application are to study the physiology of FLVCR and to test our hypotheses. As D-glucarate (and other organic (sugar) anion) transport is not known to have any role in hematopoiesis, these studies should provide novel insights into the biology of early erythroid cell development, as well as the pathogenesis of PRCA.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031823-16
Application #
6638236
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Qasba, Pankaj
Project Start
1986-12-01
Project End
2005-06-30
Budget Start
2003-04-01
Budget End
2005-06-30
Support Year
16
Fiscal Year
2003
Total Cost
$380,000
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Philip, Mary; Chiu, Edison Y; Hajjar, Adeline M et al. (2016) TLR Stimulation Dynamically Regulates Heme and Iron Export Gene Expression in Macrophages. J Immunol Res 2016:4039038
Yang, Zhantao; Keel, Siobán B; Shimamura, Akiko et al. (2016) Delayed globin synthesis leads to excess heme and the macrocytic anemia of Diamond Blackfan anemia and del(5q) myelodysplastic syndrome. Sci Transl Med 8:338ra67
Doty, Raymond T; Phelps, Susan R; Shadle, Christina et al. (2015) Coordinate expression of heme and globin is essential for effective erythropoiesis. J Clin Invest 125:4681-91
Keel, Siobán B; Doty, Raymond; Liu, Li et al. (2015) Evidence that the expression of transferrin receptor 1 on erythroid marrow cells mediates hepcidin suppression in the liver. Exp Hematol 43:469-78.e6
Philip, Mary; Funkhouser, Scott A; Chiu, Edison Y et al. (2015) Heme exporter FLVCR is required for T cell development and peripheral survival. J Immunol 194:1677-85
Egan, Daniel N; Yang, Zhantao; Phillips, John et al. (2015) Inducing iron deficiency improves erythropoiesis and photosensitivity in congenital erythropoietic porphyria. Blood 126:257-61
Byon, John C H; Chen, Jing; Doty, Raymond T et al. (2013) FLVCR is necessary for erythroid maturation, may contribute to platelet maturation, but is dispensable for normal hematopoietic stem cell function. Blood 122:2903-10
Keel, Sioban B; Phelps, Susan; Sabo, Kathleen M et al. (2012) Establishing Rps6 hemizygous mice as a model for studying how ribosomal protein haploinsufficiency impairs erythropoiesis. Exp Hematol 40:290-4
Hromas, Robert; Abkowitz, Janis L; Keating, Armand (2012) Facing the NIH funding crisis: how professional societies can help. JAMA 308:2343-4
Jaacks, Lindsay M; Young, Melissa F; Essley, Bridget V et al. (2011) Placental expression of the heme transporter, feline leukemia virus subgroup C receptor, is related to maternal iron status in pregnant adolescents. J Nutr 141:1267-72

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