Abstract

The aim of this research is to enhance understanding of the regulation of erythropoiesis and the application of this knowledge to clinical anemias and polycythemias. We have purified human colony forming units-erythroid (CFU-E) and have identified erythropoietin (EPO) receptors on these cells. We now propose to purify blood burst-forming units-erythroid (BFU-E) and determine the time course of the evolution of EPO receptors during BFU-E development and differentiation. We will also determine the effect of interleukin-3 (IL-3) granulocyte colony-stimulating factor, granulocytemacorphage colony-stimulating factor, and insulin-like growth factor-I (IGF-I) on down- or up-modulation of EPO receptors. We have also found that while tumor necrosis factor (TNF) and IL-1 depress normal human bone marrow CFU-E development, purified CFU-E are not inhibited by these factors. Thus, TNF and IL-1 are apparently acting on accessory cells to produce a factor that is released and inhibits CFU-E. We will determine the identity of these intermediate accessory cells, purify the factor that is being released, and measure the effect of this factor on human CFU-E EPO receptors to determine if TNF and/or IL-1 down- module EPO receptors as a mechanism for producing the anemia. We will also further characterize the EPO receptor during erythroid differentiation. A heterobifunctional, photoreactive, cleavable, iodinated cross-linker will provide radioactive EPO receptors which will be characterized for molecular size, isoelectric point, glycosylation and phosphorylation capacity. The EPO receptor gene will be obtained and will be used to measure the effect of EPO and IGF-I on EPO receptor mRNA in highly purified murine CFU-E as they differentiate. These studies will enhance our knowledge of the events that are controlled by EPO and they will enhance our under-standing of the anemia of chronic disorders. They should also provide a firm base of information for further understanding a wide variety of additional clinical anemia and polycythemias that may occur through the malfunction of normal EPO control mechanisms.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK015555-21
Application #
3225410
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1974-10-01
Project End
1994-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
21
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212

  Publications

Zhao, Zhizhuang Joe; Vainchenker, William; Krantz, Sanford B et al. (2005) Role of tyrosine kinases and phosphatases in polycythemia vera. Semin Hematol 42:221-9
Dai, Chunhua; Chung, Ik-Joo; Krantz, Sanford B (2004) In human immature BFU-E tumor necrosis factor-alpha not only downregulates CDK6 but also directly produces apoptosis which is prevented by stem cell factor. Exp Hematol 32:911-7
Chung, Ik-Joo; Dai, Chunhua; Krantz, Sanford B (2003) Stem cell factor increases the expression of FLIP that inhibits IFNgamma -induced apoptosis in human erythroid progenitor cells. Blood 101:1324-8
Xu, Ming-Jiang; Sui, Xingwei; Zhao, Runxiang et al. (2003) PTP-MEG2 is activated in polycythemia vera erythroid progenitor cells and is required for growth and expansion of erythroid cells. Blood 102:4354-60
Zhao, Runxiang; Fu, Xueqi; Li, Qingshan et al. (2003) Specific interaction of protein tyrosine phosphatase-MEG2 with phosphatidylserine. J Biol Chem 278:22609-14
Dai, Chunhua; Chung, Ik-Joo; Jiang, Shazi et al. (2003) Reduction of cell cycle progression in human erythroid progenitor cells treated with tumour necrosis factor alpha occurs with reduced CDK6 and is partially reversed by CDK6 transduction. Br J Haematol 121:919-27
Ling, Jianhua; Pi, Wenhu; Bollag, Roni et al. (2002) The solitary long terminal repeats of ERV-9 endogenous retrovirus are conserved during primate evolution and possess enhancer activities in embryonic and hematopoietic cells. J Virol 76:2410-23
Zhao, Runxiang; Guerrah, Abdelmadjid; Tang, Hua et al. (2002) Cell surface glycoprotein PZR is a major mediator of concanavalin A-induced cell signaling. J Biol Chem 277:7882-8
Xu, Ming-jiang; Zhao, Runxiang; Cao, Hongxi et al. (2002) SPAP2, an Ig family receptor containing both ITIMs and ITAMs. Biochem Biophys Res Commun 293:1037-46
Qi, Ying; Zhao, Runxiang; Cao, Hongxi et al. (2002) Purification and characterization of protein tyrosine phosphatase PTP-MEG2. J Cell Biochem 86:79-89

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