Abstract

Project 1 consists of three subprojects. Subproject 1 will test the hypothesis that iron is transported across erythroid mitochondrial membranes as Fe(II). A ferroxidase is required on the inner mitochondrial membrane for effective iron uptake. Ferrochelatase is likely the required ferroxidase. This hypothesis will be tested with isolated mitochondria obtained from induced MEL cells. Genes responsible for erythroid-specific mitochondrial iron transport will be cloned and characterized and the effects of mutant ferrochelatase will be determined. Subproject 2 will define the properties of two iron regulatory element binding proteins, IRE-BP1 and IRE-BP2. The role of each of these proteins will be determined by targeted gene disruptions in ES cells and in transgenic animals. Subproject 3 will result in the creation of a model of human familial porphyria cutanea tarda (PCT) by targeted disruption of the uroporphyrinogen decarboxylase (URO-D) gene and the creation of transgenic animals heterozygous for the disruption. These animals will be used to test the hypothesis that phenotypic expression of PCT is dependent on a P450-mediated reaction which oxidizes the substrate of URO-D.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Specialized Center (P50)
Project #
5P50DK049219-05
Application #
6105681
Study Section
Project Start
1998-09-22
Project End
2000-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Utah
Department
Type
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

Prasher, J M; Elenitoba-Johnson, K S; Kelley, L L (2001) Loss of p53 tumor suppressor function is required for in vivo progression of Friend erythroleukemia. Oncogene 20:2946-55
Mojica, M P; Perry, S S; Searles, A E et al. (2001) Phenotypic distinction and functional characterization of pro-B cells in adult mouse bone marrow. J Immunol 166:3042-51
Lok, C N; Ponka, P (2000) Identification of an erythroid active element in the transferrin receptor gene. J Biol Chem 275:24185-90
Hsieh, F F; Barnett, L A; Green, W F et al. (2000) Cell cycle exit during terminal erythroid differentiation is associated with accumulation of p27(Kip1) and inactivation of cdk2 kinase. Blood 96:2746-54
Wiesmann, A; Kim, M; Georgelas, A et al. (2000) Modulation of hematopoietic stem/progenitor cell engraftment by transforming growth factor beta. Exp Hematol 28:128-39
Spangrude, G J; Cooper, D D (2000) Paradigm shifts in stem-cell biology. Semin Hematol 37:10-Mar
Wiesmann, A; Phillips, R L; Mojica, M et al. (2000) Expression of CD27 on murine hematopoietic stem and progenitor cells. Immunity 12:193-9
Searles, A E; Pohlmann, S J; Pierce, L J et al. (2000) Rapid, B lymphoid-restricted engraftment mediated by a primitive bone marrow subpopulation. J Immunol 165:67-74
Wiesmann, A; Spangrude, G J (1999) Marrow engraftment of hematopoietic stem and progenitor cells is independent of Galphai-coupled chemokine receptors. Exp Hematol 27:946-55
Perry, S S; Kim, M; Spangrude, G J (1999) Direct effects of cyclosporin A on proliferation of hematopoietic stem and progenitor cells. Cell Transplant 8:339-44

Showing the most recent 10 out of 19 publications