Abstract

Erythropoiesis and hemoglobin regulation will be examined in vitro and in vivo. The hypotheses are: (1) The fetal hemoglobin (Hb F) expression program of adult erythroid progenitor cells can be modified, and (2) The progenitors of fetuses and adults are distinct cell populations. The long term goal is to learn how to increase Hb F in vivo in patients with hemoglobinopathies. The immediate aims are: (1) To modulate erythropoiesis and Hb F in vitro with cellular and soluble factors, (2) To investigate similar modulations in vivo, (3) To characterize the progenitors of fetuses and adults, and (4) To purify erythroid progenitors. Progenitor cells will be obtained from adults, newborn infants, and fetuses, and from normals as well as patients with hemoglobinopathies, and other hematologic diseases. The progenitor cells will be cultured in semi-solid medium with added erythropoietin. Globin synthesis will be assayed by polyacrylamide gel electrophoresis. Cellular components to be evaluated include monocytes, T cells, and T subsets. Soluble factors include conditioned media, burst promoting activity, fetal sheet sera, and hemin. The role of cell cycle active drugs such as hydroxyurea and 5-azacytidine will be investigated. Studies will be performed with agents added in vitro, and patients who receive relevant drugs will be evaluated in vivo and in vitro. The progenitors of fetuses and adults will be characterized according to parameters which affect growth and/or globin gene expression, such as the influence of cellular and soluble factors. Purification of progenitors will employ physical and immunologic methods to remove irrelevant cells (negative selection) as well as select specifically for progenitors (positive selection). The purified cells will be used to prepare monoclonal antibodies to progenitors, to test the clonal model for ontogenic switching, and to examine directly the mechanism of action of factors which influence erythropoiesis and/or globin gene expression.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL026132-07
Application #
3338468
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1983-08-01
Project End
1991-07-31
Budget Start
1986-08-01
Budget End
1987-07-31
Support Year
7
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Mount Sinai School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029

  Publications

Weinberg, R S; Acosta, R; Knobloch, M E et al. (1995) Low oxygen enhances sickle and normal erythropoiesis and fetal hemoglobin synthesis in vitro. Hemoglobin 19:263-75
Weinberg, R S; Thomson, J C; Lao, R et al. (1993) Stem cell factor amplifies newborn and sickle erythropoiesis in liquid cultures. Blood 81:2591-9
Alter, B P (1992) Leukemia and preleukemia in Fanconi's anemia. Cancer Genet Cytogenet 58:206-8;discussion 209
Weinberg, R S; He, L Y; Alter, B P (1992) Erythropoiesis is distinct at each stage of ontogeny. Pediatr Res 31:170-5
Alter, B P; Knobloch, M E; He, L et al. (1992) Effect of stem cell factor on in vitro erythropoiesis in patients with bone marrow failure syndromes. Blood 80:3000-8
Drachtman, R A; Alter, B P (1992) Dyskeratosis congenita: clinical and genetic heterogeneity. Report of a new case and review of the literature. Am J Pediatr Hematol Oncol 14:297-304
Alter, B P (1992) Arm anomalies and bone marrow failure may go hand in hand. J Hand Surg Am 17:566-71
Alter, B P; He, L; Acosta, R et al. (1992) Sickle and thalassemic erythroid progenitor cells are different from normal. Hemoglobin 16:447-67
Alter, B P; Knobloch, M E; Weinberg, R S (1991) Erythropoiesis in Fanconi's anemia. Blood 78:602-8
Drachtman, R A; Geissler, E N; Alter, B P (1991) TaqI RFLP at the c-kit oncogene locus (KIT). Nucleic Acids Res 19:6975

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