The major goals of this project are 1) to create a genome-based description of human erythropoiesis, and 2) to use that description to develop novel therapies for diseases involving erythroid cells. Erythroid diseases encompass a broad range of anemias, hemoglobinopathies and malarial syndromes. Accomplishments achieved during the last year: 1. The initiation of clinical research projects related to the underlying focus of erythroid biology. A Senior Clinical Research Fellow and Nurse Practitioner were recruited for these efforts. The NIDDK IRB has approved our protocol entitled: ?Clinical and Laboratory Investigation of Humans with Informative Erythroid Phenotypes? and patients are being accrued. Genome-based and other molecular analyses of clinical samples are being planned to study a variety of diseases involving erythroid cells. Clinical samples from umbilical cord blood, infants and adults have been collected to determine the pattern of globin gene transcription and silencing during human development. 2. An ongoing interest of the lab involves the study of signal transduction cascades and growth among fully committed erythroid cells as a method of increasing levels of fetal hemoglobin in adult humans. Conceptually, this work is aimed toward new therapies for the treatment of sickle-cell diseases and beta-thalassemias. In this context, we developed a standard experimental assay of cultured human erythroid progenitor cells obtained from normal volunteers to identify cytokines capable of modulating erythroid growth and fetal hemoglobin production during adult erythropoiesis. Stem cell factor (SCF) was identified as having significant effects upon erythroid growth and fetal hemoglobin production even among committed proerythroblasts. During the last year, we continued studies of fetal hemoglobin modulation and began a targeted chemical biology approach toward the identification of additional signaling moieties that regulate fetal hemoglobin production. That approach led to the discovery that TGF-beta, SCF and Erythropoietin act in concert to increase fetal hemoglobin production. Those increases were pancellular, and resulted in production of HbF to levels that may be sufficient to reverse the sickle phenotype in vivo. Molecular biology studies were confirmed that the signaled increased HbF was accomplished at the genetic level by reversal of gamma-globin gene silencing. 3. Continued characterization of novel erythroid transcription and genes. Based upon interests in hemoglobin switching, a genomics project was undertaken to determine differences between the fetal and adult reticulocyte transcriptome. One of the initial discoveries from the project was the description of a novel human globin gene within the alpha globin gene cluster on Chromosome 16. Characterization of that gene revealed a developmentally-staged pattern of expression during ontogeny, and regulated expression during erythroid maturation. Additional candidate genes were also identified that may help regulate fetal-to-adult hemoglobin switching. 4. Hembase: a description of the human erythroid transcriptome. Previously, we reported the sequencing of human erythroblast libraries to generate an informatic database describing the erythroid transcriptome. That database, called Hembase (http://hembase.niddk.nih.gov/), is comprised of homology comparisons from our Expressed Sequence Tag (EST) collection with sequences contained within other publicly available databases. The database continues to be updated and linked to updated versions of the human genome available through the national Center of Biotechnology Information.
| de Vasconcellos, Jaira F; Lee, Y Terry; Byrnes, Colleen et al. (2016) HMGA2 Moderately Increases Fetal Hemoglobin Expression in Human Adult Erythroblasts. PLoS One 11:e0166928 |
| Oneal, Patricia A; Gantt, Nicole M; Schwartz, Joseph D et al. (2006) Fetal hemoglobin silencing in humans. Blood 108:2081-6 |
| Miller, Jeffery Lynn (2006) Patchwork HBA1 and HBA2 genes. Haematologica 91:289A |
| Bhanu, Natarajan V; Trice, Tiffany A; Lee, Y Terry et al. (2005) A sustained and pancellular reversal of gamma-globin gene silencing in adult human erythroid precursor cells. Blood 105:387-93 |
| Miller, Jeffery L (2005) Signaled expression of fetal hemoglobin during development. Transfusion 45:1229-32 |
| Goh, Sung-Ho; Lee, Y Terry; Bhanu, Natarajan V et al. (2005) A newly discovered human alpha-globin gene. Blood 106:1466-72 |
| Aerbajinai, Wulin; Lee, Y Terry; Wojda, Urszula et al. (2004) Cloning and characterization of a gene expressed during terminal differentiation that encodes a novel inhibitor of growth. J Biol Chem 279:1916-21 |
| Pal, Saumen; Nemeth, Michael J; Bodine, David et al. (2004) Neurokinin-B transcription in erythroid cells: direct activation by the hematopoietic transcription factor GATA-1. J Biol Chem 279:31348-56 |
| Bhanu, Natarajan V; Trice, Tiffany A; Lee, Y Terry et al. (2004) A signaling mechanism for growth-related expression of fetal hemoglobin. Blood 103:1929-33 |
| Goh, Sung-Ho; Jackson, Kaedrea A; Terry Lee, Y et al. (2004) Identification of an alternate delta-globin mRNA in adult human erythroid cells. Genomics 84:431-4 |
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