Erythroid diseases encompass a broad range of anemias, hemoglobinopathies and malarial syndromes. The major goals of this project are 1) understand human pathology involving erythroid cells at the molecular level using a genome-based analysis of information 2) create a genome-based description of human erythropoiesis, and 3) integrate information-, experimental-, and clinical-based approaches to develop novel therapies for diseases involving erythroid cells. ? ? Accomplishments achieved during the last year: ? ? ? 1. The expansion of clinical research projects related to the underlying focus of erythroid biology. A clinical research team is now in place consisting of myself, a Senior Clinical Research Fellow and a Nurse Practitioner to conduct studies. The purpose of these studies is to enhance our bridge basic and clinical knowledge of erythroid biology consistent with Roadmap goal of the NIH. Genome-based and other molecular analyses of clinical samples are being conducted to study a variety of diseases involving erythroid cells.? ? During the last year, approximately 70 patients have been recruited and evaluated at the NIH Clinical Center on the Bethesda Campus. The majority of patients have been identified as having hemoglobin related diseases and enrolled in a protocol (05-DK-0085) entitled ?Clinical and Laboratory Investigation of Humans with Informative Erythroid Phenotypes?. In addition, patient recruitment has begun for a second protocol (06-DK-0142) entitled ?Peripheral Blood Collection of Adult Stem Cells?. Finally, major collaborative efforts were pursued to study blood from over 100 children studied with Dr. Naomi Luban at Children?s National Medical Center. Based upon this project, the pattern of fetal hemoglobin loss and silencing during normal postnatal human development was defined. That work is now being expanded to include patients with hemoglobinopathies and to develop and better understand fetal hemoglobin reactivation in adults. ? ? 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. 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. ? ? During the last year, the model system described above was used to begin a series of laboratory projects aimed toward determining the molecular basis of cytokine-signaled increases in gamma globin gene and protein expression. This work was coordinated with the clinical efforts described above.? ? 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. ? ? During the last year, ongoing collaborative studies were pursued to determine whether mu globin transcripts are translated and assembled into functional hemoglobin molecules. In addition, a number of additional candidate genes are being characterized to determine their involvement in globin gene switching or erythroid mediated pathologies associated with hemoglobinopathies. Again, the focus of this work shifted during the last year from the expansion of general knowledge toward patient-specific questions based upon the expansion of clinical projects described above.? ? 4. Internet-based description of erythroid biology. At the request of the erythroid biology community, the laboratory has continued efforts to update and expand the description of erythroid cell genetics in the context of post-genome biology. Previously, we reported the sequencing of human erythroblast libraries to generate an informatic database describing the erythroid transcriptome. Named Hembase (http://hembase.niddk.nih.gov/), the database is comprised of homology comparisons from our Expressed Sequence Tag (EST) collection with sequences contained within other publicly available databases.? ? During the last year, the Hembase database was rebuilt according to the March 2006 annotation of the human genome. In addition, several disease-related search functions (Blood Groups, Cytoskeleton, Heme Synthesis, Hemoglobin, Hemolysis Related Enzymes)were integrated into Hembase to provide a genome-based organization of erythroid diseases.
| 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 |
| 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 |
| Miller, Jeffery L (2004) A genome-based approach for the study of erythroid biology and disease. Blood Cells Mol Dis 32:341-3 |
| Goh, Sung-Ho; Lee, Y Terry; Bouffard, Gerard G et al. (2004) Hembase: browser and genome portal for hematology and erythroid biology. Nucleic Acids Res 32:D572-4 |
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