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ARRA Investments in Hematologic Diseases

Public Health Burden
It is difficult to measure the public health burden due to hematologic disorders, but it is believed to be underestimated, due in part to the wide range of disorders affecting blood cell production, anemia and iron metabolism.  ARRA-funded hematology-related research projects address a spectrum of basic and early translational research approaches.

Discovering mechanisms of Hematologic Disorders
Recent fundamental discoveries have improved our understanding of nonmalignant hematologic processes.  Efforts to develop translational tools, including improved animal models, biomarkers, and imaging methods will improve our ability to prevent and treat nonmalignant hematologic diseases.  Some examples of projects in this area include:
  • A new, cell-based, high-throughput screen will be used to search for inexpensive, effective drugs that will reactivate the human fetal globin gene, ultimately saving lives of patients with sickle cell anemia or beta-thalassemia.1
  • Proteomics techniques are being evaluated for more widespread availability of diagnostic tools for patients with hereditary hemolytic anemia.2
  • Discoveries resulting from this project may lead to novel ways to increase fetal globin production, thereby treating hemoglobinopathies, such as sickle cell anemia and thalassemia.3
  • The ability of the cell’s machinery (ribosomes) to make protein in the absence of the gene NPM1 will be evaluated.  This study has broad implications for various forms of anemia.4
  • A project will permit a genetic engineer to construct a virus containing a correcting version of the beta-globin gene to try to cure beta-thalassemia anemia.5
  • A live cell imaging system will be purchased to view the stages of blood cell development.6
Acquiring knowledge about the molecular and cellular processes involved with production of hemoglobinized red blood cells is important to the development of therapies for anemia.
  • A project studying a novel protein, mFam55B—which was discovered by the investigator—will explore the possible functions of the protein in erythroid cell development and erythroid precursor cell function.7
  • Protein-protein interactions of transcription factor, GATA-1 with bromodomain protein, Brd3, will be examined.  Brd3 may help recently divided erythroid cells maintain their past epigenetic state, so it doesn’t need to be re-established each cell division.8
  • This study will investigate the putative role of cell adhesion molecules ICAM-4 and Lutheran in the production of red blood cells.9
  • A project will determine the effects of therapies used to treat disorders caused by ribosome abnormalities, identify mechanisms that trigger arrest in cell proliferation and cell death when ribosome production is impaired and lead to the design of new therapies.10  Mutations in ribosomal protein genes can result in a diminished production of red blood cells, causing anemia.
Iron Regulation
Iron is essential for the function of all cells, and the study of its balance and transport regulation, utilization, and storage is of utmost importance to health.
  • A project will conduct basic studies of iron entry into and release from the iron storage protein, ferritin, with potential translation into drug targeting and improved iron chelation used to treat sickle cell disease, thalassemia, and hereditary hemochromatosis.11
  • Despite effective chelation in thalassemia, patients continue to develop heart disease, multiple hormone disorders, and a shortened life span related to iron deposition in target organs.  In contrast, patients with sickle cell disease, even with a similar history of iron exposure, do not show the same levels or frequencies of iron overload in target organs.  A project will compare iron transport mechanisms in these two populations and identify factors that either limit or exacerbate deposition.  From this work, it should be possible to develop new therapies that prevent iron deposition from occurring in the heart and endocrine organs, and thereby reduce morbidity and mortality in the thalassemia population.12
Pediatric Hematology
Blood disorders that begin at birth can have lifelong consequences.  Studies of such disorders may lead to early intervention to help offset the detrimental effects of the disease.
  • Iron deficiency is common in infancy and can lead to anemia as well as developmental delays. This project will test the utility of a new, potentially more accurate blood screening test for iron deficiency and begin to determine if there is a genetic susceptibility to iron deficiency in infancy.13
  • A patient registry and tissue bank will be established for pediatric myelodysplastic syndrome (pMDS), a rare hematopoietic disease characterized by a heterogeneous group of disorders.  Such a registry will help to define the genetics of childhood MDS and identify pathways for therapy. Currently, bone marrow transplantation is the only therapeutic option for these patients.14

  1. 1R21DK080428-01A1 -- A high-throughput screen for candidate agents that may reverse gamma-globin silencing -- Martin, David IK (CA)
  2. 1R01DK080232-01A2 -- Hemolytic Anemia: Biochemical, Molecular and Proteomic Diagnostics -- Friedman, Jeffrey S (CA)
  3. 1RC1DK086956-01 -- Reactivation of Fetal Gamma-globin Genes for the Treatment of Beta-globin Disorders -- Engel, James Douglas (MI)
  4. 1RC1DK087679-01 -- Nucleophosmin and ribosomal dysfunction in hematologic diseases- Pandolfi, Pier Paolo (MA)
  5. 5K01DK063992-05 Supplement -- Gene therapy for Cooley's anemia in a new mouse model -- Rivella, Stefano (NY)
  6. 2R01DK052191-10A21 Supplement -- Erythroid Development in the Mammalian Embryo -- Baron, Margaret (NY)
  7. 1R21DK081930-01A1 -- Novel Erythroid Cell Membrane Protein- Bresnick, Emery H. (WI)
  8. 2R01DK054937-11 -- Transcriptional Networks Controlling Erythroid Differentiation- Blobel, Gerd A (PA)
  9. 2R01DK056267-09 -- Novel Functions of Red Cell Proteins Lu and LW -- Chasis, Joel A (CA)
  10. 1RC1DK087680-01 -- Model systems for hematologic disorders caused by ribosomal protein deficiency -- Thomas, George (OH)
  11. 2R01DK020251-33A2 -- Ferritin: Protein/mRNA/DNA in Fe/O Regulation/Metabolism -- Theil, Elizabeth (CA)
  12. 2R01DK057778-06A1 -- Modulation of Iron Deposition in SCD and Other Hemoglobinopathies -- Vichinsky, Elliott P. (CA)
  13. 1RC1DK086486-01 -- Hepcidin-based screening for infantile iron deficiency -- Fleming, Mark D. (MA)
  14. 1RC1DK086861-01 -- Development of a Pediatric Mylelodysplastic Syndrome Patient Registry -- Williams, David A. (MA)

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Page Last Updated on June 30, 2018 NIH...Turning Discovery Into Health®