Iron deficiency represents one of the most common human nutritional deficiencies in the world but remains surprisingly poorly characterized with regard to its effects on organ physiology. One of the most prominent clinical consequences of this condition consists of a lineage-selective suppression of marrow red cell production, even in the face of high serum erythropoietin levels. The resulting blood abnormality consists of an isolated anemia, with sparing of white blood cell and platelet levels. The erythroid suppression by iron deficiency provides a rheostatic response permitting the adjustment of iron utilization in response to available stores. A further understanding of the underlying pathway has clinical significance for several reasons. Firstly, this pathway also contributes to anemias other than in iron deficiency, such as those associated with chronic inflammation, cancer, and renal disease, conditions marked by defective iron transfer from storage to erythroid compartments. Secondly, this pathway has been purposefully harnessed to limit neoplastic proliferation in polycythemia vera, where therapeutic induction of iron deficiency restrains the clonal expansion of the erythroid compartment. Thirdly, potential treatments or conditions that override this regulatory mechanism could precipitate clinical deterioration in patients with true, severe iron deficiency. Using a novel model system of primary human hematopoietic cultures with defined levels of transferrin saturation, critical signaling targets in this pathway have been identified. In particular, clinically relevant levels of iron deprivation selectively inactivate, i.e. in an erythroid lineage-specific manner, the signaling activity of a specific class of enzymes. This effect occurs through functional inactivation of specific prosthetic groups within these enzymes and not through diminished protein expression. A retroviral genetic screen has identified a specific factor which acts upstream of these enzymes and confers on erythroid progenitors complete resistance to the effects of physiologic iron deprivation. A small molecule agonist which acts downstream of these enzymes has been identified and specifically reverses the erythroid inhibitory effects of iron deprivation. In addition, a related small molecule antagonist recapitulates the effects of iron deprivation in erythroid cultures with adequate iron levels. The goals of this project are to delineate further the molecular pathway that links iron deprivation to lineage specific regulation of erythroid development and to study in a murine model system the in vivo consequences of manipulating this pathway. These studies will potentially provide new treatment approaches for many chronic anemias resistant to erythropoietin therapy, as well as a novel means for controlling erythropoiesis in patients with polycythemia. Project Narrative: Iron deficiency represents a frequent cause of anemia and causes the bone marrow to decrease production of red blood cells. In addition to iron deficiency anemia, anemias associated with cancer, kidney disease, chronic inflammation, and aging also are associated with impaired red cell production by the bone marrow. These latter anemias arise in part because of inadequate transport of iron from storage cells to the red cell precursors in the marrow. In particular, red cell precursors sense an iron deficiency even though total body iron stores are frequently increased. This project has identified the mechanisms by which bone marrow cells sense iron availability and adjust red cell production accordingly. Preliminary studies have led to compounds which can either reverse or mimic the response of marrow cells to diminished iron availability. These studies therefore offer novel approaches for the treatment of several types of chronic anemia and for the treatment of diseases associated with excessive red cell production such as polycythemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079924-04
Application #
8020963
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Wright, Daniel G
Project Start
2008-02-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$314,904
Indirect Cost
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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