Iron is an essential element required for redox reactions involved in cellular respiration, macromolecular synthesis, and xenobiotic detoxification. In mammals, its major role is in the production of red blood cells (RBCs) and transferring of oxygen throughout the body. Despite the life sustaining requirement of iron, its highly reactive nature to catalyze the production of damaging reactive oxygen and metabolite species (ROMS) necessitates mechanisms for its sequestration and harnessing of activity. This is primarily achieved through the binding of iron to heme, hemoglobin, and ferritin in RBCs and tissues. However, in hematological disorders such as sickle cell anemia, lytic crisis, and hemochromatosis, there is an increase in unbound iron release and overload. Increased ROMS by iron overload drive pathologies in cardiovascular tissues and other peripheral organs associated with these hematological disorders. Current clinical therapies targeting iron accumulation via metal chelation or blood removal/transfusions have been met with mixed results and come with clinical consequences. Thus, better characterizing and controlling iron catalyzed reactions in the blood remain as challenges as well as open avenues for treating iron-related hematological diseases. In this NIH New Directions in Hematological Research (SHINE-II) proposal, we address these issues via biochemical, metabolomic, proteomic, and nutritional approaches and innovations. We focus these methodologies on a chemical reaction my lab has recently uncovered in which hydrogen sulfide (H2S) gas is produced by an iron- and vitamin B6- coordinated catalysis of cysteine under physiological conditions. Much like iron, H2S serves beneficial and detrimental physiological roles throughout the body which are governed by dose, exposure route, and tissue specificity. The role of iron catalyzed H2S in prevention or promotion of hematological disorders is unknown. Here, we will test the hypothesis that iron catalyzed H2S in the blood is a modifiable factor in the initiation or progression of the blood disorders sickle cell anemia and hemochromatosis. To test this hypothesis, we will pursue one central AIM and determine the mechanism and capacities for H2S production catalyzed by iron in vitro and in blood derived from models of hemolytic anemia and iron-overload. To accomplish this aim, we will 1) Employ selective and sensitive H2S and sulfhydryl detecting techniques to explore the biochemical mechanisms, requirements, and downstream signaling of iron-catalyzed H2S in vitro and in blood and tissues ex vivo, and 2) Apply sulfur amino acid and vitamin B6 based dietary interventions as a means of preventing or slowing pathologies associated with sickle cell hemolytic crisis in vivo via modulating endogenous H2S production. Utilization of these approaches to investigate this novel chemistry will underscore the significance of iron catalyzed H2S production in the blood and the therapeutic potential of controlling it in hematological diseases.

Public Health Relevance

The dysregulated accumulation of iron is a major issue and pathological driver in blood-related diseases such as hemolytic anemia and hemochromatosis due to its catalytic generation of reactive oxygen species. Novel preliminary data we have obtained indicate blood-associated free and bound iron non-enzymatically catalyze the formation of hydrogen sulfide (H2S), a gaseous molecule that has both beneficial and detrimental capabilities dependent on dose and the tissue exposed. This project will determine the mechanism for iron catalyzed H2S production in blood and how it is effected in models of hemolytic anemia and iron-overload diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL148352-01
Application #
9799425
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Bai, C Brian
Project Start
2019-07-01
Project End
2022-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195