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Iron Catalyzed H2S and its Prevalence in Hemolytic and Iron Overload Disorders

Award Number: R01HL148352
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Iron Catalyzed H2S and its Prevalence in Hemolytic and Iron Overload Disorders - PROJECT SUMMARY/ABSTRACT 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$1,538 )
2024	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	3	9/24/2024	NON-COMPETING CONTINUATION	-$1,538
														Subtotal = -$1,538

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	3	5/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $322,000 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	3	6/10/2021	NON-COMPETING CONTINUATION	$322,000
														Subtotal = $322,000

Issue Date FY: 2020 ( Subtotal = $322,000 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	2	6/12/2020	NON-COMPETING CONTINUATION	$322,000
														Subtotal = $322,000

Issue Date FY: 2019 ( Subtotal = $320,000 )
2019	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Blood Diseases and Resources Research	000	1	6/5/2019	NEW	$320,000
														Subtotal = $320,000

Grand Total All Awards = $962,462

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Iron Catalyzed H2S and its Prevalence in Hemolytic and Iron Overload Disorders

Award Number: R01HL148352

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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