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The paradoxical response to iron in pulmonary hypertension of sickle cell disease

Award Number: R01HL161004
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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The paradoxical response to iron in pulmonary hypertension of sickle cell disease - PROJECT SUMMARY/ ABSTRACT Hemolytic syndromes including sickle cell disease (SCD) are devastating illnesses that affect over 100,000 people in the United States. Each of these patients suffers a broad spectrum of cardiopulmonary complications and exercise intolerance caused by red blood cell hemolysis, high plasma levels of cell free hemoglobin (Hb), endothelial cell dysfunction, and tissue hypoxia. Pulmonary vascular disease in the form of pulmonary hypertension, is significantly increased in this population, without any adequate treatment options. This grant application and projects herein focus on elucidating the mechanistic un- derpinnings of macrophage activation and their contribution to the progression of SCD PH. Our data shows a unique macrophage (Mϕ) phenotype occurs in both deceased adult SCD patients di- agnosed with PH as well rodent models of SCD PH. This phenotype is described by intracellular accu- mulation of Hb, expression of HO-1, and mitogenic, inflammatory and vasoconstrictor mediators that are also associated with hypoxia (HX) induced PH. Furthermore, like hypoxia driven PH, SCD patient lung macrophages accumulate in the pulmonary adventitial regions surrounding remodeled pre-capillary pulmonary arterioles that show plexiform lesions and re-canalization of small pulmonary arterioles. The phenotypic similarities between rodent models and human SCD with PH indicate a novel maladaptive immune response to concomitant bouts of Hb and HX exposure. Moreover, by knocking out circulating mϕs in a rat model of group 5 PH, the response to combined Hb and hypobaric HX was significantly at- tenuated in rats, suggesting a critical role for mϕs in the exacerbation of SCD PH. We hypotheses that persistent bouts of hypoxia-induced erythrocyte sickling are a critical process that drives Mϕ removal of damaged RBCs causing accumulation of Mϕ iron, loss of Mϕ iron homeostasis and progressive SCD-PH. We further hypothesize that impaired iron homeostasis facilitates in- tracellular oxidation and exposes the local pulmonary vascular micro-environments to labile iron mediated oxidation and accelerated lung peripheral vascular remodeling. To test this hypoth- esis we propose the following specific aims. Aim 1 will determine how circulating monocytes with a high iron content are metabolically reprogramed in patients with differing severity of SCD. Aim 2 in vivo and in vitro will determine the contribution and mechanism by which iron loaded Mϕ contribute to SCD; and Aim 3 will test the effectiveness of trans- ferrin, ferroportin inhibitor, and iron chelators alone or in combination as a therapeutic intervention to halt Mϕ contributions to SCD PH. An in-depth understanding of these relationships will allow us to identify new therapeutic targets to pulmonary hypertension concomitant with SCD.


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: 2025 ( Subtotal = $600,149 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Blood Diseases and Resources Research	000	4	3/10/2025	NON-COMPETING CONTINUATION	$600,149
														Subtotal = $600,149

Issue Date FY: 2024 ( Subtotal = $657,115 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Blood Diseases and Resources Research	000	3	1/10/2024	NON-COMPETING CONTINUATION	$603,473
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Blood Diseases and Resources Research	001	3	6/21/2024	NON-COMPETING CONTINUATION	$53,642
														Subtotal = $657,115

Issue Date FY: 2023 ( Subtotal = $674,111 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Blood Diseases and Resources Research	000	2	2/6/2023	NON-COMPETING CONTINUATION	$674,111
														Subtotal = $674,111

Issue Date FY: 2022 ( Subtotal = $711,122 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Blood Diseases and Resources Research	000	1	1/20/2022	NEW	$711,122
														Subtotal = $711,122

Grand Total All Awards = $2,642,497

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The paradoxical response to iron in pulmonary hypertension of sickle cell disease

Award Number: R01HL161004

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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