Tuesday, November 4, 2025 11/4/2025

MECHANISM OF ACTION OF ERYTHROFERRONE AND PATHOLOGICAL IMPLICATIONS

Award Number: R01DK126680
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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MECHANISM OF ACTION OF ERYTHROFERRONE AND PATHOLOGICAL IMPLICATIONS - Project Summary This proposal aims to elucidate the mechanisms by which normal and pathological erythropoiesis exerts systemic effects on iron metabolism and other metabolic processes. Activation of erythropoiesis by erythropoietin (EPO) causes rapid suppression of hepcidin, with consequent increase in iron absorption and the release of iron from stores. We discovered erythroferrone (ERFE), a hormone produced by erythroblasts, as the principal mediator that acutely matches the iron supply to the changing requirements of erythropoiesis. ERFE is proposed to bind to and inactivate bone morphogenetic proteins (BMPs) that regulate hepcidin transcription. In anemias with ineffective erythropoiesis, increased ERFE concentrations may not only contribute to iron overload and worsen ineffective erythropoiesis but also promote other systemic manifestations. In this proposal, we will expand the study of the mechanism of action of ERFE, define the set of BMP ligands targeted by ERFE, and conduct a detailed structure-function study. Also, we constructed transgenic mouse lines that overexpress graded levels of ERFE in erythroblasts and develop proportional iron overload and other systemic manifestations of anemias with ineffective erythropoiesis. We will use these mice to analyze the hematological and non- hematological consequences of excessive ERFE. The specific aims of the proposed project are: 1. Characterize the structural determinants of ERFE bioactivity and the interaction of ERFE with BMPs. We will define all the members of the BMP family targeted by murine and human ERFE using assays for both bioactivity and direct physical interaction. We will define the bioactive segment of ERFE and perform complete structure-function analysis of the specific amino acids required for ERFE bioactivity. 2. Analyze the hematological effects of increased ERFE concentrations in vivo. In mouse models of graded ERFE overexpression, we will analyze the effect of ERFE on iron loading and erythropoiesis, and identify which effects are independent of hepcidin. To study the effects of high ERFE in β-thalassemia, we will introduce the ERFE transgene into the th3/+ model of β-thalassemia and examine erythropoiesis and iron overload. Finally, we will test the ability of a therapeutic anti-ERFE Mab to reverse the effects of ERFE. 3. Elucidate the nonhematological effects of increased ERFE concentrations in vivo. Using transgenic ERFE mice, we will define the effects of ERFE on the brain, somatic growth, bone and adipose tissues, and renal development, all of which were affected in our preliminary characterization. Successful completion of the proposed studies will answer longstanding questions about a fundamental aspect of human and vertebrate biology, the mechanism by which the supply of iron is matched to the varying iron requirements of erythropoiesis. The work will provide important insights into the pathogenesis of iron overload in β-thalassemia and other anemias with ineffective erythropoiesis, globally very common diseases, and enhance the understanding of the mechanisms that cause the debilitating systemic effects of these 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: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/31/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $458,477 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/24/2024	NON-COMPETING CONTINUATION	$458,477
														Subtotal = $458,477

Issue Date FY: 2023 ( Subtotal = $477,581 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/18/2023	NON-COMPETING CONTINUATION	$477,581
														Subtotal = $477,581

Issue Date FY: 2022 ( Subtotal = $584,758 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/28/2022	NON-COMPETING CONTINUATION	$477,581
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	8/25/2022	SUPPLEMENT FOR EXPANSION	$107,177
														Subtotal = $584,758

Issue Date FY: 2021 ( Subtotal = $584,758 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/28/2021	SUPPLEMENT FOR EXPANSION	$17,862
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/29/2021	NON-COMPETING CONTINUATION	$477,581
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	7/1/2021	SUPPLEMENT FOR EXPANSION	$89,315
														Subtotal = $584,758

Issue Date FY: 2020 ( Subtotal = $477,581 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/14/2020	NEW	$477,581
														Subtotal = $477,581

Grand Total All Awards = $2,583,155

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MECHANISM OF ACTION OF ERYTHROFERRONE AND PATHOLOGICAL IMPLICATIONS

Award Number: R01DK126680

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/20/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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