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Balancing Iron and Manganese Homeostasis in Hereditary Hemochromatosis

Award Number: R01DK148124
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: 05/13/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Balancing Iron and Manganese Homeostasis in Hereditary Hemochromatosis - PROJECT SUMMARY: “Balancing Iron and Manganese Homeostasis in Hereditary Hemochromatosis” Iron (Fe) and manganese (Mn) are essential for health yet toxic in excess. Fe is regulated largely by dietary absorption, while Mn is regulated largely by hepatobiliary excretion. Our understanding of Fe homeostasis has benefited greatly from studies of inherited defects in Fe transport. Our understanding of Mn homeostasis was limited in the past by a paucity of known inherited defects in Mn transport. This changed in 2012-16 with the first discoveries of inherited causes of Mn imbalance in patients with mutations in SLC30A10, SLC39A14, and SLC39A8. These membrane proteins dictate systemic Mn levels by mediating hepatobiliary and intestinal Mn transport. We previously reported that SLC30A10 deficiency results in Mn excess because SLC30A10 exports Mn from hepatocytes into bile and from enterocytes into the lumen of the gastrointestinal tract. More recently, we demonstrated that, despite impaired Mn excretion, Slc30a10-deficient mice develop increased Mn absorption. Intriguingly, this increased absorption is dependent upon divalent metal transporter 1 (DMT1) and ferroportin (FPN), two factors essential for dietary Fe absorption. While SLC30A10 deficiency is rare, upregulation of Fe absorption pathways and Mn excess are also observed in dietary Fe deficiency, the most common nutritional deficiency. In this condition, Mn excess is attributed to physiologic upregulation of DMT1 and FPN leading to increased Mn absorption, although this has yet to be tested. However, upregulation of Fe absorption does not always result in Mn excess. Mn excess is not observed in hereditary hemochromatosis, a common disease of Fe excess due to deficiency in hepcidin, an inhibitor of Fe absorption. Using a mouse model of hereditary hemochromatosis due to deficiency in hemojuvelin (Hjv), a signaling receptor essential for hepcidin expression, we recently demonstrated that hereditary hemochromatosis does not result in Mn excess because intestinal Slc30a10 normalizes Mn absorption. The goal of this application is to establish fundamental molecular mechanisms of mammalian Mn homeostasis by exploiting the observation that Fe deficiency results in Mn excess while hereditary hemochromatosis does not. We hypothesize that Mn absorption is not increased in hereditary hemochromatosis because intestinal SLC30A10 and SLC39A14 excrete absorbed Mn back into the gastrointestinal tract and because excess Fe outcompetes Mn for transport from enterocytes into blood. To test this hypothesis, we will establish the role of Dmt1, Fpn, Slc39a8, Slc39a14, and Slc30a10 in Mn homeostasis in Hjv-/- mice (aim 1), determine the impact of Fe deficiency on Mn absorption in Hjv-/- mice (aim 2), and determine the impact of Mn excess on disease severity in Hjv-/- mice (aim 3). This work will advance our understanding of the fundamental mechanisms by which the body simultaneously maintains homeostasis of Fe and Mn, two essential yet potentially toxic metals that can share transport pathways yet differ in abundance—Fe levels are much higher than Mn levels in the healthy human body. Our results will be applicable to rare conditions such as SLC30A10 deficiency and common conditions such as hereditary hemochromatosis and Fe deficiency.


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: 2026 ( Subtotal = $612,821 )
2026	2026	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/13/2026	NEW	$612,821
														Subtotal = $612,821

Grand Total All Awards = $612,821

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Balancing Iron and Manganese Homeostasis in Hereditary Hemochromatosis

Award Number: R01DK148124

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: 05/13/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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