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Molecular Mechanisms of Intestinal Metal Ion Transport During Iron Deficiency

Award Number: R01DK074867
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: 07/01/2007
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Molecular Mechanisms of Intestinal Metal Ion Transport During Iron Deficiency - Project Summary Iron deficiency (ID) is common in the U.S, causing significant morbidity. The inability to assimilate adequate amounts of dietary iron, due to increased demands (e.g. with excessive menstrual blood loss) or impaired utilization (e.g. iron malabsorption after gastric bypass surgery), frequently underlies ID. Women of child- bearing age, pregnant women, the elderly (in whom achlorhydria is common), and children and adolescents are commonly iron deficient; in these individuals, iron supplementation may be recommended. During pregnancy, anemia is common since dietary iron assimilation is often inadequate to meet iron demands to supply the developing fetus and for expansion of the maternal blood supply; iron supplementation is thus almost universally recommended. Importantly, we recently noted that high dietary iron caused severe copper deficiency, in rats and mice, with pathological consequences. These initial studies utilized supraphysiologic iron levels (>100-fold excess), but a subsequent experiment demonstrated that iron at ~4X above requirements resulted in moderate copper deficiency in rats. ID humans may consume iron at 4 times the RDA from dietary and supplemental sources. It was previously suggested that high-iron intake can antagonize copper, but this has not been validated by rigorous experimentation in animals or humans. This background then provides the rationale for this investigation in which we will test the central hypothesis that consumption of supplemental iron, at levels similar to what ID humans may consume, disrupts copper metabolism with likely pathological outcomes. Notably, copper deficiency mimics ID, as both conditions cause microcytic, hypochromic anemia. Lack of adequate iron impairs erythropoiesis in ID, while impaired iron utilization by developing erythrocytes underlies copper-deficiency anemia. Physicians may recommend higher iron dosing in patients that are refractory to supplemental iron, thus potentiating the copper deficiency. This investigation could change the existing paradigm of iron supplementation, with added copper accelerating resolution of the anemia and also preventing other pathophysiological effects of copper deficiency, including cardiomyopathy, cognitive dysfunction, and impaired immunity. Three specific aims will be pursued. Aim 1 will define the minimum amount of supplemental iron that perturbs copper homeostasis in rats and mice of both sexes. Aim 2 will identify the mechanism(s) by which supplemental iron perturbs copper homeostasis, possibly involving inhibition of intestinal copper transporters. Aim 3 will evaluate the efficacy of Fe + Cu for preventing the copper depletion associated with high-iron intake in preclinical models of human ID. This investigation may establish an argument for adding copper to iron supplements. Consuming extra copper should be without negative physiologic consequence, and could increase the effectiveness of iron supplementation programs, especially since many Americans may have marginal dietary copper intakes. This investigation could serve as a prelude to intervention trials in humans, which would be a logical extension of the experimentation proposed here.


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 )
2024	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	9/4/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2022 ( Subtotal = $467,861 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	5/2/2022	NON-COMPETING CONTINUATION	$467,861
														Subtotal = $467,861

Issue Date FY: 2021 ( Subtotal = $475,136 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	4/1/2021	NON-COMPETING CONTINUATION	$475,136
														Subtotal = $475,136

Issue Date FY: 2020 ( Subtotal = $482,182 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	3/25/2020	NON-COMPETING CONTINUATION	$482,182
														Subtotal = $482,182

Issue Date FY: 2019 ( Subtotal = $489,005 )
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	4/22/2019	NON-COMPETING CONTINUATION	$489,005
														Subtotal = $489,005

Issue Date FY: 2018 ( Subtotal = $545,617 )
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	11	6/28/2018	COMPETING CONTINUATION	$36,031
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	6/1/2018	COMPETING CONTINUATION	$50,000
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	5/31/2018	COMPETING CONTINUATION	$495,617
2018	2016	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	10	6/28/2018	EXTENSION WITH OR WITHOUT FUNDS	-$36,031
														Subtotal = $545,617

Issue Date FY: 2016 ( Subtotal = $326,250 )
2016	2016	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	2/1/2016	EXTENSION WITH OR WITHOUT FUNDS	$326,250
														Subtotal = $326,250

Issue Date FY: 2015 ( Subtotal = $326,250 )
2015	2015	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	3/4/2015	NON-COMPETING CONTINUATION	$326,250
														Subtotal = $326,250

Issue Date FY: 2014 ( Subtotal = $326,250 )
2014	2014	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	2/27/2014	NON-COMPETING CONTINUATION	$326,250
														Subtotal = $326,250

Issue Date FY: 2013 ( Subtotal = $325,707 )
2013	2013	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	2/26/2013	COMPETING CONTINUATION	$325,707
2013	2011	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	2/22/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $325,707

Issue Date FY: 2011 ( Subtotal = $263,133 )
2011	2011	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/27/2011	NON-COMPETING CONTINUATION	$263,133
														Subtotal = $263,133

Issue Date FY: 2010 ( Subtotal = $265,791 )
2010	2010	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/22/2010	NON-COMPETING CONTINUATION	$265,791
														Subtotal = $265,791

Issue Date FY: 2009 ( Subtotal = $247,950 )
2009	2009	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	4	7/6/2009	NON-COMPETING CONTINUATION	$268,476
2009	2009	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	2/11/2009	SUPPLEMENT FOR EXPANSION	$1,465
2009	2008	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Digestive Diseases and Nutrition Research	001	3	10/21/2008	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$268,476
2009	2008	STATE UNIVERSITY OF NEW YORK AT BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Digestive Diseases and Nutrition Research	000	2	10/21/2008	NON-COMPETING CONTINUATION	-$290,467
														Subtotal = $247,950

Issue Date FY: 2008 ( Subtotal = $299,977 )
2008	2008	SUNY, BUFFALO	UB Commons, Ste 211	AMHERST	NY	14228	ERIE	USA	Digestive Diseases and Nutrition Research	000	2	6/9/2008	NON-COMPETING CONTINUATION	$290,467
2008	2008	SUNY, BUFFALO	UB Commons, Ste 211	AMHERST	NY	14228	ERIE	USA	Digestive Diseases and Nutrition Research	001	1	3/18/2008	SUPPLEMENT FOR EXPANSION	$9,510
														Subtotal = $299,977

Issue Date FY: 2007 ( Subtotal = $273,371 )
2007	2007	SUNY, BUFFALO	UB Commons, Ste 211	AMHERST	NY	14228	ERIE	USA	Digestive Diseases and Nutrition Research	000	1	4/27/2007	NEW	$273,371
														Subtotal = $273,371

Grand Total All Awards = $5,114,479

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Molecular Mechanisms of Intestinal Metal Ion Transport During Iron Deficiency

Award Number: R01DK074867

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: 07/01/2007

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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