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Copper and iron in nutritional immunity

Award Number: R01DK116859
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: 01/17/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Copper and iron in nutritional immunity - The objective of this proposal is to elucidate the mechanisms by which the coppercontaining ferroxidase, ceruloplasmin, regulates nutritional immunity against bacterial infection. There is an urgent need to understand mechanisms of nutrient homeostasis in order to develop more effective treatments and therapies. Nutritional immunity describes mechanisms that alter host metal ion homeostasis during microbial infection. An important aspect of nutritional immunity is iron withholding from bacterial pathogens via hypoferremia (low plasma iron levels). Hypoferremia is regulated by peptide hormone, hepcidin, which restricts iron export into the plasma by inducing the degradation of the iron exporter, ferroportin in hepatocytes, enterocytes and macrophages. Another mechanism of nutritional immunity involves hypercupremia (high plasma copper levels). This process occurs via increased hepatic secretion of ceruloplasmin, a copper carrying ferroxidase that contains the majority of copper in the plasma. Copper is thought to facilitate killing of bacterial pathogens via macrophages of the innate immune system, however, the role of ceruloplasmin in this process is unknown. Despite its identification as an acute phase protein more than 60 years ago, the requirement for ceruloplasmin during infection remains unknown. As a ferroxidase, ceruloplasmin facilitates iron export via ferroportin, however, this function is unnecessary during infection due to ferroportin degradation. Thus, it is likely that ceruloplasmin has alternative functions during infection. Preliminary results demonstrate that ceruloplasmin knockout mice are highly susceptible to systemic infection by the bacterial pathogens Salmonella typhimurium and Staphylococcus aureus. In addition, ceruloplasmin knockout mice were found to exhibit reduced serum levels of proinflammatory cytokines when challenged with bacterial ligands to Tolllike receptors (TLRs), highlighting a possible role for ceruloplasmin in TLR signaling. In this proposal, biochemical and genetic approaches will be used to understand the contribution of ceruloplasmin to nutritional immunity. AIM1 tests the role of iron and copper on hypersensitivity of ceruloplasmin-null mice to infection. AIM 2 seeks to understand the role of ceruloplasmin in TLR signaling within macrophages. AIM 3 investigates whether macrophage or hepatocyte expression of ceruloplasmin is required for host immunity.


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 = $0 )
2024	2022	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $418,811 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/12/2021	NON-COMPETING CONTINUATION	$376,929
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/29/2022	NON-COMPETING CONTINUATION	$41,882
														Subtotal = $418,811

Issue Date FY: 2021 ( Subtotal = $417,462 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	2/2/2021	NON-COMPETING CONTINUATION	$41,747
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/27/2020	NON-COMPETING CONTINUATION	$375,715
														Subtotal = $417,462

Issue Date FY: 2020 ( Subtotal = $418,811 )
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/6/2019	NON-COMPETING CONTINUATION	$376,929
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/10/2020	NON-COMPETING CONTINUATION	$41,882
														Subtotal = $418,811

Issue Date FY: 2019 ( Subtotal = $403,233 )
2019	2019	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/16/2019	NEW	$403,233
														Subtotal = $403,233

Grand Total All Awards = $1,658,317

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Copper and iron in nutritional immunity

Award Number: R01DK116859

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: 01/17/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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