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Copper Homeostasis in Mammals

Award Number: R01DK074192
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: 02/01/2001
PERIOD OF PERFORMANCE END DATE: 02/28/2023

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Copper Homeostasis in Mammals - Copper (Cu) is an essential trace metal that is acquired from the diet and serves as a catalytic co-factor for a wide variety of enzymatic reactions that play critical roles in life. Cu deficiency leads to pathophysiological manifestations including impaired iron absorption, neutropenia, cognitive defects, peripheral neuropathy and hypertrophic cardiomyopathy. Understanding the mechanisms responsible for the accumulation of Cu in cells and tissues, the regulation of Cu accumulation, and the consequences due to dysregulated Cu acquisition are important to human health. Ctr1 is the only known Cu+ importer in mammals and while Ctr1 plays an essential role in dietary and peripheral Cu acquisition, embryonic development, cardiac function and normal growth, little is known about the mechanisms that regulate Ctr1 activity. Ctr1 exists both as a full-length protein and as a truncated form (tCtr1) lacking the extracellular Cu binding domain, which has reduced Cu uptake activity. We identified cathepsin as a protease that carries out the rate-limiting step in Ctr1 ecto-domain cleavage and demonstrated that this cleavage is stimulated by the Ctr2 integral membrane protein. Among patients in a large cardiac catheterization clinic cohort, we identified a single nucleotide polymorphism (SNP) in the human Ctr1 gene that occurs predominantly in African Americans, resulting in hyper-cleavage of the Ctr1 Cu-binding ecto-domain and decreased cellular Cu acquisition. Here we detail experiments to test the hypothesis that Ctr1 ecto-domain cleavage, through the cathepsin L/B proteases and Cu-responsive Ctr2 levels, is a critical regulatory mechanism for mammalian Cu acquisition. Our experiments will identify new components in mammalian Cu homeostasis, decipher a new mechanism for Cu- dependent proteolysis, generate a new animal model and validate a link between a defect in Ctr1 ecto-domain cleavage, Cu deficiency and hypertrophic cardiomyopathy in African Americans.


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 = -$283 )
2024	2021	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	11/1/2023	NON-COMPETING CONTINUATION	-$283
														Subtotal = -$283

Issue Date FY: 2021 ( Subtotal = $421,496 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	2/19/2021	NON-COMPETING CONTINUATION	$421,496
														Subtotal = $421,496

Issue Date FY: 2020 ( Subtotal = $421,496 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	2/12/2020	NON-COMPETING CONTINUATION	$421,496
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	18	7/27/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $421,496

Issue Date FY: 2019 ( Subtotal = $421,496 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	1/25/2019	NON-COMPETING CONTINUATION	$421,496
														Subtotal = $421,496

Issue Date FY: 2018 ( Subtotal = $421,496 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	2/9/2018	NON-COMPETING CONTINUATION	$379,347
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	16	4/23/2018	NON-COMPETING CONTINUATION	$42,149
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	16	3/16/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $421,496

Issue Date FY: 2017 ( Subtotal = $434,770 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	15	7/20/2017	COMPETING CONTINUATION	$5,500
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	5/4/2017	COMPETING CONTINUATION	$434,770
2017	2015	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	14	7/20/2017	NON-COMPETING CONTINUATION	-$5,500
2017	2015	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	5/2/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $434,770

Issue Date FY: 2015 ( Subtotal = $336,746 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	6/11/2015	NON-COMPETING CONTINUATION	$336,746
														Subtotal = $336,746

Issue Date FY: 2014 ( Subtotal = $336,884 )
2014	2014	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	7/21/2014	NON-COMPETING CONTINUATION	$336,884
														Subtotal = $336,884

Issue Date FY: 2013 ( Subtotal = $325,222 )
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	7/29/2013	NON-COMPETING CONTINUATION	$325,222
														Subtotal = $325,222

Issue Date FY: 2012 ( Subtotal = $337,148 )
2012	2012	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	7/31/2012	NON-COMPETING CONTINUATION	$337,148
														Subtotal = $337,148

Issue Date FY: 2011 ( Subtotal = $387,671 )
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	7/12/2011	COMPETING CONTINUATION	$387,671
2011	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/11/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,671

Issue Date FY: 2010 ( Subtotal = $257,185 )
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	2/19/2010	NON-COMPETING CONTINUATION	$257,185
														Subtotal = $257,185

Issue Date FY: 2009 ( Subtotal = $259,782 )
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	2/19/2009	NON-COMPETING CONTINUATION	$233,803
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	3/5/2009	NON-COMPETING CONTINUATION	$25,979
														Subtotal = $259,782

Issue Date FY: 2008 ( Subtotal = $259,782 )
2008	2008	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Digestive Diseases and Nutrition Research	000	7	2/5/2008	NON-COMPETING CONTINUATION	$259,782
														Subtotal = $259,782

Issue Date FY: 2007 ( Subtotal = $264,799 )
2007	2007	DUKE UNIVERSITY	BOX 104135	DURHAM	NC	27708	DURHAM	USA	Digestive Diseases and Nutrition Research	000	6	2/27/2007	NON-COMPETING CONTINUATION	$264,799
														Subtotal = $264,799

Issue Date FY: 2006 ( Subtotal = $271,833 )
2006	2006	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Digestive Diseases and Nutrition Research	000	5	2/27/2006	OTHER REVISION	$271,833
														Subtotal = $271,833

Grand Total All Awards = $5,157,524

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Copper Homeostasis in Mammals

Award Number: R01DK074192

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: 02/01/2001

PERIOD OF PERFORMANCE END DATE: 02/28/2023

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