Wednesday, April 2, 2025 4/2/2025

Molecular Mechanisms of Active Copper Transport

Award Number: R01DK071865
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Molecular Mechanisms of Active Copper Transport - PROJECT SUMMARY This proposal is to continue studies aimed to understand how absorption of different nutrients is coregulated by small intestine in health and disease. Proper nutrient absorption by gastrointestinal tract is essential for human health; dysregulation of GI function results in a broad spectrum of human disorders and in extreme cases, death. We have discovered an unexpected and tight relationship between copper transport and fat absorption in both healthy intestine and in the animal model of Wilson disease (WD). We demonstrated that copper modulates maturation and trafficking of chylomicrons, the major carriers of dietary fat, and identified specific steps in chylomicron processing that are sensitive to copper levels. Moreover, fatty acids regulate trafficking and localization of Cu transporters in enterocytes, providing a feedback loop. We will now identify the molecular mechanism of this co-regulation and examine how it is altered in human disease. In Specific Aim 1, we will characterize the role of the copper transporters ATP7A and SLC31A1 in chylomicrons secretion by examining the effects of their intracellular localization on ApoB trafficking, lipid content, and chylomicrons secretion. Experiments in Specific Aim 2 will elucidate how intestinal ANKRD9 senses ATP levels and facilitates ApoB and Slc31a1 trafficking in enterocytes; this will be done by characterizing the ANKRD9 macromolecular complexes and identifying ANKRD9 ATP-sensing site(s). Specific Aim 3 will determine how Cu misbalance impacts metabolic status of human intestine in WD by characterizing the duodenal proteomes of non-treated and chelator treated WD patients, as well as non-WD controls. Single cell nuclear sequencing of human WD tissue will establish how Cu misbalance impacts cell speciation in intestine and the metabolic state of human intestine.


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 = $532,089 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	2/28/2025	NON-COMPETING CONTINUATION	$532,089
														Subtotal = $532,089

Issue Date FY: 2024 ( Subtotal = $575,501 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	18	8/13/2024	COMPETING CONTINUATION	$0
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	4/24/2024	COMPETING CONTINUATION	$575,501
														Subtotal = $575,501

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	9/5/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $446,181 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	3/8/2022	NON-COMPETING CONTINUATION	$401,561
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	3/30/2022	NON-COMPETING CONTINUATION	$44,620
														Subtotal = $446,181

Issue Date FY: 2021 ( Subtotal = $446,181 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	3/19/2021	NON-COMPETING CONTINUATION	$446,181
														Subtotal = $446,181

Issue Date FY: 2020 ( Subtotal = $446,181 )
2020	2020	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	3/20/2020	NON-COMPETING CONTINUATION	$446,181
														Subtotal = $446,181

Issue Date FY: 2019 ( Subtotal = $496,181 )
2019	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	14	9/6/2019	COMPETING CONTINUATION	$50,000
2019	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	6/10/2019	COMPETING CONTINUATION	$446,181
2019	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	1/28/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $496,181

Issue Date FY: 2017 ( Subtotal = $354,543 )
2017	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	8/17/2017	NON-COMPETING CONTINUATION	$354,543
														Subtotal = $354,543

Issue Date FY: 2016 ( Subtotal = $354,543 )
2016	2016	JOHNS HOPKINS UNIVERSITY	1101 E 33RD STREET, STE-C-210	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	7/26/2016	NON-COMPETING CONTINUATION	$354,543
														Subtotal = $354,543

Issue Date FY: 2015 ( Subtotal = $354,543 )
2015	2015	JOHNS HOPKINS UNIVERSITY	1101 E 33RD STREET, STE-C-210	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	9/22/2015	COMPETING CONTINUATION	$354,543
														Subtotal = $354,543

Issue Date FY: 2014 ( Subtotal = $330,250 )
2014	2014	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	6/18/2014	NON-COMPETING CONTINUATION	$330,250
														Subtotal = $330,250

Issue Date FY: 2013 ( Subtotal = $318,691 )
2013	2013	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	6/26/2013	NON-COMPETING CONTINUATION	$318,691
														Subtotal = $318,691

Issue Date FY: 2012 ( Subtotal = $330,250 )
2012	2012	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	6/15/2012	NON-COMPETING CONTINUATION	$330,250
														Subtotal = $330,250

Issue Date FY: 2011 ( Subtotal = $330,249 )
2011	2011	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	6/20/2011	NON-COMPETING CONTINUATION	$330,249
														Subtotal = $330,249

Issue Date FY: 2010 ( Subtotal = $449,951 )
2010	2010	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	9/17/2010	COMPETING CONTINUATION	$449,951
2010	2009	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	9/17/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $449,951

Issue Date FY: 2009 ( Subtotal = $312,404 )
2009	2009	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	8/11/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$312,404
2009	2008	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97201	MULTNOMAH	USA	Digestive Diseases and Nutrition Research	000	4	7/29/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $312,404

Issue Date FY: 2008 ( Subtotal = $314,523 )
2008	2008	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97201	MULTNOMAH	USA	Digestive Diseases and Nutrition Research	000	4	6/27/2008	NON-COMPETING CONTINUATION	$314,523
														Subtotal = $314,523

Issue Date FY: 2007 ( Subtotal = $378,438 )
2007	2007	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97201	MULTNOMAH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/12/2007	SUPPLEMENT FOR EXPANSION	$28,593
2007	2007	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97201	MULTNOMAH	USA	Digestive Diseases and Nutrition Research	000	3	8/13/2007	NON-COMPETING CONTINUATION	$349,845
														Subtotal = $378,438

Issue Date FY: 2006 ( Subtotal = $307,364 )
2006	2006	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97201	MULTNOMAH	USA	Digestive Diseases and Nutrition Research	000	2	8/9/2006	NON-COMPETING CONTINUATION	$307,364
														Subtotal = $307,364

Issue Date FY: 2005 ( Subtotal = $308,733 )
2005	2005	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97201	MULTNOMAH	USA	Digestive Diseases and Nutrition Research	000	1	7/28/2005	NEW	$308,733
														Subtotal = $308,733

Grand Total All Awards = $7,386,796

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Molecular Mechanisms of Active Copper Transport

Award Number: R01DK071865

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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