Wednesday, July 2, 2025 7/2/2025

Rethinking the zinc-copper relationship in Wilson Disease

Award Number: R15DK114747
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: 08/15/2017
PERIOD OF PERFORMANCE END DATE: 07/31/2025

Group Awards By:

View Award Description

Rethinking the zinc-copper relationship in Wilson Disease - Wilson Disease (WD) is an inherited disorder of copper (Cu) metabolism that results in pathogenic Cu accumulation in the liver and brain as well as secondary organ damage largely related to liver injury. WD diagnosis and treatment are challenging, while an important gap in treatment includes a lack of measurable biomarkers that specifically report on treatment. An estimated 1:100 people carry a pathogenic mutation in the ATP7B Cu transporter that is deficient in WD, while the global prevalence estimate for WD is 1:30,000, with higher prevalence in specific communities (e.g., Canary Islands 1:2,600 and South Korea 1:3,500). The current understanding of WD progression is that pathogenesis develops from damage to the liver and its key functions. Cu excess is expected to induce oxidative damage to cellular structures; this injury appears to be more important later in disease progression, while the early and specific molecular effects of Cu accumulation appear to be in liver metabolic function, specifically lipid metabolism and mitochondrial activity. WD treatments can be classified as either zinc (Zn) salts or Cu chelators. Poor response to these therapies necessitates liver transplant. One major challenge in successful treatment is a lack of compliance, which is influenced by adverse side effects or cumbersome therapeutic schedules. Treatment sometimes induces paradoxical neurological deterioration. Given these challenges, knowledge of biomarkers that respond to treatment will be valuable to personalize WD therapy. Recent work, including our own, indicates that Zn-containing proteins are specifically affected in WD and that liver metabolic processes, many regulated by Zn proteins, are changed. The proposed work will build on this knowledge to define candidate biomarkers responsive to WD treatment. We will leverage a well-characterized WD mouse model in a treatment study to identify metabolite, gene expression and metal responses in liver and serum that are induced by Cu chelator or Zn treatments. The project executes the following Specific Aims: 1) Define treatment-responsive metabolite biomarkers induced by Cu chelator or Zn treatment in the Atp7b-/- mouse model of WD. Prior work has identified candidate biomarkers of WD in mice and humans, but these biomarkers are indicative of several liver diseases. Our approach will define candidate markers in liver and serum that respond specifically to WD treatment. 2) Determine sex-specific transition metal responses to WD treatments. Both animal models and humans appear to have sex- differentiated Cu and Zn homeostatic control, indicating it is important to understand how WD treatments have differential impacts by sex. 3) Define Cu and Zn interactions in cell health. Crosstalk between Cu and Zn is not well defined and may be important beyond WD treatment. This aim will use a non-WD hepatoma cell and wild-type mouse models to determine impacts of Cu chelation or zinc supplementation. This translational project will leverage existing data and a new, rich, sex-specific, dataset of metabolites, metals, and cellular Cu- Zn interactions to identify candidate biomarkers for enhancement of WD treatment.


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: 2023 ( Subtotal = -$23,632 )
2023	2022	UNIVERSITY OF ALASKA ANCHORAGE	3211 PROVIDENCE DR	ANCHORAGE	AK	99508	ANCHORAGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	10/1/2022	COMPETING CONTINUATION	-$23,632
														Subtotal = -$23,632

Issue Date FY: 2022 ( Subtotal = $439,694 )
2022	2022	UNIVERSITY OF ALASKA ANCHORAGE	3211 PROVIDENCE DR	ANCHORAGE	AK	99508	ANCHORAGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/18/2022	COMPETING CONTINUATION	$439,694
2022	2022	UNIVERSITY OF ALASKA ANCHORAGE	3211 PROVIDENCE DR	ANCHORAGE	AK	99508	ANCHORAGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	9/29/2022	COMPETING CONTINUATION	$23,632
2022	2017	UNIVERSITY OF ALASKA ANCHORAGE	3211 PROVIDENCE DR	ANCHORAGE	AK	99508	ANCHORAGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/29/2022	NEW	-$23,632
														Subtotal = $439,694

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2017	UNIVERSITY OF ALASKA ANCHORAGE	3211 PROVIDENCE DR	ANCHORAGE	AK	99508	ANCHORAGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/1/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	UNIVERSITY OF ALASKA ANCHORAGE	3211 PROVIDENCE DR	ANCHORAGE	AK	99508	ANCHORAGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/20/2018	NEW	$439,784
2018	2017	UNIVERSITY OF ALASKA ANCHORAGE	3211 PROVIDENCE DR	ANCHORAGE	AK	99508	ANCHORAGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/18/2018	NEW	-$439,784
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $439,784 )
2017	2017	UNIVERSITY OF ALASKA ANCHORAGE	3211 PROVIDENCE DR	ANCHORAGE	AK	99508	ANCHORAGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/11/2017	NEW	$439,784
														Subtotal = $439,784

Grand Total All Awards = $855,846

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Rethinking the zinc-copper relationship in Wilson Disease

Award Number: R15DK114747

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: 08/15/2017

PERIOD OF PERFORMANCE END DATE: 07/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer