Copper (Cu) plays key catalytic and regulatory functions for biochemical reactions that are critical to normal growth, development and health. Menkes disease and Wilson's disease are two severe human genetic disorders of Cu metabolism that result in childhood mortality and hepatic and neurological dysfunction, respectively. Inappropriate copper balance is linked to myeloneuropathy, prion disease, Alzheimer's and cardiovascular disease and cancer. Consequently, it is critical to understand the mechanisms by which cells control the acquisition, distribution and utilization of Cu. While the identify and functions of the Cu import, intracellular distribution and efflux machinery are beginning to be understood, we know very little about the physiological role of the Ctr2 protein, the regulation of Cu import and how organisms establish global Cu homeostasis.
Three specific aims are outlined in this application, which are inter- related by the information they will decipher on the mechanisms of action of the mammalian Cu transport machinery and its regulation at the cellular and systemic level. In the first specific aim the physiological role of the mammalian Ctr2 protein in Cu acquisition will be ascertained through the analysis of mouse Ctr2 knock out mutants, through biochemical and cell biological experiments in cultured cells and through the analysis of Ctr2 mutant proteins. In the second specific aim the regulation of the Ctr1 Cu importer and the Ctr2 protein will be deciphered through an analysis of their post- translational regulation in cell culture. In the third specific aim experiments are outlined to identify a novel blood-borne signal that allows inter-organ communication between peripheral organs such as the heart and the copper acquisition and storage organs. Taken together, these investigations will decipher key functional roles and cellular and systemic regulatory mechanisms for the Cu acquisition machinery, the function of which is essential for normal growth, development and human health.

Public Health Relevance

Copper is an essential element for human health and the inability to properly regulate copper balance is associated with lethal childhood disease, liver and neurological disease, Alzheimer's disease, cardiovascular disease and cancer. The research outlined in this application is designed to understand how mammals properly acquire copper and how copper acquisition is regulated. These studies may identify pathways and potential therapeutic avenues that are important in human diseases of copper balance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK074192-11
Application #
8300126
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
2001-02-01
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
11
Fiscal Year
2012
Total Cost
$337,148
Indirect Cost
$119,648
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Öhrvik, Helena; Logeman, Brandon; Turk, Boris et al. (2016) Cathepsin Protease Controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-binding Ectodomain. J Biol Chem 291:13905-16
Srivastava, Shekhar; Panda, Saswati; Li, Zhai et al. (2016) Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1. Elife 5:
Öhrvik, Helena; Thiele, Dennis J (2015) The role of Ctr1 and Ctr2 in mammalian copper homeostasis and platinum-based chemotherapy. J Trace Elem Med Biol 31:178-82
Allensworth, Jennifer L; Evans, Myron K; Bertucci, François et al. (2015) Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer. Mol Oncol 9:1155-68
Öhrvik, Helena; Logeman, Brandon; Noguchi, Glyn et al. (2015) Ctr2 Regulates Mast Cell Maturation by Affecting the Storage and Expression of Tryptase and Proteoglycans. J Immunol 195:3654-64
García-Santamarina, Sarela; Thiele, Dennis J (2015) Copper at the Fungal Pathogen-Host Axis. J Biol Chem 290:18945-53
Shawki, Ali; Anthony, Sarah R; Nose, Yasuhiro et al. (2015) Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese. Am J Physiol Gastrointest Liver Physiol 309:G635-47
Ohrvik, Helena; Thiele, Dennis J (2014) How copper traverses cellular membranes through the mammalian copper transporter 1, Ctr1. Ann N Y Acad Sci 1314:32-41
Brady, Donita C; Crowe, Matthew S; Turski, Michelle L et al. (2014) Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 509:492-6
Öhrvik, Helena; Nose, Yasuhiro; Wood, L Kent et al. (2013) Ctr2 regulates biogenesis of a cleaved form of mammalian Ctr1 metal transporter lacking the copper- and cisplatin-binding ecto-domain. Proc Natl Acad Sci U S A 110:E4279-88

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