The trace element copper (Cu) is essential for normal growth and development due to its role in a wide variety of biochemical reactions that carry out processes including energy generation, connective tissue maturation, neuropeptide processing, blood clotting, iron distribution and oxidative stress protection. Dietary Cu deprivation or diseases of Cu homeostasis result in impaired motor function, severe cognitive disorders, embryonic and neonatal developmental abnormalities, cardiac hypertrophy, defective angiogenesis and reduced aortic elasticity, anemia and many other pathophysiological states. While a number of genes and their corresponding proteins have been identified in yeast and mammals that function in Cu uptake and distribution at the cellular level, there are many gaps in our knowledge of the function of these components in mammalian physiology. This proposal describes avenues of investigation, using mice as a model mammalian system, to decipher the mechanisms of action and physiological roles of two mammalian Cu transport proteins, Ctrl and Ctr2. In the first specific aim genetic, cell biology and biochemical experiments are outlined to understand the physiological functions of the Ctrl Cu importer in dietary Cu acquisition and in systemic Cu distribution. The second specific aim outlines experiments to dissect the function of the Ctr2 Cu transporter, which localizes to intracellular vesicular compartments, in intracellular Cu transport at the cellular level and its role in mammalian physiology. Taken together, these studies will address critical gaps in our knowledge on the regulation and physiological function of the Ctrl and Ctr2 Cu transport proteins in driving Cu-dependent biochemical reactions that are critical for normal mammalian growth and development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK074192-09
Application #
7775088
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
2001-02-01
Project End
2011-07-31
Budget Start
2010-03-01
Budget End
2011-07-31
Support Year
9
Fiscal Year
2010
Total Cost
$257,185
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Logeman, Brandon L; Wood, L Kent; Lee, Jaekwon et al. (2017) Gene duplication and neo-functionalization in the evolutionary and functional divergence of the metazoan copper transporters Ctr1 and Ctr2. J Biol Chem 292:11531-11546
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; 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
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
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
García-Santamarina, Sarela; Thiele, Dennis J (2015) Copper at the Fungal Pathogen-Host Axis. J Biol Chem 290:18945-53
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
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

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