Control of copper homeostasis by regulation of the high affinity copper transporter Ctr1

dc.contributor.advisor

Thiele, Dennis J

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Logeman, Brandon Lee

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2018-03-20T17:56:33Z

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2019-12-15T09:17:09Z

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2017

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Pharmacology

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Copper is an essential element due to its unique ability to cycle between redox states under biological conditions. This property makes copper an ideal catalytic co-factor for enzymes that function in energy generation, iron acquisition, oxygen transport, cellular metabolism, peptide hormone maturation, blood clotting, signal transduction and a variety of other cellular processes. However, excess copper can lead to free radical mediated membrane damage, protein oxidation, and DNA cleavage along with improper metallation of Fe-S clusters. The inability to properly acquire and handle copper is associated with severe genetic diseases of both deficiency and overload as exemplified in Menkes and Wilsons diseases, respectively. Thus, characterizing the acquisition, regulation, and homeostasis of this essential metal is imperative for our understanding of human biology.

The studies presented here utilize a diverse array of techniques including yeast and mouse genetics, recombinant protein expression, purification and biochemical characterization of copper homeostasis proteins, evolutionary genetic analysis, in vitro copper transport assays, and cell culture studies to decipher novel aspects of mammalian copper biology. Critical findings include the discovery of a previously unknown regulator of Copper transporter 1 (Ctr1), and analysis of the evolutionary history of mammalian Ctr proteins, the development of biochemical techniques to probe copper transport mechanisms in a purified system, and the identification of a novel polymorphism in the human Ctr1 gene that has functional consequences. These unique insights lay the foundation for a greater understanding of the basic mechanisms for copper homeostasis in both healthy and diseased states.

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https://hdl.handle.net/10161/16363

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Molecular biology

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Biochemistry

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copper

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Ctr1

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Ctr2

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Control of copper homeostasis by regulation of the high affinity copper transporter Ctr1

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Dissertation

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21

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