This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Copper is an essential, yet toxic micronutrient that plays a critical role in a number of physiological processes and in the development of diseases. Organisms must acquire copper from the diet and deliver it to copper-requiring proteins while preventing toxic accumulation and release of free reactive form of copper. An important emerging area is the identification of the components in copper metabolism and the characterization of their functions, interactions and regulations in achieving systemic copper homeostasis. Our long-term research goals are to elucidate mechanisms of the homeostatic copper metabolism in mammals and to determine the molecular basis of defects in copper metabolism that causes copper-related diseases. Our previous studies on the Ctr1 mammalian copper transporter have laid the foundation and provided novel tools for the investigation of Ctr1 functions and implications of aberrant copper transport in diseases. This proposal addresses the roles of the Ctr1 copper transporter in systemic copper homeostasis using cell lines and mouse models with the following specific aims: (1) We will determine the roles played by Ctr1 in dietary copper absorption in the intestine using an intestinal cell line and mice in which Ctr1 expression levels are genetically modulated. (2) We will identify underlying mechanisms causing organ-specific copper accumulation defects of Ctr1 heterozygous (Ctr1+/-) mice. This study will elucidate the role and mode of actions of Ctr1 and the interactions among components that play roles in achieving systemic copper homeostasis. (3) We will generate and characterize inter-crossed mice between Ctr1+/- or Ctr1 over-expressing mice and mouse model of human Wilson disease (a copper toxicity disease) or Alzheimer s disease (a copper -related disease with complex etiology), to elucidate the roles of defects in Ctr1-mediated copper uptake in the progression of these diseases. Collectively, the proposed studies will determine the roles of the mammalian Ctr1 copper transporter in systemic copper homeostasis, and ultimately provide critical information to develop better strategies to treat copper-related disorders.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR017675-05
Application #
7381838
Study Section
Special Emphasis Panel (ZRR1-RI-A (02))
Project Start
2006-07-01
Project End
2007-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$207,910
Indirect Cost
Name
University of Nebraska Lincoln
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
555456995
City
Lincoln
State
NE
Country
United States
Zip Code
68588
Garza-Lombó, Carla; Schroder, Annika; Reyes-Reyes, Elsa M et al. (2018) mTOR/AMPK signaling in the brain: Cell metabolism, proteostasis and survival. Curr Opin Toxicol 8:102-110
Marshall, Darrell D; Powers, Robert (2017) Beyond the paradigm: Combining mass spectrometry and nuclear magnetic resonance for metabolomics. Prog Nucl Magn Reson Spectrosc 100:1-16
Anandhan, Annadurai; Lei, Shulei; Levytskyy, Roman et al. (2017) Glucose Metabolism and AMPK Signaling Regulate Dopaminergic Cell Death Induced by Gene (?-Synuclein)-Environment (Paraquat) Interactions. Mol Neurobiol 54:3825-3842
Rose, Jordan; Brian, Christian; Woods, Jade et al. (2017) Mitochondrial dysfunction in glial cells: Implications for neuronal homeostasis and survival. Toxicology 391:109-115
Boone, Cory H T; Grove, Ryan A; Adamcova, Dana et al. (2017) Oxidative stress, metabolomics profiling, and mechanism of local anesthetic induced cell death in yeast. Redox Biol 12:139-149
Markley, John L; Brüschweiler, Rafael; Edison, Arthur S et al. (2017) The future of NMR-based metabolomics. Curr Opin Biotechnol 43:34-40
Duszenko, Nikolas; Buan, Nicole R (2017) Physiological Evidence for Isopotential Tunneling in the Electron Transport Chain of Methane-Producing Archaea. Appl Environ Microbiol 83:
Anandhan, Annadurai; Jacome, Maria S; Lei, Shulei et al. (2017) Metabolic Dysfunction in Parkinson's Disease: Bioenergetics, Redox Homeostasis and Central Carbon Metabolism. Brain Res Bull 133:12-30
Gebregiworgis, Teklab; Nielsen, Helle H; Massilamany, Chandirasegaran et al. (2016) A Urinary Metabolic Signature for Multiple Sclerosis and Neuromyelitis Optica. J Proteome Res 15:659-66
Navarro-Yepes, Juliana; Anandhan, Annadurai; Bradley, Erin et al. (2016) Inhibition of Protein Ubiquitination by Paraquat and 1-Methyl-4-Phenylpyridinium Impairs Ubiquitin-Dependent Protein Degradation Pathways. Mol Neurobiol 53:5229-51

Showing the most recent 10 out of 177 publications