Our previous research demonstrates that insufficient copper (Cu) during perinatal development has a major impact on the central nervous system leading to severe long-term neurochemical and behavioral consequences. The broad long-range goal of this research is to identify the neurochemical roles for Cu which will lead to a better understanding of the elusive mechanisms of Cu deficient neuropathology. Our ongoing research in rodents demonstrates that there are selected regional neurochemical alterations induced by Cu deficiency including changes in Cu levels, catecholamine pools, and altered activity of cuproenzymes. Our research also suggests that restoration of brain Cu following perinatal deficiency may be difficult, if not impossible. More importantly, we have been able to show that at least one sensory-motor function, acoustic startle, is exquisitely altered in Cu-repleted rats even after months of nutritional supplementation.
The specific aims of this focused multidisciplinary project are both descriptive and mechanism based.
AIM 1 : Firstly, we wish to establish the critical time period and dietary Cu level necessary for expression of permanent behavior alterations and neuropathology. To accomplish these goals, experiments will be conducted using Sprague Dawley rats. Dietary Cu deficiency will be produced during perinatal development and post lactation to investigate nutrition-related responses in the developing nervous system. In all cases, the Cu-deficient or Cu-repleted rats will be compared to Cu-adequate control animals.
AIM 2 : Secondly, we will identify the mechanism(s) for impaired brain development. Specifically, we will test the hypothesis that low brain norepinephrine is responsible for the altered brain development (hypomyelination and delayed synaptogenesis) and altered auditory startle by including studies with L-3,4-dihydroxyphenylserine (L-DOPS) to bypass the Cu-dependent enzyme dopamine-beta-monooxygenase. Biochemical and behavioral endpoints will be employed.
AIM 3 : Thirdly, we will identify the mechanism(s) for neuronal pathology. These experiments are based on the hypothesis that necrosis and apoptosis are driven by alterations in brain mitochondrial function. We will study isolated mitochondria and test specific hypotheses related to mechanisms of apoptosis and necrosis. Collectively, accomplishment of these aims will lead to a better understanding of the molecular mechanisms of Cu and are relevant because failure to accumulate Cu during brain development may lead to permanent alterations in neurotransmission, abnormal behavior, and diminished cognitive capacity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD039708-01
Application #
6226388
Study Section
Nutrition Study Section (NTN)
Program Officer
Hanson, James W
Project Start
2001-03-01
Project End
2004-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
1
Fiscal Year
2001
Total Cost
$161,825
Indirect Cost
Name
University of Minnesota Duluth
Department
Biochemistry
Type
Schools of Medicine
DUNS #
071508873
City
Duluth
State
MN
Country
United States
Zip Code
55812
Broderius, Margaret; Mostad, Elise; Prohaska, Joseph R (2012) Suppressed hepcidin expression correlates with hypotransferrinemia in copper-deficient rat pups but not dams. Genes Nutr 7:405-14
Prohaska, Joseph R; Broderius, Margaret (2012) Copper deficiency has minimal impact on ferroportin expression or function. Biometals 25:633-42
Gletsu-Miller, N; Broderius, M; Frediani, J K et al. (2012) Incidence and prevalence of copper deficiency following roux-en-y gastric bypass surgery. Int J Obes (Lond) 36:328-35
Bastian, Thomas W; Anderson, Jeremy A; Fretham, Stephanie J et al. (2012) Fetal and neonatal iron deficiency reduces thyroid hormone-responsive gene mRNA levels in the neonatal rat hippocampus and cerebral cortex. Endocrinology 153:5668-80
Mostad, Elise J; Prohaska, Joseph R (2011) Glycosylphosphatidylinositol-linked ceruloplasmin is expressed in multiple rodent organs and is lower following dietary copper deficiency. Exp Biol Med (Maywood) 236:298-308
Bastian, Thomas W; Lassi, Katie C; Anderson, Grant W et al. (2011) Maternal iron supplementation attenuates the impact of perinatal copper deficiency but does not eliminate hypotriiodothyroninemia nor impaired sensorimotor development. J Nutr Biochem 22:1084-90
Prohaska, Joseph R (2011) Impact of copper limitation on expression and function of multicopper oxidases (ferroxidases). Adv Nutr 2:89-95
Lyons, Jacob A; Prohaska, Joseph R (2010) Perinatal copper deficiency alters rat cerebellar purkinje cell size and distribution. Cerebellum 9:136-44
Bastian, Thomas W; Prohaska, Joseph R; Georgieff, Michael K et al. (2010) Perinatal iron and copper deficiencies alter neonatal rat circulating and brain thyroid hormone concentrations. Endocrinology 151:4055-65
Broderius, Margaret; Mostad, Elise; Wendroth, Krista et al. (2010) Levels of plasma ceruloplasmin protein are markedly lower following dietary copper deficiency in rodents. Comp Biochem Physiol C Toxicol Pharmacol 151:473-9

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