The long-term goals of this proposal are to elucidate the mechanisms by which the nutrient copper is made available for neonatal growth and development. Genetic mutations that disturb copper balance in children can give rise to disease. The most severe of these is Menkes disease, a lethal pediatric disorder that is caused by mutations in the ATP7A copper transporter. Other diseases attributable to mutations in ATP7A include occipital horn syndrome and peripheral motor neuron disease. Moreover, copper and/or the ATP7A protein is implicated in pathogenic processes underlying certain diseases of significant concern, including Alzheimer's disease, cancer chemotherapy resistance, and cardiovascular diseases. Thus, it is clear that understanding the role of ATP7A in specific tissue types is of high significance, not only in areas of copper physiology, but also disease pathogenesis. Progress in understanding the function of ATP7A in specific tissue types has been hampered in large part because null mutations in ATP7A are embryonic lethal in mice. To overcome these obstacles, we have developed a floxed ATP7A mouse model in which ATP7A can be deleted in specific tissues. In the preliminary studies, we demonstrate using an intestinal epithelial cell-specific knockout, that ATP7A is essential for transporting dietary copper into the blood stream to meet the copper demands of neonatal growth. We are now uniquely positioned to answer several long-standing questions in the field.
In Specific Aim 1, we will test whether ATP7A-mediated copper transport in the intestine is essential to meet the maternal demands during gestation and lactation.
In Specific Aim 2, we will test the novel hypothesis that ATP7A functions in the export of copper from hepatocytes to supply copper to the peripheral organs in the neonatal period, particularly if copper intake via milk is limiting.
In Specific Aim 3, we will test the hypothesis that ATP7A in mammary epithelial cells is required for loading of copper into milk to meet the high demand for copper in suckling mice. By identifying the organ-specific pathways by which ATP7A supplies copper for neonatal growth and development, the results of our proposal are certain to have a sustained and powerful impact on the field.

Public Health Relevance

Copper is an essential nutrient for many biological processes, including growth and development. This proposal will uncover the molecular basis for copper acquisition during pregnancy, lactation and the neonatal period.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093386-02
Application #
8332257
Study Section
Special Emphasis Panel (ZRG1-EMNR-P (02))
Program Officer
Maruvada, Padma
Project Start
2011-09-15
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$409,732
Indirect Cost
$123,035
Name
University of Missouri-Columbia
Department
Biochemistry
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Zhu, Sha; Shanbhag, Vinit; Hodgkinson, Victoria L et al. (2016) Multiple di-leucines in the ATP7A copper transporter are required for retrograde trafficking to the trans-Golgi network. Metallomics 8:993-1001
Ladomersky, Erik; Petris, Michael J (2015) Copper tolerance and virulence in bacteria. Metallomics 7:957-64
Hodgkinson, Victoria L; Zhu, Sha; Wang, Yanfang et al. (2015) Autonomous requirements of the Menkes disease protein in the nervous system. Am J Physiol Cell Physiol 309:C660-8
Hodgkinson, Victoria L; Dale, Jeffery M; Garcia, Michael L et al. (2015) X-linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron. J Pathol 236:241-50
Zlatic, Stephanie; Comstra, Heather Skye; Gokhale, Avanti et al. (2015) Molecular basis of neurodegeneration and neurodevelopmental defects in Menkes disease. Neurobiol Dis 81:154-61
Wang, Yanfang; Zhu, Sha; Weisman, Gary A et al. (2012) Conditional knockout of the Menkes disease copper transporter demonstrates its critical role in embryogenesis. PLoS One 7:e43039
Wang, Yanfang; Zhu, Sha; Hodgkinson, Victoria et al. (2012) Maternofetal and neonatal copper requirements revealed by enterocyte-specific deletion of the Menkes disease protein. Am J Physiol Gastrointest Liver Physiol 303:G1236-44