Copper (Cu) is essential for the growth, development, and normal function of human organisms. The defects in Cu homeostasis are associated with a broad spectrum of pathologies including Menkes disease, Wilson disease, MEDNIK syndrome, and others. So far, the studies of human Cu homeostasis have focused primarily on the function and regulation of Cu transporters and small Cu carriers. With this program of study, we will begin to learn how mammalian Cu transporters and their regulators work together to modulate the nutrient transport in intestine. The small intestine is responsible for the absorption of all essential nutrients. We discovered that the availability of Cu in enterocytes strongly influenced the abundance of chylomicrons, the primary carriers of dietary fat. We have also identified the fat-responsive protein ANKRD9 as a regulator of Cu transport and hypothesize that ANKRD9 is a molecular integrator of the pathways involved in the intestinal fat and Cu transport. The proposed program of studies will test the central hypothesis that the Cu homeostasis and lipid (fat) metabolism in enterocytes are functionally linked and co-regulated. Studies under Specific Aim 1 will characterize the mechanism of ATP7B regulation and investigate how the intestinal Cu storage compartments are formed.
Specific Aim 2 will determine how Cu and dietary fat affect each other transport in enterocytes and elucidate the mechanism behind the Cu-dependent formation of chylomicrons.
Specific Aim 3 will characterize the function of ANKRD9 in the small intestine and its role in coupling copper and fat metabolism. The studies will open a new chapter in understanding of intestinal Cu physiology, contribute to better understanding of human disorders associated with Cu misbalance and, ultimately, help to design better treatments for these disorders.

Public Health Relevance

This project aims to elucidate how the small intestine coordinates the absorption of such essential nutrients as copper and dietary fat. The results will help to better understand the role of copper in pathophysiology of such disorders as Menkes disease, Wilson disease, MEDNIK syndrome, and obesity, and will facilitate the development of better treatments for the disorders associated with copper misbalance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071865-15
Application #
9949699
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Maruvada, Padma
Project Start
2005-08-01
Project End
2023-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
15
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Yu, Corey H; Yang, Nan; Bothe, Jameson et al. (2017) The metal chaperone Atox1 regulates the activity of the human copper transporter ATP7B by modulating domain dynamics. J Biol Chem 292:18169-18177
Jayakanthan, Samuel; Braiterman, Lelita T; Hasan, Nesrin M et al. (2017) Human copper transporter ATP7B (Wilson disease protein) forms stable dimers in vitro and in cells. J Biol Chem 292:18760-18774
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Schushan, Maya; Bhattacharjee, Ashima; Ben-Tal, Nir et al. (2012) A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism. Metallomics 4:669-78

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