The long term of this study is to provide detailed mechanistic understanding of Wilson's disease (WD). WD is a severe and potentially fatal human disorder of copper homeostasis, caused by mutations in the copper transporter ATP7B. The disease is associated with copper overload in tissues, particularly in the liver, and a wide spectrum of hepatic, neurologic, and psychiatric abnormalities. Currently, specific molecular pathways through which copper triggers WD are poorly understood. The proposed studies will use a multidisciplinary approach based on modern methodologies to identify biochemical and cellular events that lead to the onset and progression of WD. The experiments measuring oxidation state of glutathione and proteins will determine whether in WD copper acts by modifying the redox environment of cellular compartments (Specific Aim 1). The role of hnRNP A2 in cell response to copper overload will be determined by characterizing its intracellular localization, interacting proteins, and a subset of transcripts affected by hnRNPA2 up-regulation (Specific Aim 2). Metabolic changes in the brain of Atp7b-/- mice will be characterized by corelating time-dependent copper distribution with changes in lipids and mRNA profiles at different stages of the disease (Specific Aim 3). Cell injury and behavior changes will be evaluated in conjunctions with analysis of molecular and metabolic changes.

Public Health Relevance

The project focuses on elucidating the mechanisms of pathology development in Wilson's disease, a severe genetic disorder in humans with hepatic and neurologic manifestations. The studies will identify key molecular factors and proceses that underlie the development and progresion of pathologic changes in Wilson's disease. The results will contribute to improvement of diagnostic and treatment of this potentially fatal disorder of copper metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101502-02
Application #
8523921
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Anderson, Vernon
Project Start
2012-08-15
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$372,904
Indirect Cost
$123,787
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Lutsenko, Svetlana (2014) Modifying factors and phenotypic diversity in Wilson's disease. Ann N Y Acad Sci 1315:56-63