Asparaginase is an integral part of the treatment for acute lymphoblastic leukemia, the most common childhood cancer. Asparaginase produces hepatotoxicity resulting in treatment-related metabolic complications that include fatty liver, reduced plasma proteins, and coagulation problems that lead to thromboembolism and cerebrovascular events. Our long-term goal is to increase the safety and efficacy of asparaginase. The objective of this proposal is to discover mechanisms by which asparaginase causes adverse metabolic effects. To accomplish this, we propose to identify key molecular events that modulate hepatic dysfunction by asparaginase. Our preliminary data demonstrate that asparaginase increases phosphorylation of the translation factor, eIF2, by GCN2. Deletion of GCN2 precludes adaptive responses to asparaginase and enhances endoplasmic reticulum (ER) stress, leading to induction of another eIF2 kinase called PKR-like ER- resident Kinase (PERK). The central hypothesis is that activation of eIF2 kinases prevent and/or mitigate hepatic dysfunction by asparaginase. We plan to test our hypothesis and accomplish the objective of this application by pursuing the following specific aims:
Aim 1) Identify the role of GCN2 in liver during asparaginase treatment;
Aim 2) Determine the role of PERK in liver during asparaginase treatment;
Aim 3) Characterize age differences in eIF2 kinase signaling in liver by asparaginase. To accomplish the above aims, asparaginase will be administered to both wild-type mice and mice deleted for the eIF2 kinases, GCN2 and/or PERK. Time course analysis will focus on how modulation of eIF2 kinase signaling and activation of ER stress relates to development of liver dysfunction. In addition, asparaginase will be administered to mice of varying ages and key molecular and metabolic responses to asparaginase will be assessed. This proposal is innovative in that it seeks to identify the progression of molecular events that lead to liver dysfunction by asparaginase at different ages. The work proposed is significant as it will help identify pediatric patients at risk for adverse metabolic events by asparaginase during the developmental continuum. The results will also be used to develop and test new methods of prevention and/or treatment.

Public Health Relevance

The proposed project is relevant to public health as it seeks to improve the treatment regimen for acute lymphoblastic leukemia, the most common childhood cancer. This proposal aims to reduce and prevent adverse metabolic events caused by asparaginase by identifying the molecular events that cause liver dysfunction.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
3R01HD070487-04S1
Application #
8777667
Study Section
Special Emphasis Panel (ZHD1-DSR-K (10))
Program Officer
Taylor-Zapata, Perdita
Project Start
2013-12-03
Project End
2015-04-30
Budget Start
2013-12-03
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$77,500
Indirect Cost
$27,500
Name
Rutgers University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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Wilson, Gabriel J; Bunpo, Piyawan; Cundiff, Judy K et al. (2013) The eukaryotic initiation factor 2 kinase GCN2 protects against hepatotoxicity during asparaginase treatment. Am J Physiol Endocrinol Metab 305:E1124-33
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