A formidable challenge in the treatment of primary and metastatic brain cancers, especially in children, is the long-term neurocognitive deficiencies resulting from cranial irradiation (IR)-induced hippocampal neuronal apoptosis. Our laboratory has discovered a novel functional connection between the metabolic kinase GSK3? and the Non- homologous End-joining (NHEJ) pathway that repair DNA double-strand breaks (DSBs). Furthermore, our preliminary data revealed that the NHEJ mediator 53BP1 is directly phosphorylated by GSK3?;meanwhile, increased expression of the classic GSK3? substrate ?-catenin is associated with enhanced repair of IR-induced DSBs and survival in hippocampal neurons. Thus, we hypothesize that GSK3? regulates NHEJ-mediated repair of DSBs and determines neuron cytotoxicity following IR via suppression of 53BP1 and ?-catenin function. In addition, tumor cells which contain abnormal GSK3 ? activity will not exhibit GSK3?-mediated protection from IR-induced cytotoxicity. A series of in vitro and in vivo experiments are proposed to test our hypotheses:
Aim 1 will identify the GSK3 ? phosphorylation sites in 53BP1 and determine whether GSK3 ? -specific phosphorylation direct 53BP1 function in NHEJ and in survival of irradiated hippocampal neurons.
Aim 2 will determine whether GSK3 ? regulates 53BP1 through suppressing ? - catenin that may promote NHEJ activity by increasing 53BP1 transcription, or by directly interacts with 53BP1.
Aim 3 will determine if abnormal GSK3 ? activity determine brain tumor cell resistance to the prophylactic GSK3 ? -inhibition mediated protection from radiation induced cytotoxicity.

Public Health Relevance

In an effort to decrease neurotoxicity and improve patient quality of life, pharmacologic agents which exhibit neuroprotective effects are being rigorously investigated. Thus, the goal of this proposal is to determine the mechanisms of action that protect neurons from irradiation-induced hippocampal neuronal apoptosis with a view toward prevention of neurocognitive toxicity from cranial IR.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA163838-01A1
Application #
8337105
Study Section
Special Emphasis Panel (ZRG1-OTC-C (04))
Program Officer
Pelroy, Richard
Project Start
2012-07-12
Project End
2017-04-30
Budget Start
2012-07-12
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$387,463
Indirect Cost
$133,389
Name
Ohio State University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210