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EXPERIMENT INFORMATION

Radiation and Gliomagenesis: A Sensitive Model System to Evaluate the Tumorigenic Potential of HZE Particles (NNX10AE08G)
Principal Investigator
Research Area:
Radiation health
Species Studied
Scientific Name: Species: Cells

Description
OBJECTIVES:
There is a paucity of systematic studies carried out with well-defined model systems to evaluate the tumorigenic potential of HZE particles that are presumed to pose a significant cancer risk to astronauts. The investigators have shown that these particles induce DNA double-strand breaks (DSBs) that are repaired slowly and incompletely and trigger persistent DNA damage signaling events. In order to evaluate the carcinogenic consequences of such unrepaired DNA lesions, they utilized genetically engineered astrocytes and neural stem cells (NSCs) as well as transgenic mouse models representing progressive steps in the development of Glioblastoma Multiforme (GBM). These lethal brain tumors are the third leading cause of cancer-related death among adults aged 30 to 50 years that are known to be induced by ionizing radiation. The past years have seen unprecedented advances in the genomic analyses of adult GBM tumors by the Cancer Genome Atlas Network, which reveal that these tumors have radically altered genomes with five key genetic changes dominating: loss of Ink4a, Arf, p53, or PTEN and amplification of estimated glomerular filtration rate (EGFR) (especially the constitutively active EGFRvIII). The investigators developed astrocyte and NSC lines as well as mouse models with targeted deletions of these genes in logical combinations representing the progression of primary or secondary GBMs. This genetic progression model, though reductionist in approach, provides a realistic framework for evaluating and understanding how known genetic mutations may cooperate with charged particle radiation and contribute to the initiation and progression of high-grade gliomas. The investigators hypothesized that poorly repaired DNA damage produced by charged particles will result in malignant progression towards brain cancer, and that this progression can be accelerated by predisposing oncogenic activations/tumor suppressor losses. More importantly, these "pre-initiated" murine astrocytes/NSCs will allowed investigators to rapidly quantify the transforming potential of charged particles relative to gamma rays both in vitro and in vivo.

This study had the following specific aims:

  1. Evaluation of DNA damage responses to charged particles in neural stem cells (NSCs) and astrocytes in vitro and in vivo.
  2. Evaluation of the tumorigenic potential of charged particles relative to gamma rays in vitro and in vivo.
  3. Identification of the genetic and gene expression changes underlying particle-induced tumorigenesis.


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Keywords
DNA damage
HZE particles
Radiation effects

Data Information
Data Availability
Archive is complete. Data sets are not publicly available but can be requested.
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Parameters
Ink4a
INK4a-ARF
Ink4b
MET amplification
MET signaling
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Mission/Study Information
Mission Launch/Start Date Landing/End Date Duration
Ground 05/01/2009 In Progress

Human Research Program (HRP) Human Research Roadmap (HRR) Information
Crew health and performance is critical to successful human exploration beyond low Earth orbit. The Human Research Program (HRP) investigates and mitigates the highest risks to human health and performance, providing essential countermeasures and technologies for human space exploration. Risks include physiological and performance effects from hazards such as radiation, altered gravity, and hostile environments, as well as unique challenges in medical support, human factors, and behavioral health support. The HRP utilizes an Integrated Research Plan (IRP) to identify the approach and research activities planned to address these risks, which are assigned to specific Elements within the program. The Human Research Roadmap is the web-based tool for communicating the IRP content.

The Human Research Roadmap is located at: https://humanresearchroadmap.nasa.gov/

+ Click here for information of how this experiment is contributing to the HRP's path for risk reduction.

Additional Information
Managing NASA Center
Johnson Space Center (JSC)
Responsible NASA Representative
Institutional Support
National Aeronautics and Space Administration (NASA)
Proposal Date
02/01/2010
Proposal Source
2009 Space Radiobiology NNJ09ZSA001N