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The Potential Detrimental Impact of Galactic Cosmic Radiation on Central Nervous System and Hematopoietic Stem Cells

Patel, Rutulkumar Upendrabhai
http://rave.ohiolink.edu/etdc/view?acc_num=case1544624848230223

Abstract Details

2018, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Space travel is associated with many primary hazards, but the risk associated with space radiation induced damage to the central nervous system (CNS) and hematopoietic stem cells (HSCs) could be the limiting factor for the future exploration missions. The major component of space radiation is galactic cosmic radiation (GCR) and it is composed of high-linear energy transfer (LET) radiation. The lack of human data and poor understanding of high-LET radiobiology make current risk prediction models less reliable to assess the potential risk associated with long-term space travel. Thus, we irradiated C57bl/6 mice with a low-LET (γ-rays or 1H ions) or high-LET (28Si ions or 56Fe ions) ionizing radiation (IR) and performed a battery of behavioral tests at 5 and 9 month post exposure to study CNS defects. We found that each radiation source showed distinct effects on the behavioral tests performed, with most prominent impact on non-spatial memory, suggesting that the initial damage and subsequent molecular changes caused by each ion species were inherently unique. MLH1 is a major component of MMR and a recent study has demonstrated that human CD34+ HSCs loses expression of MLH1 due to promoter hypermethylation as a function of age. Given that the upper end of astronauts are ~46 years old, HSCs with compromised MMR function will be exposed to high-LET space radiation leading to increase HSC malignancies. Therefore, we irradiated Mlh1+/+ and Mlh1+/- mice with different doses of γ-rays, 1H, 28Si, or 56Fe particles. We found that loss of Mlh1 significantly increases the incidence of lymphomagenesis in Mlh1+/- mice post IR compared to sham-irradiated Mlh1+/- or irradiated Mlh1+/+ mice. In addition, the early incidence and higher frequency of lymphomagenesis was dependent on radiation quality factor with a maximum impact observed at 28Si ion IR. Further, the molecular signature of the lymphomas revealed a striking correlation to human leukemias, implying the relevance of using a MMR compromised mouse model to recapitulate middle-aged human HSCs. Collectively, our findings provide deeper insight into the long-term detrimental impact of space radiation induced behavioral deficits and HSC malignancy that may limit our future space exploration missions without tough interventions.
Scott Welford (Advisor)
Stanton Gerson (Committee Member)
Derek Taylor (Committee Chair)
Marvin Nieman (Committee Member)
Jennifer Yu (Committee Member)
193 p.
Oncology; Radiation
Space radiation, Hematopoietic stem cells, Central nervous system, lymphomagenesis

Recommended Citations

Citations

  • Patel, R. U. (2018). The Potential Detrimental Impact of Galactic Cosmic Radiation on Central Nervous System and Hematopoietic Stem Cells [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1544624848230223

    APA Style (7th edition)

  • Patel, Rutulkumar. The Potential Detrimental Impact of Galactic Cosmic Radiation on Central Nervous System and Hematopoietic Stem Cells. 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1544624848230223.

    MLA Style (8th edition)

  • Patel, Rutulkumar. "The Potential Detrimental Impact of Galactic Cosmic Radiation on Central Nervous System and Hematopoietic Stem Cells." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1544624848230223

    Chicago Manual of Style (17th edition)

case1544624848230223
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.