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Fiscal Year: FY 2017  Task Last Updated:  01/24/2018 
PI Name: Boerma, Marjan  Ph.D. 
Project Title: Center for Research on Cardiac, Vascular, and Acute Effects of Space Radiation 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Radiation Effects Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) ARS:Risk of Acute Radiation Syndromes Due to Solar Particle Events (SPEs)
 (2) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Acute01: Determine the dose response for acute effects induced by SPE-like radiation, including synergistic effects arising from other spaceflight factors (e.g. altered gravity (µ-gravity), stress, altered immune function, or other) that modify and/or enhance the biological response (IRP Rev G)
 (2) Acute07:What are the most effective biomedical or dietary countermeasures to mitigate acute radiation risks?
 (3) Degen01:How can tissue specific experimental models be developed for the major degenerative tissue risks, including cardiovascular, lens, digestive, endocrine, and other tissue systems in order to estimate space radiation risks for degenerative diseases? (IRP Rev F)
 (4) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
 (5) Degen03:What are the progression rates and latency periods for radiation-induced degenerative diseases, and how do progression rates depend on age, sex, radiation type, or other physiological or environmental factors? (IRP Rev F)
 (6) Degen05:What quantitative procedures or theoretical models are needed to extrapolate molecular, cellular, or animal results to predict degenerative tissue risks in astronauts? How can human epidemiology data best support these procedures or models?
 (7) Degen06:What are the most effective biomedical or dietary countermeasures to mitigate degenerative tissue risks? By what mechanisms are the countermeasures likely to work? Are these CMs additive, synergistic, or antagonistic to other Risks? (IRP Rev F)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: mboerma@uams.edu  Fax:   
PI Organization Type: UNIVERSITY  Phone: 501-686-6599  
Organization Name: University of Arkansas, Little Rock 
PI Address 1: 4301 W. Markham Street, Slot 522-10 
PI Address 2: Slot 522-10 
PI Web Page:  
City: Little Rock  State: AR 
Zip Code: 72205-7101  Congressional District: 
Comments:  
Project Type: GROUND  Solicitation:  2013 NSBRI-RFA-13-02 Center for Space Radiation Research (CSRR) 
Start Date: 06/01/2014  End Date:  05/31/2017 
No. of Post Docs: No. of PhD Degrees: 
No. of PhD Candidates: No. of Master' Degrees: 
No. of Master's Candidates: No. of Bachelor's Degrees: 
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment:

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Mao, Xiao  M.D. ( Loma Linda University )
Hauer-Jensen, Martin  M.D., Ph.D. ( University of Arkansas for Medical Sciences )
Kodell, Ralph  Ph.D. ( University of Arkansas for Medical Sciences )
Koturbash, Igor  M.D., Ph.D. ( University of Arkansas for Medical Sciences )
Tackett, Alan  Ph.D. ( University of Arkansas for Medical Sciences )
Nelson, Gregory  Ph.D. ( Loma Linda University ) 
Grant/Contract No.: NCC 9-58-RE03701 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: The Center for Research on Cardiac, Vascular, and Acute Effects of Space Radiation consisted of teams of investigators from the University of Arkansas for Medical Sciences (UAMS), Loma Linda University (LLU), the University of Arizona (UAZ), and Georgetown University. We used multiple animal models to characterize acute effects of protons at doses lower than addressed in previous animal studies, and experiments involved exposure of animals and cell cultures to protons and heavy ions to examine degenerative cardiovascular effects. We pursued the following Specific Aims: 1) Define acute effects of low-dose proton irradiation on the hematopoietic system, skin, heart, and retina; 2) Examine acute effects of low-dose protons in combination with modeled microgravity; 3) Evaluate acute effects of protons on the adaptive immune response; 4) Determine effects of heavy ion and proton irradiation on cardiac and vascular function and structure; 5) Identify acute and chronic biomarkers of cardiovascular dysfunction after particle irradiation; 6) Elucidate the role of metabolic and epigenetic changes in the cardiovascular response to radiation; 7) Determine effects of radiation dose and quality on endothelial cell functional phenotype; and 8) Test whether gamma-tocotrienol protects against cardiovascular effects of particle irradiation.

Key studies and findings under each Specific Aim:

1) Male C57BL/6 mice were irradiated at 6 months of age with a fully modulated 150 MeV proton beam to mimic a solar particle event (SPE) or cobalt-60 gamma-rays at doses of 0.1 – 0.5 Gy, and blood and spleen cells were quantified with a hematology analyzer and flow cytometry. Doses =0.1 Gy of both protons and gamma-rays caused a decrease in blood cell counts at 60 hours and 4 days, followed by a gradual repopulation after 1 week. These studies contribute to the determination of dose threshold for acute effects.

2) Mice were subjected to hindlimb unloading to remove mechanical loads from the posterior musculoskeletal system and generate a cephalic fluid shift, both of which occur in microgravity. Thus, animals were hindlimb unloaded for 7 days, irradiated at 0.5 Gy with modulated 150 MeV protons, and hindlimb unloaded for an additional 7 days. The most severe decrease in whole blood cell and lymphocyte counts was seen in animals exposed to both radiation and unloading (i.e., a significant interaction was seen between radiation and hindlimb unloading). Similarly, apoptosis and cellular senescence in the retina were most severe in the combined exposure group.

3) The mouse ear swelling test was used to assess adaptive immunity. Mice were challenged with an injection of FITC, followed 4 days later by modulated 150 MeV proton irradiation at a dose of 0.5 Gy. When mice were re-challenged after 2 weeks with an injection of fluorescein isothiocyanate (FITC) into one of the ears, relative ear swelling was significantly increased in the irradiated group compared with sham-irradiated animals. These results suggest that solar particle event (SPE)-like proton exposures may enhance the adaptive immune response, with potential negative consequences in hypersensitivity reactions and allergies.

4) Male C57BL/6 mice were used to determine cardiac function, tissue structure, and protein expression up to 9 months after exposure to 16O (600 MeV/n, 0.05 – 1 Gy), protons (150 MeV, 0.5 or 1 Gy), or 137Cs gamma-rays (0.5 – 3 Gy). 16O caused small but significant decreases and protons small increases in echocardiographic parameters. All 3 types of radiation induced protein markers of cardiac inflammatory infiltration at =1 Gy. Additionally, male Long Evans rats and male New Zealand White rabbits were exposed to 16O (600 MeV/n, 0.5 Gy) or protons (250 MeV, 0.5 Gy) and followed for 12 months after irradiation. Both rats and rabbits showed a small but significant increase in plasma levels of the injury marker cardiac troponin I (cTnI). In rabbits, this coincided with small increases in ejection fraction as measured with echocardiography. On the other hand, no significant changes were found in cardiac mast cell numbers or collagen deposition in any of the three species. In addition, no changes were seen in the structure of the retinal vasculature in irradiated mice. Altogether, cardiovascular effects of radiation were mild.

5) Proteomics was performed on samples of mouse left ventricle and plasma collected under Specific Aim 4. Pathways that were most commonly identified by Ingenuity Pathway Analysis included mitochondrial dysfunction, the nuclear receptor FXR/RXR pathway, and others.

6) Metabolomics was performed on samples of mouse left ventricle, plasma, urine, and feces collected under Specific Aim 4. Low doses of 16O (0.1 Gy and 0.25 Gy) induced more changes in metabolite profiles than 1 Gy. These profiles suggest inflammation, and oxidative and nitrosative stress. Alterations in one-carbon metabolism and DNA methylation pointed to potential molecular mechanisms by which oxygen ions modify the heart. Some of the changes in fecal metabolites could be attributed to radiation-induced changes in the microbiome.

7) Cultures of mouse and human retinal and cardiac endothelial cells were exposed to protons, heavy ions, and gamma-rays. Alterations in protein expressions were dependent on radiation type, dose, and cell type. In addition, doses =0.1 Gy caused a decrease in tubule network formation when cells were plated on a Matrigel/collagen matrix 6 hours after irradiation, indicative of a reduced capacity for early-onset angiogenesis.

8) Male C57BL/6 mice were exposed to 16O (600 MeV/n, 0.25 Gy) and administered gamma-tocotrienol (s.c., 50 mg/kg) once a day Monday – Friday for 4 weeks after irradiation. When measured 2 weeks after irradiation, gamma-tocotrienol reduced left ventricular protein levels of CD2 and collagen type III, but did not modify CD68 or mast cell tryptase levels. Analysis of echocardiography recordings and tissue samples at remaining post-radiation time points is being finalized.

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: There is renewed interest in the chronic cardiovascular effects of terrestrial exposures to low doses of ionizing radiation, such as from accidental exposure or medical and diagnostic treatments. This project has assessed chronic effects of low-dose ionizing radiation on heart and vasculature and has started the identification of potential biological mechanisms. These studies will contribute to the general understanding of the cardiovascular effects of low-dose ionizing radiation. The Armed Forces Radiobiology Research Institute (AFRRI) and other government agencies have a longstanding interest in gamma-tocotrienol as a potential countermeasure against radiation from a nuclear attack or accident and has collaborated with several investigators that have also served on the current project. Results obtained from the current studies indirectly support our efforts to develop gamma-tocotrienol as a countermeasure against terrestrial radiation exposure.

 

Task Progress: This project used animal models and endothelial cell cultures to characterize acute effects of protons at doses lower than previously studied and examine degenerative cardiovascular effects of protons and oxygen ions.

Specific Aims: 1) Define acute hematopoietic effects of low-dose protons; 2) Examine acute effects of protons in combination with simulated microgravity; 3) Evaluate effects of protons on the adaptive immune response; 4) Determine effects of heavy ions and protons on cardiac and vascular function and structure; 5) Identify biomarkers of cardiovascular dysfunction after particle irradiation; 6) Elucidate the role of metabolic and epigenetic changes in the cardiovascular response to radiation; 7) Determine effects of radiation dose and quality on endothelial cell phenotype; 8) Test whether gamma-tocotrienol protects against cardiovascular effects of radiation.

Key findings under each aim:

1) A decrease in blood cell counts up to 4 days after protons and gamma-rays at doses =0.1 Gy in mice. These studies contribute to the determination of dose threshold for acute effects;

2) A significant interaction between simulated microgravity and radiation on blood cell count, and apoptosis and cell senescence in the mouse retina;

3) An enhanced adaptive immune response in mice after protons, which may have potential negative consequences in hypersensitivity reactions;

4) Small changes in echocardiography parameters and protein markers of inflammatory infiltration in the heart of proton or oxygen ion exposed mice, rats, and rabbits. Rats and rabbits showed a small but significant increase in plasma cardiac troponin I. Mice showed no changes in retinal vascular structure months after irradiation. Altogether, cardiovascular changes were mild;

5) Proteomics performed on samples of mouse heart and plasma revealed common pathways including mitochondrial dysfunction, the nuclear receptor FXR/RXR pathway, and others;

6) Metabolomics performed on samples of mouse heart, plasma, urine, and feces revealed more changes after low doses of oxygen ions (0.1 Gy, 0.25 Gy) compared to 1 Gy. Alterations in one-carbon metabolism and DNA methylation pointed to potential molecular mechanisms by which oxygen ions modify the heart. Some of the fecal metabolites were attributed to radiation-induced changes in the microbiome;

7) Cultures of mouse and human retinal and cardiac endothelial cells were exposed to protons, heavy ions, and gamma-rays. Alterations in protein expressions were dependent on radiation type, dose, and cell type. Doses =0.1 Gy caused a decrease in tubule network formation indicative of a reduced capacity for early-onset angiogenesis;

8) Mice were administered the radiation countermeasure gamma-tocotrienol for 4 weeks after oxygen ion irradiation. At 2 weeks, gamma-tocotrienol reduced cardiac protein levels of CD2 and collagen type III, but not of CD68 or mast cell tryptase. The analysis of cardiac function and cardiac tissue structure is ongoing.

 

Bibliography Type: Description: (Last Updated: 09/19/2019) Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Chang J, Luo Y, Wang Y, Pathak R, Sridharan V, Jones T, Mao XW, Nelson G, Boerma M, Hauer-Jensen M, Zhou D, Shao L. "Low doses of oxygen ion irradiation cause acute damage to hematopoietic cells in mice." PLoS One. 2016 Jul 1;11(7):e0158097. eCollection 2016. https://doi.org/10.1371/journal.pone.0158097 ; PubMed PMID: 27367604; PubMed Central PMCID: PMC4930193 , Jul-2016
Articles in Peer-reviewed Journals Pathak R, Wang J, Garg S, Aykin-Burns N, Petersen KU, Hauer-Jensen M. "Recombinant thrombomodulin (Solulin) ameliorates early intestinal radiation toxicity in a preclinical rat model." Radiat Res. 2016 Aug;186(2):112-20. https://doi.org/10.1667/RR14408.1 ; PubMed PMID: 27459702; PubMed Central PMCID: PMC4995594 , Aug-2016
Articles in Peer-reviewed Journals Wang Y, Boerma M, Zhou D. "Ionizing radiation-induced endothelial cell senescence and cardiovascular diseases." Radiat Res. 2016 Aug;186(2):153-61. Review. https://doi.org/10.1667/RR14445.1 ; PubMed PMID: 27387862; PubMed Central PMCID: PMC4997805 , Aug-2016
Articles in Peer-reviewed Journals Boerma M. "An introduction to space radiation and its effects on the cardiovascular system." THREE. 2016 Oct 13:1-12. https://three.jsc.nasa.gov/articles/Boerma-Cardiovascular-and-IR.pdf , Oct-2016
Articles in Peer-reviewed Journals Chang J, Wang Y, Pathak R, Sridharan V, Jones T, Mao XW, Nelson G, Boerma M, Hauer-Jensen M, Zhou D, Shao L. "Whole body proton irradiation causes acute damage to bone marrow hematopoietic progenitor and stem cells in mice." Int J Radiat Biol. 2017 Dec;93(12):1312-20. Epub 2017 Aug 7. https://doi.org/10.1080/09553002.2017.1356941 ; PubMed PMID: 28782442 , Dec-2017
Articles in Peer-reviewed Journals Kiffer F, Carr H, Groves T, Anderson JE, Alexander T, Wang J, Seawright JW, Sridharan V, Carter G, Boerma M, Allen AR. "Effects of 1H + 16O charged particle irradiation on short-term memory and hippocampal physiology in a murine model." Radiat Res. 2018 Jan;189(1):53-63. https://doi.org/10.1667/RR14843.1 ; PubMed PMID: 29136391 , Jan-2018
Articles in Peer-reviewed Journals Wang Y, Chang J, Li X, Pathak R, Sridharan V, Jones T, Mao XW, Nelson G, Boerma M, Hauer-Jensen M, Zhou D, Shao L. "Low doses of oxygen ion irradiation cause long-term damage to bone marrow hematopoietic progenitor and stem cells in mice." PLoS One. 2017 Dec 12;12(12):e0189466. eCollection 2017. https://doi.org/10.1371/journal.pone.0189466 ; PubMed PMID: 29232383; PubMed Central PMCID: PMC5726652 , Dec-2017
Articles in Peer-reviewed Journals Carr H, Alexander TC, Groves T, Kiffer F, Wang J, Price E, Boerma M, Allen AR. "Early effects of 16O radiation on neuronal morphology and cognition in a murine model." Life Sciences in Space Research. 2018 May;17:63-73. Epub 2018 Mar 14. https://doi.org/10.1016/j.lssr.2018.03.001 ; PubMed PMID: 29753415 , May-2018
Articles in Peer-reviewed Journals Mao XW, Boerma M, Rodriguez D, Campbell-Beachler M, Jones T, Stanbouly S, Sridharan V, Wroe A, Nelson GA. "Acute effect of low-dose space radiation on mouse retina and retinal endothelial cells." Radiat Res. 2018 Jul;190(1):45-52. Epub 2018 May 9. https://doi.org/10.1667/RR14977.1 ; PubMed PMID: 29741442 , Jul-2018
Articles in Peer-reviewed Journals Kiffer F, Howe AK, Carr H, Wang J, Alexander T, Anderson JE, Groves T, Seawright JW, Sridharan V, Carter G, Boerma M, Allen AR. "Late effects of 1H irradiation on hippocampal physiology." Life Sci Space Res (Amst). 2018 May;17:51-62. Epub 2018 Mar 15. https://doi.org/10.1016/j.lssr.2018.03.004 ; PubMed PMID: 29753414 , May-2018
Articles in Peer-reviewed Journals Koturbash I. "2017 Michael Fry Award Lecture. When DNA is actually not a target: Radiation epigenetics as a tool to understand and control cellular response to ionizing radiation." Radiat Res. 2018 Jul;190(1):5-11. Epub 2018 Apr 26. https://doi.org/10.1667/RR15027.1 ; PubMed PMID: 29697303; PubMed Central PMCID: PMC6036898 , Jul-2018
Articles in Peer-reviewed Journals Miousse IR, Ewing LE, Kutanzi KR, Griffin RJ, Koturbash I. "DNA methylation in radiation-induced carcinogenesis: Experimental evidence and clinical perspectives." Crit Rev Oncog. 2018;23(1-2):1-11. Review. https://doi.org/10.1615/CritRevOncog.2018025687 ; PubMed PMID: 29953365; PubMed Central PMCID: PMC6369919 , Jul-2018
Articles in Peer-reviewed Journals Cheema AK, Byrum SD, Sharma NK, Altadill T, Kumar VP, Biswas S, Balgley BM, Hauer-Jensen M, Tackett AJ, Ghosh SP. "Proteomic changes in mouse spleen after radiation-induced injury and its modulation by gamma-tocotrienol." Radiat Res. 2018 Nov;190(5):449-63. Epub 2018 Aug 2. https://doi.org/10.1667/RR15008.1 ; PubMed PMID: 30070965; PubMed Central PMCID: PMC6297072 , Nov-2018
Articles in Peer-reviewed Journals Mao XW, Boerma M, Rodriguez D, Campbell-Beachler M, Jones T, Stanbouly S, Sridharan V, Nishiyama NC, Wroe A, Nelson GA. "Combined effects of low-dose proton radiation and simulated microgravity on the mouse retina and the hematopoietic system." Radiat Res. 2019 Sep;192(3):241-50. Epub 2018 Nov 15. https://doi.org/10.1667/RR15219.1 ; PubMed PMID: 30430917 , Sep-2019
Articles in Peer-reviewed Journals Howe A, Kiffer F, Alexander TC, Sridharan V, Wang J, Ntagwabira F, Rodriguez A, Boerma M, Allen AR. "Long-term changes in cognition and physiology after low-dose 16O irradiation." Int J Mol Sci. 2019 Jan 7;20(1):E188. https://doi.org/10.3390/ijms20010188 ; PubMed PMID: 30621014; PubMed Central PMCID: PMC6337104 , Jan-2019
Articles in Peer-reviewed Journals Seawright JW, Sridharan V, Landes RD, Cao M, Singh P, Koturbash I, Mao XW, Miousse IR, Singh SP, Nelson GA, Hauer-Jensen M, Boerma M. "Effects of low-dose oxygen ions and protons on cardiac function and structure in male C57BL/6J mice." Life Sciences in Space Research. 2019 Feb;20:72-84. https://doi.org/10.1016/j.lssr.2019.01.003 ; PubMed PMID: 30797436; PubMed Central PMCID: PMC6391741 , Feb-2019
Articles in Peer-reviewed Journals Kiffer F, Alexander T, Anderson JE, Groves T, Wang J, Sridharan V, Boerma M, Allen AR. "Late effects of 16O-particle radiation on female social and cognitive behavior and hippocampal physiology." Radiat Res. 2019 Mar;191(3):278-94. Epub 2019 Jan 21. https://doi.org/10.1667/RR15092.1 ; PubMed PMID: 30664396 , Mar-2019
Articles in Peer-reviewed Journals Kiffer F, Boerma M, Allen A. "Behavioral effects of space radiation: A comprehensive review of animal studies." Life Sci Space Res (Amst). 2019 May;21:1-21. Epub 2019 Feb 19. Review. https://doi.org/10.1016/j.lssr.2019.02.004 ; PubMed PMID: 31101151 , May-2019
Articles in Peer-reviewed Journals Boerma M, Sridharan V, Mao XW, Nelson GA, Cheema AK, Koturbash I, Singh SP, Tackett AJ, Hauer-Jensen M. "Effects of ionizing radiation on the heart." Mutation Research. 2016 Oct - Dec;770(Pt B):319-27. Review. Epub 2016 Jul 10. https://doi.org/10.1016/j.mrrev.2016.07.003 ; PubMed PMID: 27919338; PubMed Central PMCID: PMC5144922 , Oct-2016
Articles in Peer-reviewed Journals Casero D, Gill K, Sridharan V, Koturbash I, Nelson G, Hauer-Jensen M, Boerma M, Braun J, Cheema AK. "Space-type radiation induces multimodal responses in the mouse gut microbiome and metabolome." Microbiome. 2017 Aug 18;5(1):105. https://doi.org/10.1186/s40168-017-0325-z ; PubMed PMID: 28821301; PubMed Central PMCID: PMC5563039 , Aug-2017
Articles in Peer-reviewed Journals Jayabalan GS, Wu YK, Bille JF, Kim S, Mao XW, Gimbel HV, Rauser ME, Fan JT. "In vivo two-photon imaging of retina in rabbits and rats." Exp Eye Res. 2018 Jan;166:40-48. Epub 2017 May 5. https://doi.org/10.1016/j.exer.2017.04.009 ; PubMed PMID: 28483661 , Jan-2018
Articles in Peer-reviewed Journals Koturbash I, Merrifield M, Kovalchuk O. "Fractionated exposure to low doses of ionizing radiation results in accumulation of DNA damage in mouse spleen tissue and activation of apoptosis in a p53/Atm-independent manner." Int J Radiat Biol. 2017 Feb;93(2):148-55. Epub 2016 Oct 19. https://doi.org/10.1080/09553002.2017.1231943 ; PubMed PMID: 27758128 , Feb-2017
Articles in Peer-reviewed Journals Mao XW, Nishiyama NC, Pecaut MJ, Campbell-Beachler M, Gifford P, Haynes KE, Becronis C, Gridley DS. "Simulated microgravity and low-dose/low-dose-rate radiation induces oxidative damage in the mouse brain." Radiation Research. 2016 Jun;185(6):647-57. https://doi.org/10.1667/RR14267.1 ; PubMed PMID: 27243749 , Jun-2016
Articles in Peer-reviewed Journals Miousse IR, Chang J, Shao L, Pathak R, Nzabarushimana E, Kutanzi KR, Landes R, Tackett AJ, Hauer-Jensen M, Zhou D, Koturbash I. "Inter-strain differences in LINE-1 DNA methylation in the mouse hematopoietic system in response to exposure to low-doses of ionizing radiation." International Journal of Molecular Sciences. 2017 Jul 4;18(7):E1430. https://doi.org/10.3390/ijms18071430 ; PubMed PMID: 28677663; PubMed Central PMCID: PMC5535921 , Jul-2017
Articles in Peer-reviewed Journals Miousse IR, Kutanzi KR, Koturbash I. "Effects of ionizing radiation on DNA methylation: from experimental biology to clinical applications." International Journal of Radiation Biology. 2017 May;93(5):457-69. Review. Epub 2017 Feb 21. https://doi.org/10.1080/09553002.2017.1287454 ; PubMed PMID: 28134023; PubMed Central PMCID: PMC5411327 , May-2017
Articles in Peer-reviewed Journals Miousse IR, Tobacyk J, Melnyk S, James SJ, Cheema AK, Boerma M, Hauer-Jensen M, Koturbash I. "One-carbon metabolism and ionizing radiation: a multifaceted interaction." Biomolecular Concepts. 2017 May 24;8(2):83-92. Review. https://doi.org/10.1515/bmc-2017-0003 ; PubMed PMID: 28574375 , May-2017
Articles in Peer-reviewed Journals Pathak R, Bachri A, Ghosh SP, Koturbash I, Boerma M, Binz RK, Sawyer JR, Hauer-Jensen M. "The vitamin E analog gamma-tocotrienol (GT3) suppresses radiation-induced cytogenetic damage." Pharmaceutical Research. 2016 Sep;33(9):2117-25. Epub 2016 May 23. https://doi.org/10.1007/s11095-016-1950-0 ; PubMed PMID: 27216753; PubMed Central PMCID: PMC4967083 , Sep-2016
Articles in Peer-reviewed Journals Pathak R, Koturbash I, Hauer-Jensen M. "Detection of inter-chromosomal stable aberrations by multiple fluorescence in situ hybridization (mFISH) and spectral karyotyping (SKY) in irradiated mice." Journal of Visualized Experiments. 2017 Jan 11;(119):e55162. https://doi.org/10.3791/55162 ; PubMed PMID: 28117817; PubMed Central PMCID: PMC5352253 , Jan-2017
Articles in Peer-reviewed Journals Prior S, Miousse IR, Nzabarushimana E, Pathak R, Skinner C, Kutanzi KR, Allen AR, Raber J, Tackett AJ, Hauer-Jensen M, Nelson GA, Koturbash I. "Densely ionizing radiation affects DNA methylation of selective LINE-1 elements." Environmental Research. 2016 Oct;150:470-81. Epub 2016 Jul 14. https://doi.org/10.1016/j.envres.2016.06.043 ; PubMed PMID: 27419368; PubMed Central PMCID: PMC5003736 , Oct-2016
Articles in Peer-reviewed Journals Seawright JW, Samman Y, Sridharan V, Mao XW, Cao M, Singh P, Melnyk S, Koturbash I, Nelson GA, Hauer-Jensen M, Boerma M. "Effects of low-dose rate gamma-irradiation combined with simulated microgravity on markers of oxidative stress, DNA methylation potential, and remodeling in the mouse heart." PLoS One. 2017 Jul 5;12(7):e0180594. eCollection 2017. https://doi.org/10.1371/journal.pone.0180594 ; PubMed PMID: 28678877; PubMed Central PMCID: PMC5498037 , Jul-2017
Awards Tackett A. (Alan Tackett) "Scharlau Family Endowed Chair, December 2016." Dec-2016
Awards Boerma M. (Marjan Boerma) "Radiation Research Society J.W. Osborne Award, October 2016." Oct-2016
Awards Hauer-Jensen M. (Martin Hauer-Jensen) "J. Thomas May Distinguished Endowed Chair, August 2016." Aug-2016
Download in PDF pdf     
Fiscal Year: FY 2016  Task Last Updated:  06/10/2016 
PI Name: Boerma, Marjan  Ph.D. 
Project Title: Center for Research on Cardiac, Vascular, and Acute Effects of Space Radiation 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Radiation Effects Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) ARS:Risk of Acute Radiation Syndromes Due to Solar Particle Events (SPEs)
 (2) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Acute01: Determine the dose response for acute effects induced by SPE-like radiation, including synergistic effects arising from other spaceflight factors (e.g. altered gravity (µ-gravity), stress, altered immune function, or other) that modify and/or enhance the biological response (IRP Rev G)
 (2) Acute07:What are the most effective biomedical or dietary countermeasures to mitigate acute radiation risks?
 (3) Degen01:How can tissue specific experimental models be developed for the major degenerative tissue risks, including cardiovascular, lens, digestive, endocrine, and other tissue systems in order to estimate space radiation risks for degenerative diseases? (IRP Rev F)
 (4) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
 (5) Degen03:What are the progression rates and latency periods for radiation-induced degenerative diseases, and how do progression rates depend on age, sex, radiation type, or other physiological or environmental factors? (IRP Rev F)
 (6) Degen05:What quantitative procedures or theoretical models are needed to extrapolate molecular, cellular, or animal results to predict degenerative tissue risks in astronauts? How can human epidemiology data best support these procedures or models?
 (7) Degen06:What are the most effective biomedical or dietary countermeasures to mitigate degenerative tissue risks? By what mechanisms are the countermeasures likely to work? Are these CMs additive, synergistic, or antagonistic to other Risks? (IRP Rev F)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: mboerma@uams.edu  Fax:   
PI Organization Type: UNIVERSITY  Phone: 501-686-6599  
Organization Name: University of Arkansas, Little Rock 
PI Address 1: 4301 W. Markham Street, Slot 522-10 
PI Address 2: Slot 522-10 
PI Web Page:  
City: Little Rock  State: AR 
Zip Code: 72205-7101  Congressional District: 
Comments:  
Project Type: GROUND  Solicitation:  2013 NSBRI-RFA-13-02 Center for Space Radiation Research (CSRR) 
Start Date: 06/01/2014  End Date:  05/31/2017 
No. of Post Docs: No. of PhD Degrees: 
No. of PhD Candidates: No. of Master' Degrees: 
No. of Master's Candidates: No. of Bachelor's Degrees: 
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment:

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Mao, Xiao   ( Loma Linda University )
Hauer-Jensen, Martin  M.D., Ph.D. ( University of Arkansas for Medical Sciences )
Kodell, Ralph  Ph.D. ( University of Arkansas for Medical Sciences )
Koturbash, Igor  M.D., Ph.D. ( University of Arkansas for Medical Sciences )
Tackett, Alan  Ph.D. ( University of Arkansas for Medical Sciences )
Nelson, Gregory  Ph.D. ( Loma Linda University ) 
Grant/Contract No.: NCC 9-58-RE03701 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: The Center for Space Radiation Research (CSRR) consists of teams of investigators from the University of Arkansas for Medical Sciences (UAMS), Loma Linda University (LLU), the University of Arizona, and Georgetown University. The CSRR uses multiple animal models to characterize acute effects of protons at doses lower than addressed in previous animal studies, and experiments involve exposure of animals and cell cultures to protons and heavy ions to examine degenerative cardiovascular effects. The CSRR pursues the following Specific Aims: 1) Define acute effects of low-dose proton irradiation on the hematopoietic system, skin, heart, and retina; 2) Examine acute effects of low-dose protons in combination with modeled microgravity; 3) Evaluate acute effects of protons on the adaptive immune response; 4) Determine effects of heavy ion and proton irradiation on cardiac and vascular function and structure; 5) Identify acute and chronic biomarkers of cardiovascular dysfunction after particle irradiation; 6) Elucidate the role of metabolic and epigenetic changes in the cardiovascular response to radiation; 7) Determine effects of radiation dose and quality on endothelial cell functional phenotype; and 8) Test whether gamma-tocotrienol protects against acute and cardiovascular effects of particle irradiation.

In the grant's second year, the following progress was made:

Under Specific Aim 1, the LLU team has performed studies with male C57BL/6 mice exposed to solar particle event (SPE)-like protons (0.1 - 0.5 Gy) or Cobalt-60 gamma rays as a reference radiation and examined at 60 hours and 14 days after irradiation. Both protons and gamma-rays at doses of 0.25 and 0.5 Gy caused apoptosis in the outer plexiform layer, inner nuclear layer, and ganglion cell layer of the retina. A double staining with lectin indicated that some of the apoptotic cells were from endothelial origin. Femurs and tibiae were shipped to UAMS for the analysis of hematopoietic cell populations. Protons at 0.5 Gy increased levels of reactive oxygen species (ROS) in hematopoietic stem cells (HSCs), but did not affect numbers of hematopoietic progenitor cells (HPCs), Lin- Sca1- c-kit+ (LSK) cells, or HSCs. Gamma rays reduced the percentages of HPCs, LSK cells, and HSCs within bone marrow-derived cells in a dose dependent manner and significantly increased ROS levels in LSK cells and HSCs at a dose of 0.5 Gy.

Under Specific Aim 2, the LLU team has started studies with male C57BL/6 mice exposed to hindlimb unloading for 5 days, then exposed to SPE-like protons (0.5 Gy), followed by 5 more days of hindlimb unloading. Mice are sacrificed 4 days after completion of hindlimb unloading, and skin, heart, and eye are collected for histological and molecular analysis. These studies with radiation in combination with hindlimb unloading are ongoing.

Under Specific Aims 4 and 5, male C57BL/6 mice were exposed to oxygen ions (600 MeV/n, 0.1 - 1 Gy) or protons (150 MeV, 0.5 - 1Gy) at the NASA Space Radiation Laboratory (NSRL) and transported back to UAMS for long-term follow-up. Additional groups of male C57BL/6 mice were exposed to Cesium-137 gamma rays (0.5 - 3 Gy) as a reference radiation. Oxygen ions (thus far examined up to 9 months after exposure) did not induce significant alterations in cardiac function. Nonetheless, markers of cardiac inflammatory infiltration were induced at 2 weeks, 3 months, and 9 months after exposure. Moreover, proteomic analysis has revealed that all doses of oxygen ions induced pathways of mitochondrial dysfunction and actin cytoskeleton signaling in the heart. Cardiac histological, molecular, and –omics analyses are ongoing. In addition to the ongoing mouse model studies, experiments with rat and rabbit models were initiated. Male New Zealand White rabbits and Long Evans rats were exposed to oxygen ions (600 MeV/n, 0.5 Gy) or protons (250 MeV, 0.5 Gy) at NSRL and transported back to UAMS for follow-up. These animals will be followed for 12 months after irradiation. During follow-up, cardiac function is measured with high-resolution echocardiography.

Under Specific Aim 6, genomic DNA was isolated from mouse heart tissue obtained at 2 weeks and 3 months after oxygen ion exposure. Significant alterations in DNA methylation status coincided with changes in repetitive element (LINE-1) expression, suggesting that DNA methylation changes have functional consequences in the cardiac cells. To identify pathways that may contribute to the changes in DNA methylation, proteomic and metabolomic approaches are used to examine one carbon metabolism. In addition to the epigenetic studies under Specific Aim 6, fecal pellets were collected from mice exposed to oxygen ions and dose-dependent alterations in the composition of the microbiome were identified. Some of these changes in the microbiome can be related to metabolic profiles. In addition, untargeted metabolic profiling was used to identify potential biomarkers of cardiovascular radiation effects in urine and plasma samples of mice after exposure to oxygen ions.

Under Specific Aim 7, cultures of mouse retinal and cardiac microvascular endothelial cells were exposed to oxygen ions, silicone ions, protons (all: 0.1 - 0.5 Gy), and Cobalt-60 gamma rays (0.1 - 2 Gy), and protein markers of endothelial cell adhesion, barrier function, and regulation of vascular tone and thrombogenesis were examined. Several protein markers show the largest response to radiation at doses below 1 Gy. In addition, tube formation was inhibited when irradiated cells were seeded on a Matrigel/collagen mixture. Studies with human retinal and cardiac microvascular endothelial cells are ongoing.

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: There is renewed interest in the chronic cardiovascular effects of exposures to low doses of ionizing radiation on Earth, including exposures due to medical treatments, occupational low-dose exposures, and radiological accidents. In addition, there has been longstanding interest in gamma-tocotrienol as a potential countermeasure against radiation from a nuclear attack or accident, and our research team is involved in recently started studies for the advanced development of gamma-tocotrienol as a radiation countermeasure against accidental whole-body gamma-ray exposure. Recent clinical trials have also begun to test gamma-tocotrienol as a potential mitigator of normal tissue effects from radiotherapy in cancer treatment. The current project will elucidate chronic effects of low-dose ionizing radiation on heart and vasculature, identify biological mechanisms, and test whether gamma-tocotrienol can protect against or mitigate these effects. These studies will thereby contribute to the general understanding of the cardiovascular effects of low-dose ionizing radiation, and aid in the development of gamma-tocotrienol as a radiation countermeasure on Earth.

 

Task Progress: Under studies that were performed to identify acute effects of low dose SPE-like proton exposure, a simulated SPE proton beam was developed and used to irradiate male 6 month old mice. Mouse retinal samples were collected and examined for the effects of protons on the endothelium and on apoptotic cell death. In addition, the effects of radiation on hematopoietic stem and progenitor cell function and numbers of circulating blood cells were identified. These biological responses were compared with those of gamma-rays as a reference radiation. Experiments with mouse models of proton exposure and hindlimb unloading have begun to identify potential interactions of radiation and microgravity. Under studies that were performed to determine degenerative cardiovascular effects of exposure to low dose protons and oxygen ions, mouse, rat, and rabbit models were exposed to oxygen ions, protons, or gamma-rays, and animals are followed up to 12 months after irradiation. The effects of radiation on cardiac function and structure are being characterized. Proteomic analysis has identified molecular pathways that are altered by radiation in the mouse heart. Metabolomic analysis of plasma and urine samples has started to identify potential biomarkers of cardiovascular radiation effects. Epigenetic analyses have identified effects of radiation on DNA methylation status in the heart. Lastly, experiments with cultures of mouse retinal and cardiac microvascular endothelial cells exposed to oxygen ions, silicone ions, protons, and gamma rays have started to characterize the effects of various types of radiation on protein markers of endothelial cell adhesion, barrier function, and regulation of vascular tone and thrombogenesis. Experiments with human cardiac and retinal endothelial cells have begun.

 

Bibliography Type: Description: (Last Updated: 09/19/2019) Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Chang J, Luo Y, Pathak R, Sridharan V, Jones T, Nelson G, Boerma M, Hauer-Jensen M, Zhou D, Shao L. "Low doses of oxygen ion irradiation cause acute damage to hematopoietic cells in mice." 61st Annual Meeting of the Radiation Research Society, Weston FL, September 19-22, 2015.

61st Annual Meeting of the Radiation Research Society, Weston, FL, September 19-22, 2015. , Sep-2015

Abstracts for Journals and Proceedings Koturbash I, Miousse I, Sridharan V, Skinner C, Hauer-Jensen M, Boerma M. "Three types of space radiation cause comparable dynamic alterations in one carbon metabolism and DNA methylation and expression of repetitive elements in the murine heart." 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings Mao X, Zheng J, Hauer-Jensen M, Boerma M, Nelson G. "Acute and late impact of combined exposure to simulated microgravity and low-dose radiation in the brain: a gene network analysis." 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings Nelson G, Mao X, Jones T, Rodriguez D, Stanbouly S, Sridharan V, Hauer-Jensen M, Boerma M. "Effects of low doses of gamma rays and charged particles on mouse retinal endothelium and cultured microvascular endothelial cells." 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings Nelson GA, Mao XW, Jones T, Rodriguez D, Stanbouly S, Boerma M, Sridharan V, Hauer-Jensen M. "Low doses of gamma rays, protons and oxygen ions cause acute damage to mouse retinal endothelium and cultured microvascular endothelial cells." 61st Annual Meeting of the Radiation Research Society, Weston FL, September 19-22, 2015.

61st Annual Meeting of the Radiation Research Society, Weston FL, September 19-22, 2015. , Sep-2015

Abstracts for Journals and Proceedings Nelson GA. "The Space Radiation Environment and Its Associated Risks." Conference on Normal Tissue Radiation Effects and Countermeasures, Petit Jean Mountain, AR, May 6-9, 2015.

Conference on Normal Tissue Radiation Effects and Countermeasures, Petit Jean Mountain, AR, May 6-9, 2015. , May-2015

Abstracts for Journals and Proceedings Pathak R, Bachri A, Ghosh S, Koturbash I, Boerma M, Hauer-Jensen M. "GT3 suppresses ionizing radiation- and/or microgravity-induced genomic instability: possible role of RAD50." 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings Pathak R, Bachri A, Ghosh SP, Koturbash I, Boerma M, Hauer-Jensen M. "Does GT3 modulate ionizing radiation- and/or microgravity-induced genomic instability?" 61st Annual Meeting of the Radiation Research Society, Weston FL, September 19-22, 2015.

61st Annual Meeting of the Radiation Research Society, Weston FL, September 19-22, 2015. , Sep-2015

Abstracts for Journals and Proceedings Sridharan V, Cao M, Singh P, Jones T, Campbell-Beachler M, Nelson G, Byrum S, Tackett A, Hauer-Jensen M, Boerma M. "Effects of 16O radiation on cellular and functional alterations in the heart." 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings Tackett A, Byrum S, Sridharan V, Boerma M. "Proteomic analysis of mouse heart tissue following radiation exposure." 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings Zheng J, Hauer-Jensen M, Boerma M, Nelson GA, Mao XW. "Acute and late impact of simulated microgravity and low-dose radiation in the brain: a gene network analysis." 31st Annual Meeting of the American Society for Gravitational and Space Research, Alexandria, VA, November 11-14, 2015.

31st Annual Meeting of the American Society for Gravitational and Space Research, Alexandria, VA, November 11-14, 2015. , Nov-2015

Abstracts for Journals and Proceedings Zheng J, Wang J, Pouliot M, Authier S, Loose D, Boerma M, Hauer-Jensen M. "Gene expression profiling in non-human primate heart after total-body irradiation: a comparative study of dose- and time-dependent molecular and cellular responses." 61st Annual Meeting of the Radiation Research Society, Weston FL, September 19-22, 2015.

61st Annual Meeting of the Radiation Research Society, Weston FL, September 19-22, 2015. , Sep-2015

Articles in Peer-reviewed Journals Boerma M, Nelson GA, Sridharan V, Mao XW, Koturbash I, Hauer-Jensen M. "Space radiation and cardiovascular disease risk." World Journal of Cardiology. 2015 Dec 26;7(12):882-8. Review. http://dx.doi.org/10.4330/wjc.v7.i12.882 ; PubMed PMID: 26730293; PubMed Central PMCID: PMC4691814 , Dec-2015
Articles in Peer-reviewed Journals Koturbash I, Miousse IR, Sridharan V, Nzabarushimana E, Skinner CM, Melnyk SB, Pavliv O, Hauer-Jensen M, Nelson GA, Boerma M. "Radiation-induced changes in DNA methylation of repetitive elements in the mouse heart." Mutation Research. 2016 May;787:43-53. Epub 2016 Mar 2. http://dx.doi.org/10.1016/j.mrfmmm.2016.02.009 ; PubMed PMID: 26963372; PubMed Central PMCID: PMC4828271 , May-2016
Articles in Peer-reviewed Journals Menon SS, Uppal M, Randhawa S, Cheema MS, Aghdam N, Usala RL, Ghosh SP, Cheema AK, Dritschillo A. "Radiation metabolomics: current status and future directions." Frontiers in Oncology. 2016 Feb 2;6:20. eCollection 2016. Review. http://dx.doi.org/10.3389/fonc.2016.00020 ; PubMed PMID: 26870697; PubMed Central PMCID: PMC4736121 , Feb-2016
Articles in Peer-reviewed Journals Miouse IR, Chalbot MC, Lumen A, Ferguson A, Kavouras IG, Koturbash I. "Response of transposable elements to environmental stressors." Mutation Research/Reviews in Mutation Research. 2015 Jul-Sep;765:19-39. Epub 2015 May 30. Review. http://dx.doi.org/10.1016/j.mrrev.2015.05.003 ; PubMed PMID: 26281766; PubMed Central PMCID: PMC4544780 , Jul-2015
Articles in Peer-reviewed Journals Nelson GA. "Space radiation and human exposures, a primer." Radiation Research. 2016 Apr;185(4):349-58. Epub 2016 Mar 28. http://dx.doi.org/10.1667/RR14311.1 ; PubMed PMID: 27018778 , Apr-2016
Articles in Peer-reviewed Journals Nzabarushimana E, Prior S, Miousse IR, Pathak R, Allen AR, Latendresse J, Olsen RH, Raber J, Hauer-Jensen M, Nelson GA, Koturbash I. "Combined exposure to protons and (56) Fe leads to overexpression of Il13 and reactivation of repetitive elements in the mouse lung." Life Sciences in Space Research. 2015 Nov;7:1-8. Epub 2015 Aug 18. http://dx.doi.org/10.1016/j.lssr.2015.08.001 ; PubMed PMID: 26553631; PubMed Central PMCID: PMC4641818 , Nov-2015
Articles in Peer-reviewed Journals Ramadan SS, Sridharan V, Koturbash I, Miousse IR, Hauer-Jensen M, Nelson GA, Boerma M. "A priming dose of protons alters the early cardiac cellular and molecular response to (56)Fe irradiation." Life Sciences in Space Research. 2016 Feb;8:8-13. Epub 2015 Dec 14. http://dx.doi.org/10.1016/j.lssr.2015.12.001 ; PubMed PMID: 26948008; PubMed Central PMCID: PMC4782196 , Feb-2016
Awards Cheema A. (Amrita Cheema) "John Eisenberg Career Development Award, Georgetown University Women in Medicine, November 2015." Nov-2015
Papers from Meeting Proceedings Secomb TW. "Computational methods for modeling retinal hemodynamics and oxygen transport." 4th International Conference on Computational and Mathematical Biomedical Engineering (CMBE), Cachan (Paris), France, June 29-July 1, 2015.

In: Proceedings of the 4th International Conference on Computational and Mathematical Biomedical Engineering (CMBE). Swansea, UK: Zeta Computational Resources Ltd., 2015. p. 612-615. http://www.compbiomed.net/2015/cmbe-proceedings.htm , Jun-2015

Download in PDF pdf     
Fiscal Year: FY 2015  Task Last Updated:  07/07/2015 
PI Name: Boerma, Marjan  Ph.D. 
Project Title: Center for Research on Cardiac, Vascular, and Acute Effects of Space Radiation 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Radiation Effects Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) ARS:Risk of Acute Radiation Syndromes Due to Solar Particle Events (SPEs)
 (2) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Acute01: Determine the dose response for acute effects induced by SPE-like radiation, including synergistic effects arising from other spaceflight factors (e.g. altered gravity (µ-gravity), stress, altered immune function, or other) that modify and/or enhance the biological response (IRP Rev G)
 (2) Acute07:What are the most effective biomedical or dietary countermeasures to mitigate acute radiation risks?
 (3) Degen01:How can tissue specific experimental models be developed for the major degenerative tissue risks, including cardiovascular, lens, digestive, endocrine, and other tissue systems in order to estimate space radiation risks for degenerative diseases? (IRP Rev F)
 (4) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
 (5) Degen03:What are the progression rates and latency periods for radiation-induced degenerative diseases, and how do progression rates depend on age, sex, radiation type, or other physiological or environmental factors? (IRP Rev F)
 (6) Degen05:What quantitative procedures or theoretical models are needed to extrapolate molecular, cellular, or animal results to predict degenerative tissue risks in astronauts? How can human epidemiology data best support these procedures or models?
 (7) Degen06:What are the most effective biomedical or dietary countermeasures to mitigate degenerative tissue risks? By what mechanisms are the countermeasures likely to work? Are these CMs additive, synergistic, or antagonistic to other Risks? (IRP Rev F)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: mboerma@uams.edu  Fax:   
PI Organization Type: UNIVERSITY  Phone: 501-686-6599  
Organization Name: University of Arkansas, Little Rock 
PI Address 1: 4301 W. Markham Street, Slot 522-10 
PI Address 2: Slot 522-10 
PI Web Page:  
City: Little Rock  State: AR 
Zip Code: 72205-7101  Congressional District: 
Comments:  
Project Type: GROUND  Solicitation:  2013 NSBRI-RFA-13-02 Center for Space Radiation Research (CSRR) 
Start Date: 06/01/2014  End Date:  05/31/2017 
No. of Post Docs: No. of PhD Degrees: 
No. of PhD Candidates: No. of Master' Degrees: 
No. of Master's Candidates: No. of Bachelor's Degrees: 
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment:

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Mao, Xiao   ( Loma Linda University )
Hauer-Jensen, Martin  M.D., Ph.D. ( University of Arkansas for Medical Sciences )
Kodell, Ralph  Ph.D. ( University of Arkansas for Medical Sciences )
Koturbash, Igor  M.D., Ph.D. ( University of Arkansas for Medical Sciences )
Nelson, Gregory  Ph.D. ( Loma Linda University )
Tackett, Alan  Ph.D. ( University of Arkansas for Medical Sciences ) 
Grant/Contract No.: NCC 9-58-RE03701 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: The Center for Space Radiation Research (CSRR) consists of teams of investigators from the University of Arkansas for Medical Sciences (UAMS), Loma Linda University (LLU), the University of Arizona, and Georgetown University. The CSRR uses multiple animal models to characterize acute effects of protons at doses lower than addressed in previous animal studies, and experiments involve exposure of animals and cell cultures to protons and heavy ions to examine degenerative cardiovascular effects. The CSRR pursues the following Specific Aims: 1) Define acute effects of low-dose proton irradiation on the hematopoietic system, skin, heart, and retina; 2) Examine acute effects of low-dose protons in combination with modeled microgravity; 3) Evaluate acute effects of protons on the adaptive immune response; 4) Determine effects of heavy ion and proton irradiation on cardiac and vascular function and structure; 5) Identify acute and chronic biomarkers of cardiovascular dysfunction after particle irradiation; 6) Elucidate the role of metabolic and epigenetic changes in the cardiovascular response to radiation; 7) Determine effects of radiation dose and quality on endothelial cell functional phenotype; and 8) Test whether gamma-tocotrienol protects against acute and cardiovascular effects of particle irradiation.

In the grant's first year, the following progress was made:

Under Specific Aim 1, the proton therapy facility at LLU was used to develop a fully modulated beam (Spread Out Bragg Peak) of 150 MeV protons for simulation of solar particle event (SPE) protons. The LLU team has harvested tissues from male C57BL/6 mice at 60 hours and 14 days after protons at doses of 0, 0.1, 0.25, or 0.5 Gy and at 48 hours and 14 days after irradiation with Cobalt-60 gamma rays as a reference radiation. First analyses of the retina indicated that proton doses of 0.25 and 0.5 Gy caused apoptosis in the outer plexiform layer, inner nuclear layer, and ganglion cell layer, suggesting that SPE-like protons may cause damage to the retina at relatively low doses. Femurs and tibiae were shipped to UAMS for the analysis of hematopoietic cell populations. Preliminary results indicate that protons at 0.5 Gy increased levels of reactive oxygen species (ROS) in hematopoietic stem cells (HSCs). Nonetheless, proton exposure did not affect numbers of hematopoietic progenitor cells (HPCs), Lin- Sca1- c-kit+ (LSK) cells, or HSCs. Gamma rays reduced the percentages of HPCs, LSK cells, and HSCs within bone marrow-derived cells in a dose dependent manner and significantly increased ROS levels in LSK cells and HSCs at a dose of 0.5 Gy. In discussion with the CSRR Scientific Advisory Committee and the NASA Space Radiation Element, oxygen ions were selected as a representative heavy ion for studies on Galactic Cosmic Rays (GCR). Discussions were also held with Drs. Guida, Rusek, and La Tessa of Brookhaven National Laboratory (BNL) about potential implementation and development of simultaneous multiple ion exposures (H, He, Fe, and C or O). Experiments with these exposures would be in line with NASA's desire to implement GCR simulations with multiple ions.

Under Specific Aims 4 and 5, male C57BL/6 mice were exposed to oxygen ions (600 MeV/n) at doses of 0.1, 0.25, or 1 Gy at the NASA Space Radiation Laboratory (NSRL) 2015 spring run (NSRL15A). Before shipment to BNL, mice were subjected to high-resolution ultrasound and retinal microscopy for baseline cardiovascular readings. Animals were returned to UAMS for short- and long-term follow-up. The first tissue and blood samples were collected at 14 days after irradiation, and histological, molecular, and –omics analyses are ongoing. Since the rabbit model is one of the animal models that most closely resemble cardiovascular effects of ionizing radiation in human subjects, an animal protocol for the exposure of rabbits to low-dose particles at NSRL was submitted to the BNL Institutional Animal Care and Use Committee. Upon approval, the protocol will be forwarded to the BNL Modified Institutional Risk Committee. Drs. Boerma and Nelson had extensive discussions about the logistics of these studies with the BNL animal care staff.

Under Specific Aim 7, primary mouse retinal and cardiac microvascular endothelial cells were obtained, and cell culture protocols were optimized for each cell type. Cell cultures will be exposed to heavy ions at NSRL. Hence, cell growth kinetics and various functional assays have been standardized for implementation at BNL. Testing of cell cultures at 24 hours to 5 days after gamma ray irradiation is in progress.

In the grant's second year, the following work will be performed: Under Specific Aim 1, we will continue to collect and analyze blood and tissue samples for the determination of acute effects of low-dose SPE-like proton exposure. Under Specific Aim 2, we will start experiments in mouse models in which SPE-like proton exposure is combined with hindlimb suspension to model fluid shifts from exposure to microgravity. Under Specific Aim 4, mice that were exposed to oxygen ions in year 1 will be followed to determine late cardiovascular effects. Additional cohorts of mice will be exposed to gamma rays as a reference radiation, using the cesium source at UAMS. Under Specific Aim 5, blood and urine samples collected from both the acute and degenerative studies will be analyzed with metabolomics and proteomics, and pathway analyses will be performed to start the identification of biomarkers of radiation effects. Under Specific Aim 6, tissue samples from both the acute and degenerative studies will be analyzed with metabolomics and DNA methylation assays. Under Specific Aim 7, cultures of mouse and human primary retinal and cardiac endothelial cells will be exposed to oxygen ions at NSRL, and to gamma rays and protons at LLU. Markers of cell survival, inflammation, endothelial barrier function, and oxidative stress will be evaluated.

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: There is renewed interest in the chronic cardiovascular effects of terrestrial exposures to low doses of ionizing radiation. In addition, there has been longstanding interest in gamma-tocotrienol as a potential countermeasure against radiation from a nuclear attack or accident, and gamma-tocotrienol is currently being examined as a potential mitigator of normal tissue effects from radiotherapy in cancer treatment. The current project will elucidate chronic effects of low-dose ionizing radiation on heart and vasculature, identify biological mechanisms, and test whether gamma-tocotrienol can protect against or mitigate these effects. These studies will thereby contribute to the general understanding of the cardiovascular effects of low-dose ionizing radiation, and aid in the development of gamma-tocotrienol as a terrestrial radiation countermeasure.

 

Task Progress: In this first grant year, progress has been made under both acute effects and degenerative tissue effects studies. First, the proton therapy facility at LLU was used to develop a fully modulated beam (Spread Out Bragg Peak) of 150 MeV protons for close simulation of SPE-like protons. The proton beam was then used for proton exposure of 6-months old male C57BL/6 mice, and progress was made towards determining the acute effects of low-dose SPE-like protons on the hematopoietic system, skin, and retina. Second, mouse models were exposed to low-dose heavy ions at NSRL, and analysis of long-term alterations in cardiac function and vascular structure is ongoing. Discussions to expose rabbits to heavy ions or protons at NSRL with BNL staff have started. Lastly, mouse cardiac and retinal microvascular endothelial cells were obtained, and two- and three-dimensional cell culture conditions were optimized. Experiments to determine the endothelial response to protons, heavy ions, and gamma rays have started.

 

Bibliography Type: Description: (Last Updated: 09/19/2019) Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Boerma M, Mao XW, Nelson GA, Hauer-Jensen M. "Center for Space Radiation Research." 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015.

2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. Abstract Book, January 2015. , Jan-2015

Abstracts for Journals and Proceedings Chang J, Feng W, Wang Y, Allen AR, Turner J, Stewart B, Hauer-Jensen M, Raber J, Zhou D, Shao L. "The Early Effect of Whole Body 28Si Irradiation on Hematopoietic Stem Cells in Mice." 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015.

2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. Abstract Book, January 2015. , Jan-2015

Abstracts for Journals and Proceedings Mao XW, Song SK, Nelson GA. "High LET (56) Fe Ion Irradiation Induces Microvessel and Structural Damage in Rat Retina." 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015.

2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. Abstract Book, January 2015. , Jan-2015

Abstracts for Journals and Proceedings Miousse IR, Shao L, Chang J, Feng W, Wang Y, Allen AR, Turner J, Stewart B, Raber J, Zhou D, Koturbash I. "Exposure to Low Dose 56Fe irradiation Induces Long-Term Epigenetic Alterations in Mouse Bone Marrow Hematopoietic Progenitor and Stem Cells." 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015.

2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. Abstract Book, January 2015. , Jan-2015

Abstracts for Journals and Proceedings Pathak R, Bachri A, Brown J, Ghosh SP, Koturbash I, Boerma M, Hauer-Jensen M. "The Effect of Ionizing Radiation on Genomic Instability under Microgravity with or without GT3 Pre-treatment." 23rd Arkansas Space Grant Consortium Symposium, Hot Springs AR, April 10, 2015.

23rd Arkansas Space Grant Consortium Symposium, Hot Springs AR, April 10, 2015. Abstract Book, April 2015. , Apr-2015

Abstracts for Journals and Proceedings Pathak R, Ghosh SP, Hauer-Jensen M. "Vitamin-E Analog Gamma Tocotrienol (GT3) Suppresses Radiation-Induced Cytogenetic Damage in Mice." 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015.

2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. Abstract Book, January 2015. , Jan-2015

Abstracts for Journals and Proceedings Shao L, Li H, Feng W, Chang J, Lou Y, Pathak R, Hauer-Jensen M, Meng A, Zhou D. "Mitigation of Total Body Irradiation-Induced Long-Term Bone Marrow Injury and Genomic Instability via Induction of Selective Depletion of Senescent Hematopoietic Stem Cells and Expansion of Normal Hematopoietic Stem Cells." 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015.

2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. Abstract Book, January 2015. , Jan-2015

Articles in Peer-reviewed Journals Chang J, Feng W, Wang Y, Luo Y, Allen AR, Koturbash I, Turner J, Stewart B, Raber J, Hauer-Jensen M, Zhou D, Shao L. "Whole body proton irradiation causes long-term damage to hematopoietic stem cells in mice." Radiation Research. 2015 Feb;183(2):240-8. http://dx.doi.org/10.1667/RR13887.1 ; PubMed PMID: 25635345 , Feb-2015
Articles in Peer-reviewed Journals Pathak R, Cheema AK, Boca SM, Krager KJ, Hauer-Jenses M, Aykin-Burns N. "Modulation of radiation response by the tetrahydrobiopterin pathway." Antioxidants. 2015 Mar;4(1):68-81. http://dx.doi.org/10.3390/antiox4010068 , Mar-2015
Articles in Peer-reviewed Journals Pathak R, Shao L, Ghosh SP, Zhou D, Boerma M, Weiler H, Hauer-Jensen M. "Thrombomodulin contributes to gamma tocotrienol-mediated lethality protection and hematopoietic cell recovery in irradiated mice." PLoS One. 2015 Apr 10;10(4):e0122511. eCollection 2015. http://dx.doi.org/10.1371/journal.pone.0122511 ; PubMed PMID: 25860286; PubMed Central PMCID: PMC4393275 , Apr-2015
Download in PDF pdf     
Fiscal Year: FY 2014  Task Last Updated:  12/18/2014 
PI Name: Boerma, Marjan  Ph.D. 
Project Title: Center for Research on Cardiac, Vascular, and Acute Effects of Space Radiation 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Radiation Effects Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) ARS:Risk of Acute Radiation Syndromes Due to Solar Particle Events (SPEs)
 (2) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Acute01: Determine the dose response for acute effects induced by SPE-like radiation, including synergistic effects arising from other spaceflight factors (e.g. altered gravity (µ-gravity), stress, altered immune function, or other) that modify and/or enhance the biological response (IRP Rev G)
 (2) Acute07:What are the most effective biomedical or dietary countermeasures to mitigate acute radiation risks?
 (3) Degen01:How can tissue specific experimental models be developed for the major degenerative tissue risks, including cardiovascular, lens, digestive, endocrine, and other tissue systems in order to estimate space radiation risks for degenerative diseases? (IRP Rev F)
 (4) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
 (5) Degen03:What are the progression rates and latency periods for radiation-induced degenerative diseases, and how do progression rates depend on age, sex, radiation type, or other physiological or environmental factors? (IRP Rev F)
 (6) Degen05:What quantitative procedures or theoretical models are needed to extrapolate molecular, cellular, or animal results to predict degenerative tissue risks in astronauts? How can human epidemiology data best support these procedures or models?
 (7) Degen06:What are the most effective biomedical or dietary countermeasures to mitigate degenerative tissue risks? By what mechanisms are the countermeasures likely to work? Are these CMs additive, synergistic, or antagonistic to other Risks? (IRP Rev F)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: mboerma@uams.edu  Fax:   
PI Organization Type: UNIVERSITY  Phone: 501-686-6599  
Organization Name: University of Arkansas, Little Rock 
PI Address 1: 4301 W. Markham Street, Slot 522-10 
PI Address 2: Slot 522-10 
PI Web Page:  
City: Little Rock  State: AR 
Zip Code: 72205-7101  Congressional District: 
Comments:  
Project Type: GROUND  Solicitation:  2013 NSBRI-RFA-13-02 Center for Space Radiation Research (CSRR) 
Start Date: 06/01/2014  End Date:  05/31/2017 
No. of Post Docs:   No. of PhD Degrees:   
No. of PhD Candidates:   No. of Master' Degrees:   
No. of Master's Candidates:   No. of Bachelor's Degrees:   
No. of Bachelor's Candidates:   Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment:

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Hauer-Jensen, Martin  M.D., Ph.D. ( University of Arkansas )
Kodell, Ralph  Ph.D. ( University of Arkansas )
Koturbash, Igor  M.D., Ph.D. ( University of Arkansas )
Mao, Xiao Wen  M.D. ( Loma Linda University )
Nelson, Gregory  Ph.D. ( Loma Linda University )
Tackett, Alan  Ph.D. ( University of Arkansas ) 
Grant/Contract No.: NCC 9-58-RE03701 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: Recent evidence strongly suggests that humans will face increased risks for adverse effects on heart and blood vessels from radiation exposure during space travel; however, these risks are not well defined. The proposed Center for Research on Cardiac and Vascular Effects of Space Radiation comprises teams from four institutions with experts in the fields of space radiation, cardiovascular radiation injury, and modern techniques of molecular analysis. The goal is to characterize the cardiovascular risks of space radiation. Studies will begin with mouse models and then proceed to rabbits to enhance translation to the human situation. Animals will be exposed to accelerated charged particles relevant to radiation in interplanetary space, and monitored for up to 9 months comparable to many years observation in humans. Heart function will be measured non-invasively at regular intervals with high-resolution ultrasound. Heart tissue will be obtained at different time points to investigate pathological changes, including scar tissue and inflammation. Cutting-edge molecular techniques will be used to examine thousands of proteins and DNA segments to understand mechanisms of radiation injury and aid in the discovery of sensitive biomarkers. We will also examine blood vessels in the heart and the retina of the eye, based on evidence that space radiation causes changes in the retinal blood vessel network, similar to those associated with reduced vision due to aging. Sensitive staining techniques will be used to reconstruct the structure of blood vessels in the retina and heart. Lastly, we will test whether gamma-tocotrienol, a safe dietary antioxidant and the strongest natural product radiation protector yet discovered, will reduce the effects of space radiation on heart and blood vessels. Altogether, these studies use innovative methods to characterize acute and degenerative cardiovascular effects of space radiation, and will help develop safe and effective countermeasures to protect humans against these effects.

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: 0

 

Task Progress: New project for FY2014.

 

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