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Project Title:  Effects of Chronic High LET Radiation on the Human Heart Reduce
Fiscal Year: FY 2022 
Division: Human Research 
Research Discipline/Element:
TRISH--TRISH 
Start Date: 11/01/2020  
End Date: 04/30/2024  
Task Last Updated: 10/28/2022 
Download report in PDF pdf
Principal Investigator/Affiliation:   Weil, Michael  Ph.D. / Colorado State University 
Address:  Department of Environmental & Radiological Health Sciences 
1618 Campus Delivery 
Fort Collins , CO 80521-2807 
Email: michael.weil@colostate.edu 
Phone: 970-491-5902  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Colorado State University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Chatterjee, Anushree  Ph.D. University of Colorado at Boulder 
Brandl, Alexander  Ph.D. Colorado State University 
Chicco, Adam  Ph.D. Colorado State University 
Wu, Joseph  M.D., Ph.D. Stanford University 
Project Information: Grant/Contract No. NNX16AO69A-RAD0105 
Responsible Center: TRISH 
Grant Monitor:  
Center Contact:   
Unique ID: 14101 
Solicitation / Funding Source: 2020 TRISH Space Radiation Solicitation TSRAD-2020. Translational Research Institute for Space Health (TRISH) Human-Based Models to Study Effects of Space Radiation and Countermeasures 
Grant/Contract No.: NNX16AO69A-RAD0105 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: None
Human Research Program Risks: None
Human Research Program Gaps: None
Flight Assignment/Project Notes: NOTE: End date changed to 04/30/2024 per E. Urquieta/TRISH (Ed., 3/8/24).

NOTE: Start/End dates changed to 11/1/2020 and 10/31/2023, respectively, per E. Urquieta/TRISH (Ed., 9/14/21)

Task Description: We have detected adverse cardiac effects in mice and rats exposed to either high energy (HZE) ions or low dose rate neutrons, radiation exposures which simulate those in space. We propose to extend these findings to an engineered model of human cardiac tissue, identify biomarkers of radiation-induced cardiac damage, and test potential countermeasures against damage. To do this, we have assembled a team of experienced researchers from Colorado State University, Stanford University, and the University of Colorado. We will design and commission a facility that will allow us to expose engineered heart tissue (EHTs) to high linear energy transfer (LET) neutron radiation at low dose rate nearly continuously for more than a month. We will use the facility to irradiate EHTs fabricated using human induced pluripotent stem cells (hiPSCs) differentiated to cardiomyocytes, endothelium, and fibroblasts seeded into a fibrin/collagen-based extracellular matrix scaffold cast between flexible silicon posts. This is a robust physiological tissue model to identify functional and molecular changes, and we have previously flown hiPSC-derived cardiomyocytes aboard the International Space Station (ISS). Additional EHTs will be sham irradiated or irradiated with low dose rate gamma rays. The irradiated tissues will be screened for a panel of functional outcomes with known clinical relevance. Gene expression patterns will be determined to identify pathogenic gene networks that can be targeted with countermeasures, and media supernatants will be collected for metabolomics and proteomic analyses for biomarker discovery. Several small molecule countermeasures will be tested to attenuate adverse outcomes in the irradiated EHT based on published and preliminary studies in rodents and cell models. Among these is aspirin which targets oxidative stress, mitochondrial dysfunction and mtDNA damage, and inflammation implicated in our rodent models. We will also test overexpression of adeno-associated virus (AAV) transduced Nrf2 and antisense peptide nucleic acids (PNAs) directed against gene pathways identified in transcriptomic analyses as a novel and rapid multiplexed genetic countermeasure approach. Results from this proposed study will have the potential to improve risk assessments for space radiation induced cardiovascular disease, lead to methodologies for inflight detection for cardiac damage which, in turn, will inform decisions on whether countermeasures should be administered to individual crew members, and lead to the identification of those countermeasures.

Research Impact/Earth Benefits: This project has generated a human EHT model in the past calendar year, which had been used to study radiation-induced cardiotoxicity. We proved the feasibility of using this heart model for the deployment of radioprotective drugs.

Task Progress & Bibliography Information FY2022 
Task Progress: The aims of this project are to:

1. Develop a neutron irradiation resource that will enable complex tissue models to be chronically exposed to space-relevant, protracted high LET radiation at low-dose rate.

2. Characterize the damage to model cardiac tissues irradiated with low-dose rate neutrons and gamma rays with the intent of establishing relative biological effectiveness (RBE) for those types of damage with potential clinical consequences.

3. Use the model to identify biomarkers, particularly circulating biomarkers, for early detection of cardiac damage. Use the model to test potential countermeasures against cardiac dysfunction and damage.

Our key findings are that a space-relevant dose of gamma ray radiation delivered at low-dose rate causes mitochondrial damage and respiratory dysfunction in cultured human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes, fibroblasts, and hiPSC-derived engineered heart tissues (EHTs). Contractile function of EHTs was also impaired. Shifts in the fibroblast and EHT transcriptome correlate with observed functional defects, particularly genes related to mitochondrial function, oxidative stress and DNA damage. Proof-of-concept countermeasure studies demonstrated protective effects of a mitochondria-targeted antioxidant (MitoTEMPO) against gamma radiation-induced damage in a human fibroblast cell line, which have now been extended to human engineered heart tissues (EHTs). Initial testing also indicated antisense peptide nucleic acids (PNA FASTmers) are not toxic to cardiomyocytes and might impact mitochondrial function, enabling us to move forward with additional testing of these countermeasures in EHTs.

The impact of these findings is that they provide strong corroborating evidence for mitochondrial injury in human cell lines and EHTs that we previously observed in mouse and rat heart tissues following protracted exposure to low-dose rate neutron irradiation in vivo. This means that we can extrapolate the findings from our rodent models of space radiation-induced cardiac dysfunction to humans, and further validate candidate countermeasures identified in EHTs and in rodent models.

Over the upcoming year, we will irradiate EHTs with low-dose rate neutrons using the new D-T neutron irradiator recently installed at Colorado State University (CSU) to evaluate high LET radiation effects on mitochondrial function and contractile function, search for biomarkers of neutron-irradiation damage in the EHT secretome, and expand our testing of countermeasures against radiation injury mediated by oxidative stress and DNA damage using treatments such as aspirin, MitoTEMPO, and FASTmers targeting regulators of NRF2.

Bibliography: Description: (Last Updated: 09/27/2023) 

Show Cumulative Bibliography
 
Articles in Peer-reviewed Journals Cao X, Weil MM, Wu JC. "Clinical trial in a dish for space radiation countermeasure discovery." Life Sci Space Res. 2022 May 27. https://doi.org/10.1016/j.lssr.2022.05.006 , May-2022
Articles in Peer-reviewed Journals Courtney CM, Sharma S, Fallgren C, Weil MM, Chatterjee A, Nagpal P. "Reversing radiation-induced immunosuppression using a new therapeutic modality." Life Sci Space Res. 2022 May 11. https://doi.org/10.1016/j.lssr.2022.05.002 , May-2022
Articles in Peer-reviewed Journals Ding LH, Fallgren CM, Yu Y, McCarthy M, Edmondson EF, Ullrich RL, Weil MM, Story MD. "Orthologs of human circulating miRNAs associated with hepatocellular carcinoma are elevated in mouse plasma months before tumour detection." Sci Rep. 2022 Jun 28;12:10927. https://doi.org/10.1038/s41598-022-15061-5 ; PubMed PMID: 35764780; PubMed Central PMCID: PMC9240017 , Jun-2022
Articles in Peer-reviewed Journals Bokhari RS, Beheshti A, Blutt SE, Bowles DE, Brenner D, Britton R, Bronk L, Cao X, Chatterjee A, Clay DE, Courtney C, Fox DT, Gaber MW, Gerecht S, Grabham P, Grosshans D, Guan F, Jezuit EA, Kirsch DG, Liu Z, Maletic-Savatic M, Miller KM, Montague RA, Nagpal P, Osenberg S, Parkitny L, Pierce NA, Porada C, Rosenberg SM, Sargunas P, Sharma S, Spangler J, Tavakol DN, Thomas D, Vunjak-Novakovic G, Wang C, Whitcomb L, Young DW, Donoviel D. "Looking on the horizon; potential and unique approaches to developing radiation countermeasures for deep space travel." Life Sci Space Res. 2022 Aug 7. https://doi.org/10.1016/j.lssr.2022.08.003 , Aug-2022
Articles in Peer-reviewed Journals Boutros SW, Krenik D, Holden S, Unni VK, Raber J. "Common cancer treatments targeting DNA double strand breaks affect long-term memory and relate to immediate early gene expression in a sex-dependent manner." Oncotarget. 2022;13:198-213. https://doi.org/10.18632/oncotarget.28180 ; PubMed PMID: 35106123; PubMed Central PMCID: PMC8794536 , Jan-2022
Articles in Peer-reviewed Journals Eslinger PJ, Anders S, Ballarini T, Boutros S, Krach S, Mayer AV, Moll J, Newton TL, Schroeter ML, de Oliveira-Souza R, Raber J, Sullivan GB, Swain JE, Lowe L, Zahn R. "The neuroscience of social feelings: Mechanisms of adaptive social functioning." Neurosci Biobehav Rev. 2021 Sep;128:592-620. https://doi.org/10.1016/j.neubiorev.2021.05.028 ; PubMed PMID: 34089764; PubMed Central PMCID: PMC8388127 , Sep-2021
Articles in Peer-reviewed Journals Huff JL, Poignant F, Rahmanian S, Khan N, Blakely EA, Britten RA, Chang P, Fornace AJ, Hada M, Kronenberg A, Norman RB, Patel ZS, Shay JW, Weil MM, Simonsen LC, Slaba TC. "Galactic cosmic ray simulation at the NASA Space Radiation Laboratory–Progress, challenges and recommendations on mixed-field effects." Life Sci Space Res. 2022 Sep 10. https://doi.org/10.1016/j.lssr.2022.09.001 , Sep-2022
Project Title:  Effects of Chronic High LET Radiation on the Human Heart Reduce
Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
TRISH--TRISH 
Start Date: 11/01/2020  
End Date: 10/31/2023  
Task Last Updated: 12/02/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Weil, Michael  Ph.D. / Colorado State University 
Address:  Department of Environmental & Radiological Health Sciences 
1618 Campus Delivery 
Fort Collins , CO 80521-2807 
Email: michael.weil@colostate.edu 
Phone: 970-491-5902  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Colorado State University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Chatterjee, Anushree  Ph.D. University of Colorado at Boulder 
Brandl, Alexander  Ph.D. Colorado State University 
Chicco, Adam  Ph.D. Colorado State University 
Wu, Joseph  M.D., Ph.D. Stanford University 
Project Information: Grant/Contract No. NNX16AO69A-RAD0105 
Responsible Center: TRISH 
Grant Monitor:  
Center Contact:   
Unique ID: 14101 
Solicitation / Funding Source: 2020 TRISH Space Radiation Solicitation TSRAD-2020. Translational Research Institute for Space Health (TRISH) Human-Based Models to Study Effects of Space Radiation and Countermeasures 
Grant/Contract No.: NNX16AO69A-RAD0105 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: None
Human Research Program Risks: None
Human Research Program Gaps: None
Flight Assignment/Project Notes: NOTE: Start/End dates changed to 11/1/2020 and 10/31/2023, respectively, per E. Urquieta/TRISH (Ed., 9/14/21)

Task Description: We have detected adverse cardiac effects in mice and rats exposed to either high energy (HZE) ions or low dose rate neutrons, radiation exposures which simulate those in space. We propose to extend these findings to an engineered model of human cardiac tissue, identify biomarkers of radiation-induced cardiac damage, and test potential countermeasures against damage. To do this, we have assembled a team of experienced researchers from Colorado State University, Stanford University, and the University of Colorado. We will design and commission a facility that will allow us to expose engineered heart tissue (EHTs) to high linear energy transfer (LET) neutron radiation at low dose rate nearly continuously for more than a month. We will use the facility to irradiate EHTs fabricated using human induced pluripotent stem cells (hiPSCs) differentiated to cardiomyocytes, endothelium, and fibroblasts seeded into a fibrin/collagen-based extracellular matrix scaffold cast between flexible silicon posts. This is a robust physiological tissue model to identify functional and molecular changes, and we have previously flown hiPSC-derived cardiomyocytes aboard the International Space Station (ISS). Additional EHTs will be sham irradiated or irradiated with low dose rate gamma rays. The irradiated tissues will be screened for a panel of functional outcomes with known clinical relevance. Gene expression patterns will be determined to identify pathogenic gene networks that can be targeted with countermeasures, and media supernatants will be collected for metabolomics and proteomic analyses for biomarker discovery. Several small molecule countermeasures will be tested to attenuate adverse outcomes in the irradiated EHT based on published and preliminary studies in rodents and cell models. Among these is aspirin which targets oxidative stress, mitochondrial dysfunction and mtDNA damage, and inflammation implicated in our rodent models. We will also test overexpression of adeno-associated virus (AAV) transduced Nrf2 and antisense peptide nucleic acids (PNAs) directed against gene pathways identified in transcriptomic analyses as a novel and rapid multiplexed genetic countermeasure approach. Results from this proposed study will have the potential to improve risk assessments for space radiation induced cardiovascular disease, lead to methodologies for inflight detection for cardiac damage which, in turn, will inform decisions on whether countermeasures should be administered to individual crew members, and lead to the identification of those countermeasures.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2021 
Task Progress: New project for FY2021.

Bibliography: Description: (Last Updated: 09/27/2023) 

Show Cumulative Bibliography
 
 None in FY 2021