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.
|
|
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
|
|