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Project Title:  Countermeasures to Radiation Induced Cardiomyopathy Reduce
Images: icon  Fiscal Year: FY 2022 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 02/01/2019  
End Date: 01/31/2023  
Task Last Updated: 12/07/2021 
Download report in PDF pdf
Principal Investigator/Affiliation:   Edwards, John  Ph.D. / New York Medical College 
Address:  Department of Physiology 
15 Dana Rd 
Valhalla , NY 10595-1554 
Email: j_edwards@nymc.edu 
Phone: 914-594-4166  
Congressional District: 17 
Web:  
Organization Type: UNIVERSITY 
Organization Name: New York Medical College 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Eisenberg, Carol  Ph.D. New York Medical College 
Rota, Marcello  Ph.D. New York Medical College 
Key Personnel Changes / Previous PI: 2021 report: Research Assistant no longer on the project. December 2020 report: No Changes.
Project Information: Grant/Contract No. 80NSSC19K0436 
Responsible Center: NASA JSC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Solicitation / Funding Source: 2017-2018 HERO 80JSC017N0001-BPBA Topics in Biological, Physiological, and Behavioral Adaptations to Spaceflight. Appendix C 
Grant/Contract No.: 80NSSC19K0436 
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: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
(2) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
Human Research Program Gaps: (1) Cancer-502:Systematically identify safe and effective countermeasures to reduce radiation carcinogenesis (IRP Rev M)
(2) CVD-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease (IRP Rev L)
(3) CVD-201:Selection of countermeasures and procedures to be tested based on previous objectives (IRP Rev L)
Flight Assignment/Project Notes: NOTE: End date changed to 1/31/2023 per NSSC information (Ed., 2/7/22)

NOTE: End date changed to 1/31/2022 per NSSC information (Ed., 8/12/21)

Task Description: These projects seek to study the consequences of galactic cosmic radiation (GCR) exposure. Space travel increases solar and cosmic particle radiation exposure, which is significantly elevated once travel moves beyond low Earth orbit. This includes a combination of high-energy protons and heavy ions such as Fe56, Si28, and O16. Low dose radiation induced damage is observed months or years after exposure. Our preliminary findings observed that GCR induced degradation of cardiac function with a phenotype that was similar to that observed following doxorubicin treatment. Although there are significant differences from GCR, survivors of cancer that have undergone low-LET (linear energy transfer) radiotherapy are also at risk for several adverse health outcomes including abnormal pulmonary function, endocrine disorders, neurocognitive impairment, and heart failure. All these organ systems are characterized by a low turnover of cells and it is possible that an accelerated cell death and/or the failure of regeneration by progenitor cells may be the underlying cause of organ failure. Although this project initially focused on protection from cardiomyopathies, our findings have implications across all organ systems.

These projects have focused on developing countermeasures to GCR using small molecules from a FDA (Food & Drug Administration) approved library, as well as additional molecules identified by NASA personnel as high priority compounds. These drugs are part of other ongoing investigations and their inclusion will be useful in making comparisons across platforms. With regard to the Map to Human Research, this project primarily addresses two Risks. All are designated as High LxC for longer endurance missions or long-term health and wellbeing.

Countermeasures fall into three categories; radio protectors are given prophylactically or concurrently to prevent damage. Radiation therapeutics are those that stimulate repair or regeneration processes. Radionuclide eliminators discorporate or block absorption of internalized radionuclides. This project will focus on radio protectors and radiation therapeutics with the hope of developing protocols that will diminish the need for radiation therapeutics.

Research Impact/Earth Benefits: The focus of this NASA funded research project is to develop countermeasures to cosmic radiation exposure with the goal of protecting flight crews on long duration missions. However, the findings of this project will also benefit those with more Earth-bound problems. We know that airline pilots and flight attendants have a small but significantly higher risk of cancer that is directly attributable to the chronic exposure to cosmic radiation during their careers. Radiation therapy has been used for the treatment of cancer for many years, and it has long been known that these survivors are at risk for other illnesses related to their treatment. Proton Therapy is an increasingly popular radiation protocol for cancer treatments. This protocol generates similar types of radiation and energy levels that are part of the solar radiation spectrum. And unfortunately, we live in an age when terrorists might eventually gain access to weapons that will generate very high radiation exposures. Hopefully this won’t happen but the lessons learned from the present investigation will have overlap to the nuclear countermeasures that others are studying. The results from the current project will hopefully contribute to the knowledge base that other fields will find useful.

Task Progress & Bibliography Information FY2022 
Task Progress: Our approach has utilized a high throughput screen of small molecules from an FDA approved drug library. We have as a partial bias, degradation of mitochondrial function as one readout. Several studies using RNA-seq and other “omics” analyses have repeated identified mitochondrial dysfunction as participating in the response to high-LET radiation [4-6]. Mitochondrial dysfunction is also one antecedent event in the transition from a healthy to cancerous cell and in part underlies the Warburg effect, a hallmark of cancer cells [7-10]. Related to this, radiation-induced cardiac dysfunction leading to heart failure remains a significant clinical problem. The heart is almost completely reliant on aerobic metabolism and healthy mitochondria are critical for cardiomyocyte function. Some of our preliminary studies have demonstrated degradation of cardiac function and mtDNA integrity as a delayed consequence of low dose 56Fe (50 cGy) radiation exposure.

We have participated in several campaigns at the NASA Space Radiation Laboratory (NSRL). All protocols to date have use cultured cells including H9c2 (myoblasts), RBL-2H3 (mast cell), Hy926 (endothelial), and ES-D3 (stem/pluripotent cell). For all campaigns, cells were exposed to a total of 75 cGy using the simplified 5-ion GCR protocol developed by NSRL. Our initial studies used a follow-on paradigm, where the drugs were introduced shortly after GCR exposure.

Of 725 drugs, more than 500 showed degradation of cellular function or were ineffective for managing exposure to GCR. Within the160 drugs observed to be useful, 33 are known anti-inflammatories, while some other were also thought to have a lesser capacity as anti-inflammatory. The library included 54 COX inhibitors and of the 7 deemed effective all were COX-2 specific. Meta-analysis of COX-2 inhibition found that the anti-inflammatory effect reduced metastases following primary cancer [11]. In the context of our studies, it is important to understand that the H9c2 cell line contains the proinflammatory TLR4/NFkappaB/TNFalpha pathways which may underlie its radiation-induced increases in IL-1ß and TNFalpha and other cytokines [12-15]. 12 of 25 angiotensin converting enzyme inhibitors or AT1 antagonists were observed to be effective, while no AT2 antagonists appeared useful. The library contained 20 drugs that bound to adrenergic receptors of which 5 were deemed effective, although given their direct impact on blood pressure they are not likely to be useful as countermeasures. A common theme among the effective drugs was that they are mediated by GPCR/G coupled proteins, a class of signaling proteins that mediate and control cellular function.

Distinct from those described, 5-HT3 antagonists appear to be useful. Those found not to be useful were non-selective or had high affinity for other 5-HT receptor isoforms (i.e., 5-HT2a). Unlike other 5-HT receptors which are GPCR/G coupled proteins, the 5-HT3 receptors are Ca+2 activated small K+ ion channel receptors. Others have reported that 5-HT3 antagonism may ameliorate the effects of damaging radiation and may serve to protect against radiation-induced bystander effects [16, 17]. Clinically the 5-HT3 antagonists are used for the treatment of nausea and vomiting and are currently serving in that capacity aboard the International Space Station (ISS).

The follow-on paradigm examined the restorative capability of a candidate drug when presented shortly following exposure to GCR and a short list of useful leads was developed. To determine if the delayed presentation of protective drugs impacted on recovery, cells exposed to GCRsim or control conditions were maintained in culture for one month before treatment was undertaken. Although most drugs were without effect, a few were still protective even when treatment was delayed. This included metformin and sulfacarbamide, both antidiabetic therapeutics as well as dolasetron, a 5-HT3 antagonist.

Using a pretreatment paradigm in which drugs were added the day prior to GCR exposure and then the cells were maintained in culture for a week, we have found that metformin, sulfacarbamide, and olmesartan offered the highest level of protection. Several others including bilastine, ramelteon, or granisetron also demonstrated some protective efficacy.

We have as a partial bias, degradation of mitochondrial function as a central readout. Several studies using RNA-seq and other “omics” analyses have repeatedly identified mitochondrial dysfunction as participating in the response to high-LET radiation. Mitochondrial dysfunction is one antecedent event in the transition from a healthy to cancerous cell.

Separate from examining mitochondrial and cellular dysfunction as readouts, we have developed a novel cell line using an Afp-tdTomato construct, as a biomarker for the transition to a cancerous cell. The construct is analogous to the Afp-mCherry construct described by M. Weil for the Carcinogenesis NASA Specialized Center of Research (NSCOR) [19]. Validation protocols using either ethidium bromide (0.4 µg/ml) treatment or UVC light (4 j/m2) exposure significantly increased Afp-tdTomato expression. GCRsim (75 cGy) significantly increased tdTomato expression compared to the No-Radiation control cells. Using the follow-on protocols, to date only a select group of drugs have been tested. Of those dimethyl fumarate, sulfacarbamide, and pargyline all appear to be promising leads.

We have developed a Afp-tdTomato expressing cell line that is responsive to GCR as well as different carcinogenic reagents. We have also demonstrated that some of the lead candidates will at least partially rescue the cells from GCR induced Afp driven expression. We are currently evaluating the efficacy of other biomarkers thought to beleading indicators for carcinogenesis: neuron specific enolase (SCLC, neuroblastoma), tyrosinase (breast), EGFR (NSCLC), HER2 (breast, ovarian, pancreatic, & g-i), LDH-A (lymphoma, leukemia, Warburg). We are currently evaluating the impact of GCR on the expression levels of these biomarkers in the Hy926 and H9c2 cell lines. Those results should will allow us to identify which biomarkers are more responsive to GCR. The use of the tdTomato expression vectors will allow for screening protocols to identify the transformation processes towards carcinogenesis.

The Comet DNA Assay, gammaH2Ax levels, and micronuclei formation have all been used to measure DNA damage in response to stress environments. These measures are important since they focus on one major pathway leading to carcinogenesis. Colony formation or the clonogenic assay has long been used as a measure of the cell’s proliferative ability [20]. Successful cellular proliferation incorporates many different aspects of cell well-being including DNA integrity as well as cellular and mitochondrial function. We have adapted the cell doubling time protocols to examine the impact of GCR on cell function. Similar to the clonogenic assay this approach also examines overall cell well-being. Unlike the clonogenic assay that typically has an incubation time of 2-3 weeks, our protocol incubates the cells for only 2-3 days. We have previously adapted this protocol to demonstrate that a single exposure to doxorubicin had an early and persistent effect to increase cell doubling time reflective of continued cell stress1. Recently we have been able to test this potential approach. We observed that with GCR (75 cGy GCRsim) treatment, the irradiated cells had a significant increase in cell doubling time. Of the select group of candidates, we observed that dimethyl fumarate or olmesartan significantly decreased cell doubling time of the GCR treated cells. The use of the flow cytometer to analyze these cells confers a novel advantage in that we are able to measure forward scatter and side scatter of all cells. Forward scatter is an estimator for cell size, while side scatter reflects intracellular complexity. We have used this approach in the past to differentiate mature from immature mast cells [1]. The Forward*Side Scatter Index is the product using the geometric means for forward and side scatter from each sample. To some extent it is analogous to the ColonyArea function available from Image J for the clonogenic assay [21]. Although somewhat preliminary we have observed that GCR treatment significantly depressed the Forward*Side Scatter Index.

Cancer development from a single cell undergoing transformation progresses through the steps of initiation, promotion, proliferation, to metastasis. It is not likely that the cell doubling time protocol or the colony formation assay alone could differentiate between healthy or malignant growth. The Forward*Side Scatter Index may be useful. The proliferative phase of cancer development is characterized by accelerated growth but potentially unlikely that these cells would develop the same level of complexity or size of a normal cell. In conjunction with lactate release or lactate dehydrogenases release assays could potentially differentiate between these different forms of proliferation, which would be useful in a countermeasure screen.

The focus of these projects has been to perform a high throughput screen to identify reasonable countermeasures to GCR for long duration missions. Starting from a FDA approved drug library we have taken the candidates from several hundred down to a select group nearing twenty. The complexity of the problem is that the response to space radiation is more than just ion species, time, or dose dependent. It is also dependent on the specific risk factor that is being ameliorated--that different organ systems may have different sensitivities. However, there are common threads, that include [2] chronic inflammation, chronic elevated oxidant stress, and direct DNA damage. These are all relevant whether one is focused on cardiomyopathy, carcinogenesis, or a decline in cognitive function. All are partially mediated through mitochondrial dysfunction which warrants the attention paid to it thus far. Going forward, more closely examining the common signaling pathways associated with the initiation of carcinogenesis or cardiomyopathy to identify the best leading indicators as biomarkers may offer the best path for countermeasure development. This will be followed by development of the tdTomato expression vectors that should facilitate future screens.

References

[1] Mitry MA, Laurent D, Keith BL, Sira E, Eisenberg CA, Eisenberg LM, Joshi S, Gupte S, Edwards JG: Accelerated cardiomyocyte senescence contributes to late-onset doxorubicin-induced cardiotoxicity. Am J Physiol Cell Physiol 2020, 318:C380-C91.

[2] Hudson MM, Ness KK, Gurney JG, Mulrooney DA, Chemaitilly W, Krull KR, Green DM, Armstrong GT, Nottage KA, Jones KE, Sklar CA, Srivastava DK, Robison LL: Clinical ascertainment of health outcomes among adults treated for childhood cancer. Jama 2013, 309:2371-81.

[4] McDonald JT, Stainforth R, Miller J, Cahill T, da Silveira WA, Rathi KS, Hardiman G, Taylor D, Costes SV, Chauhan V, Meller R, Beheshti A: NASA GeneLab Platform Utilized for Biological Response to Space Radiation in Animal Models. Cancers (Basel) 2020, 12.

[5] Ikeda H, Muratani M, Hidema J, Hada M, Fujiwara K, Souda H, Yoshida Y, Takahashi A: Expression Profile of Cell Cycle-Related Genes in Human Fibroblasts Exposed Simultaneously to Radiation and Simulated Microgravity. Int J Mol Sci 2019, 20.

[6] Beheshti A, Ray S, Fogle H, Berrios D, Costes SV: A microRNA signature and TGF-beta1 response were identified as the key master regulators for spaceflight response. PLoS One 2018, 13:e0199621.

[7] Patel J, Baptiste BA, Kim E, Hussain M, Croteau DL, Bohr VA: DNA Damage and Mitochondria in Cancer and Aging. Carcinogenesis 2020.

[8] Vyas S, Zaganjor E, Haigis MC: Mitochondria and Cancer. Cell 2016, 166:555-66.

[9] Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ, Hu W, Feng Z: Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci U S A 2011, 108:16259-64.

[10] Fujiwara M, Marusawa H, Wang HQ, Iwai A, Ikeuchi K, Imai Y, Kataoka A, Nukina N, Takahashi R, Chiba T: Parkin as a tumor suppressor gene for hepatocellular carcinoma. Oncogene 2008, 27:6002-11.

[11] Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z: Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012, 379:1591-601.

[12] Baradaran Rahim V, Khammar MT, Rakhshandeh H, Samzadeh-Kermani A, Hosseini A, Askari VR: Crocin protects cardiomyocytes against LPS-Induced inflammation. Pharmacol Rep 2019, 71:1228-34.

[13] Tang M, Pan H, Zheng Z, Guo Y, Peng J, Yang J, Luo Y, He J, Yan S, Wang P, Zhang Y, Zhou Y: Prostaglandin E1 protects cardiomyocytes against hypoxia-reperfusion induced injury via the miR-21-5p/FASLG axis. Biosci Rep 2019.

[14] Zhang X, Li M, Wang H: Astragaloside IV Alleviates the Myocardial Damage Induced by Lipopolysaccharide via the Toll-Like Receptor 4 (TLR4)/Nuclear Factor kappa B (NF-kappaB)/Proliferator-Activated Receptor alpha (PPARalpha) Signaling Pathway. Med Sci Monit 2019, 25:7158-68.

[15] Zheng Y, Li S, Hu R, Cheng F, Zhang L: GFI-1 Protects Against Lipopolysaccharide-Induced Inflammatory Responses and Apoptosis by Inhibition of the NF-kappaB/TNF-alpha Pathway in H9c2 Cells. Inflammation 2019.

[16] Poon RC, Agnihotri N, Seymour C, Mothersill C: Bystander effects of ionizing radiation can be modulated by signaling amines. Environ Res 2007, 105:200-11.

[17] Curtis JJ, Vo NTK, Seymour CB, Mothersill CE: Serotonin and 5-HT3 receptors sensitize human skin cells to direct irradiation cell death but not to soluble radiation-induced bystander signals. Environ Res 2019, 180:108807.

[19] Weil M, Ullrich RL, Ding L, Emmett M, Yu Y, Bacher J, Halberg R, Raber J, Ray F, Thamm H, Borak TB, Story MD: CARCINOGENESIS NSCOR: OVERVIEW. NASA Human Research Program; Investigators Workshop 2020.

[20] Rafehi H, Orlowski C, Georgiadis GT, Ververis K, El-Osta A, Karagiannis TC: Clonogenic assay: adherent cells. J Vis Exp 2011.

[21] Guzman C, Bagga M, Kaur A, Westermarck J, Abankwa D: ColonyArea: an ImageJ plugin to automatically quantify colony formation in clonogenic assays. PLoS One 2014, 9:e92444.

Bibliography Type: Description: (Last Updated: 02/07/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Nikisher B, Haran H, Weiss M, Tefft K, Edwards JG. "Countermeasures to Radiation Induced Cellular Dysfunction." Presented at the 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021.

Abstracts. 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021. , Feb-2021

Abstracts for Journals and Proceedings Nikisher B, Haran H, Weiss M, Tefft K, Edwards JG. "Small Molecule Countermeasures to Radiation Induced Cellular Dysfunction." Presented to Novel Extraplanetary Radiation Countermeasures Initiative (NERCI) at NASA, January 4, 2021.

Archives: Novel Extraplanetary Radiation Countermeasures Initiative (NERCI), January 2021. , Jan-2021

Abstracts for Journals and Proceedings Edwards S, Tchernikov A, Edwards J. "The Use of Low-Dose Radiation Pre-Treatments as a Potential Countermeasure to Space Radiation Exposure." 37th Annual Meeting of the American Society for Gravitational and Space Research, Baltimore, MD, November 3-6, 2021.

Abstracts. 37th Annual Meeting of the American Society for Gravitational and Space Research, Baltimore, MD, November 3-6, 2021. , Nov-2021

Project Title:  Countermeasures to Radiation Induced Cardiomyopathy Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 02/01/2019  
End Date: 01/31/2022  
Task Last Updated: 12/09/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Edwards, John  Ph.D. / New York Medical College 
Address:  Department of Physiology 
15 Dana Rd 
Valhalla , NY 10595-1554 
Email: j_edwards@nymc.edu 
Phone: 914-594-4166  
Congressional District: 17 
Web:  
Organization Type: UNIVERSITY 
Organization Name: New York Medical College 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Eisenberg, Carol  Ph.D. New York Medical College 
Rota, Marcello  Ph.D. New York Medical College 
Key Personnel Changes / Previous PI: December 2020 report: No Changes.
Project Information: Grant/Contract No. 80NSSC19K0436 
Responsible Center: NASA JSC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Solicitation / Funding Source: 2017-2018 HERO 80JSC017N0001-BPBA Topics in Biological, Physiological, and Behavioral Adaptations to Spaceflight. Appendix C 
Grant/Contract No.: 80NSSC19K0436 
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: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
(2) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
Human Research Program Gaps: (1) Cancer-502:Systematically identify safe and effective countermeasures to reduce radiation carcinogenesis (IRP Rev M)
(2) CVD-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease (IRP Rev L)
(3) CVD-201:Selection of countermeasures and procedures to be tested based on previous objectives (IRP Rev L)
Flight Assignment/Project Notes: NOTE: End date changed to 1/31/2022 per NSSC information (Ed., 8/12/21)

Task Description: The present application seeks to study the consequences of galactic cosmic radiation (GCR) exposure. Space travel increases solar and cosmic particle radiation exposure which is significantly elevated once travel moves beyond low Earth orbit. This includes a combination of high-energy protons and heavy ions such as Fe56, Si28, and O16.

Radiation induced cardiomyopathies are observed months or years after exposure. Our preliminary findings observed that GCR induced degradation of cardiac function with a phenotype that was similar to that observed following doxorubicin treatment [1]. Although there are significant differences from GCR, survivors of cancer that have undergone low-LET (linear energy transfer) radiotherapy are also at risk for several adverse health outcomes including abnormal pulmonary function, endocrine disorders, neurocognitive impairment, and heart failure [2, 3]. All these organ systems are characterized by a low turnover of cells and it is possible that an accelerated cell death and/or the failure of regeneration by progenitor cells may be the underlying cause of organ failure. Although this project initially focused on protection from cardiomyopathies, our findings has implications across all organ systems.

This project has focused developing countermeasures to GCR using small molecules from a FDA (Food & Drug Administration) approved library, as well as additional molecules identified by NASA personnel as high priority compounds. These drugs are part of other ongoing investigations and their inclusion will be useful in making comparisons across platforms. With regard to the Map to Human Research, this project primarily addresses two Risks. All are designated as High LxC for longer endurance missions or long-term health and wellbeing.

Countermeasures fall into three categories: Radio protectors are given prophylactically or concurrently to prevent damage. Radiation therapeutics are those that stimulate repair or regeneration processes. Radionuclide eliminators discorporate or block absorption of internalized radionuclides. This project will focus on radio protectors and radiation therapeutics with the hope of developing protocols that will diminish the need for radiation therapeutics.

Drug screening will be performed on two levels; 1) broad screening using analysis that allows for high throughput, and 2) focused analysis of high value target molecules. The hierarchy for success will be: 1) ability to protect cellular function, 2) ability to protect mitochondrial function, 3) ability to ameliorate radiation induced senescence, 4) ability to protect DNA. An FDA-approved drug library from MedChem Express was chosen over other commercially library because it includes a larger number drugs directed towards DNA damage, anti-inflammation. The complete FDA approved library available from MedChem Express of more than 1500 drugs was reduced to 725 drugs, by selecting against drugs that were antibiotics or anti-parasitic. Priority was given to drugs that indicated role for DNA repair, were anti-oxidant, or anti-inflammatory.

References

[1] Mitry MA, Laurent D, Keith BL, Sira E, Eisenberg CA, Eisenberg LM, Joshi S, Gupte S, Edwards JG: Accelerated cardiomyocyte senescence contributes to late-onset doxorubicin-induced cardiotoxicity. Am J Physiol Cell Physiol 2020, 318:C380-C91.

[2] Hudson MM, Ness KK, Gurney JG, Mulrooney DA, Chemaitilly W, Krull KR, Green DM, Armstrong GT, Nottage KA, Jones KE, Sklar CA, Srivastava DK, Robison LL: Clinical ascertainment of health outcomes among adults treated for childhood cancer. Jama 2013, 309:2371-81.

[3] Dekkers IA, Blijdorp K, Cransberg K, Pluijm SM, Pieters R, Neggers SJ, van den Heuvel-Eibrink MM: Long-term nephrotoxicity in adult survivors of childhood cancer. Clin J Am Soc Nephrol 2013, 8:922-9.

Research Impact/Earth Benefits: The focus of this NASA funded research project is to develop countermeasures to cosmic radiation exposure with the goal of protecting flight crews on long duration missions. However, the findings of this project will also benefit those with more Earth-bound problems. We know that airline pilots and flight attendants have a small but significantly higher risk of cancer that is directly attributable to the chronic exposure to cosmic radiation during their careers. Radiation therapy has been used for the treatment of cancer for many years, and it has long been known that these survivors are at risk for other illnesses related to their treatment. Proton Therapy is an increasingly popular radiation protocol for cancer treatments. This protocol generates similar types of radiation and energy levels that are part of the solar radiation spectrum. And unfortunately, we live in an age when terrorists might eventually gain access to weapons that will generate very high radiation exposures. Hopefully this won’t happen but the lessons learned from the present investigation will have overlap to the nuclear countermeasures that others are studying. The results from the current project will hopefully contribute knowledge base that other fields will find useful.

Task Progress & Bibliography Information FY2021 
Task Progress: Our approach has utilized a high throughput screen of small molecules from an FDA approved drug library. We have as a partial bias, degradation of mitochondrial function as one readout. Several studies using RNA-seq and other “omics” analyses have repeated identified mitochondrial dysfunction as participating in the response to high-LET radiation. Mitochondrial dysfunction is also one antecedent event in the transition from a healthy to cancerous cell and in part underlies the Warburg effect, a hallmark of cancer cells. Related to this, radiation-induced cardiac dysfunction leading to heart failure remains a significant clinical problem. The heart is almost completely reliant on aerobic metabolism and healthy mitochondria are critical for cardiomyocyte function. Some of our preliminary studies have demonstrated degradation of cardiac function and mtDNA integrity as a delayed consequence of low dose 56Fe (50 cGy) radiation exposure.

We have participated in three campaigns at the NASA Space Radiation Laboratory (NSRL: 19B, 19C, & 20C). All protocols to date have use cultured cells including H9c2 (myoblasts), RBL-2H3 (mast cell), Hy926 (endothelial), and ES-D3 (stem/pluripotent cell). For all campaigns, cells were exposed to a total of 75 cGy using the simplified 5-ion GCR protocol developed by NASA for use at NSRL. A follow-on paradigm was used, where the drugs were introduced shortly after GCR exposure.

Run 19B included one pass through the library using 10 microM of each drug and included tests for mitochondrial function, cellular senescence, and anti-oxidant capacity. Of 725 drugs, more than 150 showed some improvement over the untreated GCR exposed cells, while more than 500 showed degradation or were ineffective. A composite score was derived for each drug and the top 160 prioritized for further testing. In the broadest terms, what we learned from 19B was that drugs used in chemotherapy, the treatment of HIV infections, as well as the antifungal drugs were not useful and likely detrimental. The "statins" generated ambiguous results.

Within the160 drugs, 33 are known anti-inflammatories, while some others were also thought to have a lesser capacity as anti-inflammatory. The library included 54 COX inhibitors. Of the 7 deemed effective all were COX2 inhibitors and none were COX1 specific. 12 of 25 angiotensin converting enzyme inhibitors or AT1 antagonists were observed to be effective, while no AT2 antagonists appeared useful. The library contained 20 drugs that bound to adrenergic receptors of which 5 were deemed effective, although given their direct impact on blood pressure they are not likely to be useful as countermeasures. A common theme among the effective drugs was that they interacted with GPCR/G coupled proteins, a class of signaling proteins that mediate and control cellular function. Distinct from this are the 5-HT3 antagonists considered useful. The 5-HT3 receptors are Ca+2 activated small K+ channels. Most of the other 5-HT3 antagonists that were not deemed effective were those that bound to other 5-HT receptor isoforms or also bound to other serotonergic receptors. Clinically the 5-HT3 antagonists are used for the treatment of nausea and vomiting and are currently serving in that capacity aboard the International Space Station (ISS).

Different classes of anti-diabetic medications were also observed to be useful. These included the sulfonylurea class (i.e., sulfacarbamide and glimepride) as well as repaglinide and all of these drugs are insulin secretagogues that act to stimulate insulin release from the pancreas. A common element may be their impact in intracellular Ca+2 levels, an impact that may be similar to the 5-HT3 class. Metformin was also identified as being useful and its typical role is to suppress glucose release from the liver postprandial. We also found that three of the dipeptidyl peptidase DDP-4 inhibitors (i.e., anagliptin) improved cellular function follow GCR exposure. Potentially with respect to their effect in the H9c2 cells following exposure to GCR, the efficacy of the DPP4 inhibitors may be linked to their anti-inflammatory effects mediated by the NF κ B pathway. Although the efficacies of anti-diabetic drugs in vivo are understood, it is not clear what the underlying mechanism(s) of protection might have been in response to the GCR.

These experiments all utilized a follow-on paradigm that examined the restorative capability of a candidate drug when presented shortly following exposure to GCR. To determine if the delayed presentation of protective drugs impacted on recovery, cells exposed to GCRsim or control conditions were maintained in culture for one month before treatment was undertaken. Although most drugs were without effect, a few were still protective even when treatment was delayed. This included metformin and sulfacarbamide, both antidiabetic therapeutics as well as dolasetron.

Using a pretreatment protocol, where the drugs were added the day prior to GCR exposure and the cells maintained in culture for a week, the results observed were similar to the follow-on protocols. Metformin, sulfacarbamide, and olmesartan offered the highest level of protection, while several others also demonstrated some protective efficacy.

As with most labs throughout the country the COVID19 crisis shut the lab down. This included cancellation of NSRL 20A & 20B. We were operating at about 2% for two months (03/20-05/20) and then at about 30-40% for the next three (06/20-09/20/2020). Currently we are still under restricted access which has hampered training new students, as well as bringing in personnel to perform onsite maintenance and repairs of equipment.

Separate from examining mitochondrial and cellular dysfunction as readouts, we have developed a novel cell line using an Afp-tdTomato construct, as a biomarker for the transition to a cancerous cell. Validation protocols using either ethidium bromide (0.4 µg/ml) treatment and to a lesser extent UVC light (4 j/m2) exposure significantly increased Afp-tdTomato expression. During the 20C campaign we were able to begin to test these cells. GCRsim (75 cGy) significantly increased tdTomato expression compared to the No-Radiation control cells. To date only a select group of drugs from among those promoted from previous studies have been tested. Of those dimethyl fumarate, sulfacarbamide, and pargyline all appear to be promising leads. Pargyline is an monoamine oxidase (MAO) inhibitor is in part an anti-oxidant but in vivo promotes insulin release and enhanced glucose uptake. Using a pretreatment paradigm we observed that although most drugs were without effect, some did partially block GCR induced increases in tdTomato expression. Of note sulfacarbamide partially ameliorated GCR induced increases in Afp-tdTomato expression.

We had developed a LRPCR protocol to demonstrate mtDNA damage in the diabetic heart. We have just begun to apply the approach to determine DNA damage following GCR as a readout for the efficacy of candidate drugs. One hour following GCRsim (75 cGy) exposure, mtDNA damage was significantly increased compared to the No Rad control group.

Cultured cells allow for testing under highly controlled conditions. The use of cultured cells is a cost-effective means for decreasing the timelines of drug discovery as well as reducing the number of animals needed for downstream stream testing. Using relatively pure cell types will allow us to begin to differentiate tissue specific responses to different protection protocols. However, this approach may also be a limitation, in that using a single cell type may miss interactions important at the tissue level. For example, in response to some stresses, mast cells of the heart release histamine and cytokines that are likely to be responsible for accelerated senescence of nearby cells.

Collectively our findings are consistent with previous observations in that drugs that modulate inflammation and anti-oxidant pathways are likely to be useful. Uniquely we have observed that some 5-HT3 antagonists and some drugs used clinically in the management of diabetes appear to be useful when tested across different testing platforms, but their underlying mechanisms is not apparent.

Bibliography Type: Description: (Last Updated: 02/07/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Weiss M, Tefft K, Nikisher B, Katsett A, Edwards JG. "Countermeasures to Radiation Induced Cellular Dysfunction." 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020.

Abstracts. 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020. , Jan-2020

Abstracts for Journals and Proceedings Edwards JG, Weiss M, Tefft K, Nikisher B, Katsett A. "Countermeasures to the impact of cosmic radiation exposure on myocardial mitochondrial function." Experimental Biology 2020, San Diego, CA, April 4-7, 2020. Virtual Only.

FASEB Journal. 2020 Apr;34(1Suppl). https://doi.org/10.1096/fasebj.2020.34.s1.06568 , Apr-2020

Articles in Peer-reviewed Journals Mitry MA, Laurent D, Keith BL, Sira E, Eisenberg CA, Eisenberg LM, Joshi S, Gupte S, Edwards JG. "Accelerated cardiomyocyte senescence contributes to late-onset doxorubicin-induced cardiotoxicity." Am J Physiol Cell Physiol. 2020 Feb 1;318(2):C380-C391. https://doi.org/10.1152/ajpcell.00073.2019 ; PMID: 31913702; PMCID: PMC7052608 , Feb-2020
Project Title:  Countermeasures to Radiation Induced Cardiomyopathy Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 02/01/2019  
End Date: 01/31/2021  
Task Last Updated: 12/03/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Edwards, John  Ph.D. / New York Medical College 
Address:  Department of Physiology 
15 Dana Rd 
Valhalla , NY 10595-1554 
Email: j_edwards@nymc.edu 
Phone: 914-594-4166  
Congressional District: 17 
Web:  
Organization Type: UNIVERSITY 
Organization Name: New York Medical College 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Eisenberg, Carol  Ph.D. New York Medical College 
Rota, Marcello  Ph.D. New York Medical College 
Key Personnel Changes / Previous PI: December 2019 report: Have added one Research Assistant.
Project Information: Grant/Contract No. 80NSSC19K0436 
Responsible Center: NASA JSC 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2017-2018 HERO 80JSC017N0001-BPBA Topics in Biological, Physiological, and Behavioral Adaptations to Spaceflight. Appendix C 
Grant/Contract No.: 80NSSC19K0436 
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: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
(2) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
Human Research Program Gaps: (1) Cancer-502:Systematically identify safe and effective countermeasures to reduce radiation carcinogenesis (IRP Rev M)
(2) CVD-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease (IRP Rev L)
(3) CVD-201:Selection of countermeasures and procedures to be tested based on previous objectives (IRP Rev L)
Task Description: The present application seeks to study the long-term consequences of cosmic radiation exposure. Space travel increases solar particle radiation exposure which is significantly elevated once travel moves beyond low Earth orbit. This includes a combination of high-energy protons and heavy ions such as 56Fe, 28Si, and 16O. The adverse risk of radiation-induced heart failure is also evident as a long-term consequence of accidental radiation exposure or cancer treatment. Survivors of cancer are also at risk for other adverse health outcomes including abnormal pulmonary function, endocrine disorders, neurocognitive impairment, and osteoporosis. All of these organ systems are characterized by a low turnover of cells and it is likely that an accelerated cell death and/or the failure of regeneration by the pluripotent cells may be the underlying cause of organ failure. Although this application will focus on heart failure, our findings will have implications for many organ systems.

Our preliminary studies observed degradation of cardiovascular function in a model of cosmic radiation (High-Linear Energy Transfer) exposure. Mice were exposed to 50 cGy (Fe56) at 3 months of age and then studied at 24 months of age. Degradation of cardiac function was evident by significant decreases in myocardial contractility and relaxation. Concomitant with this were significant changes in mitochondrial and stem/progenitor cell function. In the present ground based application, we propose to evaluate the impact of High-Linear Energy Transfer (LET); to identify the pathway to heart failure; and evaluate three distinct protocols as potential countermeasures.

Hypothesis: Radiation-induced cardiomyopathy is the result of a cell specific failure. Cell specific failure is the result of an inability to maintain the balance of repair/replacement that ultimately leads to activation of degradation pathways and accelerated cell loss. This study will utilize both cultured cells as well as Swiss Webster mice to be randomly assigned to control or single heavy ion high-LET exposure groups. Phase 1 will use single exposures to high-LET exposure of 1) 56Fe (50 cGy) or 2) Proton (200 cGy). Phase 2 will utilize a mixed field exposure following the guidelines of the Human Exploration Research Opportunities (HERO) Announcement (80JSC017N0001-BPBA; Appendix C). All exposures will be performed at the NASA Space Radiation Laboratory at Brookhaven National Laboratory. We plan to study three distinct countermeasures including 1) MitoTempo, 2) Metformin, and 3) Lisinopril. MitoTempo is an antioxidant that partitions to the mitochondria. Metformin, an antidiabetic mainstay, has more recently been shown to have significant anticancer properties. Lisinopril, an inhibitor of the angiotensin system, has been shown to mitigate radiation injuries from Low-LET exposure. Evaluations will be made on several levels, to include 1) Determination of cardiovascular function, 2) Identification of cell specific failure, and 3) Intracellular determination of damage focusing on genomic and mitochondrial DNA damage. Cell failure in terms of metabolic failure, accelerated senescence, as well as DNA damage will be determined. A number of investigations in Space Biology are currently ongoing at New York Medical College (NYMC) and collaborations and sharing of resources will enhance the research products derived from funding this application.

Radiation induced cardiomyopathies are observed months or years after exposure. The present application will separate the insult from the consequences. Our preliminary findings demonstrated significant degradation of cardiac function similar to the accelerated aging phenotype observed with chemotherapy. It may not be relevant that any single cell dies but that the balance of cell death and cell replacement is upset. Although focused on the heart, these investigations will have widespread application to other organ systems and collectively serve the long term health and well being of flight crews.

Research Impact/Earth Benefits: Space travel has many dangers including chronic exposure to cosmic radiation. Cosmic radiation has a higher level of energy than the typical x-ray a person would receive in the dentist’s office. And as such it is more damaging. On Earth, the magnetosphere and our atmosphere absorbs nearly all of the energy from this form of radiation. However, as one ascends to the upper levels of our atmosphere the levels of exposure increases. And once the astronauts are beyond low Earth orbit this goes up even more. Currently it is estimated that the mission to Mars will expose the flight crew levels beyond the allowable lifetime limit for radiation exposure.

The focus of this NASA funded research project is to develop countermeasures to cosmic radiation exposure with the goal of protecting flight crews on long duration missions. However, the findings of this project will also benefit those with more Earth bound problems. Radiation therapy has been used for the treatment of cancer for many years, and it has long been known that these survivors are at risk for other illnesses related to their treatment. Proton Therapy is an increasingly popular radiation protocol for cancer treatments. This protocol generates similar types of radiation and energy levels that are part of the cosmic radiation spectrum. We also know that airline pilots and flight attendants have a small but significantly higher risk of cancer that is directly attributable to the chronic exposure to cosmic radiation during the course of their careers. And unfortunately we live in an age when terrorists might eventually gain access to weapons that will generate very high radiation exposures. Hopefully this won’t happen but the lessons learned from the present investigation will have overlap to the nuclear countermeasures that others are studying. The results from the current project will hopefully contribute knowledge base that other fields will find useful.

Task Progress & Bibliography Information FY2020 
Task Progress: Countermeasures to Radiation Induced Cardiomyopathy--The major goal of this project is to develop countermeasures to prevent long-term cardiovascular degradation as a consequence of space flight due to cosmic radiation exposure.

It focuses on the use of small molecules from a commercially available FDA (Food & Drug Administration) approved library, in addition to molecules identified by NASA personnel as high priority compounds. These drugs are part of other ongoing investigations and their inclusion will be useful in making comparisons across platforms. With regard to the Map to Human Research, this project primarily addresses two Risks and to a lesser extent one other. All are designated as High LxC for longer endurance missions or long-term health and wellbeing.

The heart is a heterogeneous organ. Although cardiomyocytes are relatively radio-resistant they comprise only 50-60% by cell number of the whole heart. Other cell types include smooth muscle, endothelial cells, fibroblasts, and cardiac progenitor cells. The radio sensitivity of these different cell types is unknown. Clinically, radiation-induced cardiac dysfunction leading to heart failure remains a significant problem. This is of even greater concern if chemotherapy is part of the treatment protocols. Analysis of heart transplantation patients found cancer treatment as the underlying cause in 2-3% of all heart transplant cases.

Countermeasures fall into three categories--Radio protectors are given prophylactically or concurrently to prevent damage. Radiation therapeutics are those that stimulate repair or regeneration processes. Radionuclide eliminators discorporate or block absorption of internalized radionuclides. This project will focus on radio protectors with the hope of developing protocols that will diminish the need for radiation therapeutics.

Drug screening will be performed on two levels: 1) broad screening using analysis that allows for high throughput, and 2) focused analysis of high value target molecules. The hierarchy for success will be: 1) ability to protect cellular function, 2) ability to protect cell viability, 3) ability to ameliorate radiation induced senescence, 4) ability to protect DNA. An FDA-approved drug library from MedChem Express was chosen over other commercially libraries because it includes a larger number drugs directed towards DNA damage, anti-inflammation, and has been cited in a number of recent drug screens. The complete FDA approved library available from MedChem Express of more than 1500 drugs was reduced to 725 drugs, by selecting against drugs that were antibiotics or anti-parasitic. Priority was given to drugs that indicated role for DNA repair, were anti-oxidant, or anti-inflammatory. The MedChem Express library also included 8 of 9 drugs identified by NASA as high value.

Progress Report

NASA Space Radiation Laboratory (NSRL) Run 19B was our first run at NSRL and H9c2 cells (originally derived from the heart) were exposed to a total of 75 cGy using a simplified 5-ion GCR protocol developed by NASA at the NSRL facility. One pass through the library using 10 microM of each drug included tests for mitochondrial function, cellular senescence, and anti-oxidant capacity was accomplished. Of 725 drugs, more than 150 showed some improvement over the untreated GCR exposed cells, while more than 500 showed degradation of function or were ineffective. A composite score was developed for each drug and the top 160 were prioritized for further testing. In the broadest terms, what we learned from 19B was that drugs used in chemotherapy, the treatment of HIV infections, as well as the antifungal drugs were not useful and likely detrimental. The "statins" generated ambiguous results.

For NSRL 19C Run, the H9c2 and RBL-2H3 mast cell lines were exposed to a total of 75 cGy using a simplified 5-ion GCR protocol developed by NASA at the NSRL facility. Following GCR exposure cells were moved on to test plates and treated for 7 days using 1 microM of each drug. Cells were tested for viability, oxidant stress, cellular senescence, and mitochondrial function. Z-scores were calculated and a composite score was developed for each drug.

Within the160 drugs, 33 are considered to have some anti-inflammatory capacity. 5 of the 5-HT3 antagonists considered useful were 5-HT3 specific, while for others the specificity was not indicated. Most of the other 5-HT antagonists that were not deemed effective were those that bound to other 5-HT isoforms or also bound to other serotonergic receptors. This suggests that the 5-HT3 specific pathways maybe of some importance. The 5-HT3 receptors are Ca+2 activated small K+ channels and used clinically for the treatment of nausea and vomiting. Some groups have reported that 5HT3 antagonism may ameliorate the effects of damaging radiation.

12 of 25 angiotensin converting enzyme inhibitors or AT1 antagonists were observed to be effective, while no AT2 antagonists appeared useful. 10 of 46 drugs identified as interacting with histamine receptors were deemed effective and mostly interacted with the H1 receptor isoform. Another anti-inflammatory inhibitory pathway included 54 COX inhibitors some of which were effective. All of the 7 drugs deemed effective were COX2 inhibitors and none were COX1 specific. The library contained 20 drugs that bound to adrenergic receptors of which 5 were deemed effective, although given their direct impact on blood pressure they are not likely to be useful as countermeasures.

A common theme among the effective drugs was that they interacted with GPCR/G coupled proteins, a class of signaling proteins that mediate and control cellular function. That COX2 but not COX1, AT1 but not AT2 receptor antagonists, or 5HT3 antagonists but no other 5HT isoforms suggest that some unique pathways were more relevant than others. Collectively they appeared to modulate inflammation and anti-oxidant pathways and this may be useful in the management of cosmic radiation exposure for long duration flight crews.

Utilization of cultured cells will allow us to expose, monitor, and analyze cells under highly controlled conditions. The data derived from these experiments will also demonstrate the relative robustness of the different cell types to cosmic radiation. And using a relatively pure cell type will allow us to differentiate the responses to different protection protocols, something that cannot be done in animals. Our previous studies have suggested that the terminally differentiated cells may be more sensitive to oxidant stress than pluripotent cells. However, this approach may also be a limitation, in that using a single cell type may miss interactions important at the tissue level. For example, in response to some stresses, mast cells of the heart release histamine and cytokines that are likely to be responsible for accelerated senescence of nearby cells. The counter experiment to these limitations would be to study mast cells using Transwell inserts that permit the co-culture of different cell types.

The goal of this project is the development of reasonable countermeasures to manage the acute and long-term consequences of High-LET exposure. To that end, we are screening a library of FDA approved drugs, using an approach that will rule in or rule out the tested molecules. The use of cultured cells maintained long-term to narrow down the long list of drugs is cost effective by decreasing the timeline of the project as well as vastly reducing the number of animals that would ultimately be needed to validate our findings. One value added aspect to this approach is the redundancies observed within a class of drugs may be indicative of the relative importance of a specific pathway. Although the use of sequential "mixed" beam irradiation is not completely replicative of space radiation exposure, it is the most cost effective ground based protocol to date. That being said any interpretations of the data would need to be cognizant of these limitations.

Collectively our results to date are consistent with other studies that modulation of cellular inflammation and anti-oxidant pathways may be useful in the management of cosmic radiation exposure for long duration flight crews. Going forward, we plan to expand the cell types tested to include endothelial, fibroblast, and iPSCs cells, all of which are highly important in the long-term maintenance of the heart. Also we will begin to look more closely at the pathways associated with inflammation as an underlying cause in the transition of a normal healthy cell to a cancerous cell.

Bibliography Type: Description: (Last Updated: 02/07/2022) 

Show Cumulative Bibliography Listing
 
 None in FY 2020
Project Title:  Countermeasures to Radiation Induced Cardiomyopathy Reduce
Images: icon  Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 02/01/2019  
End Date: 01/31/2021  
Task Last Updated: 03/20/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Edwards, John  Ph.D. / New York Medical College 
Address:  Department of Physiology 
15 Dana Rd 
Valhalla , NY 10595-1554 
Email: j_edwards@nymc.edu 
Phone: 914-594-4166  
Congressional District: 17 
Web:  
Organization Type: UNIVERSITY 
Organization Name: New York Medical College 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Eisenberg, Carol  Ph.D. New York Medical College 
Rota, Marcello  Ph.D. New York Medical College 
Project Information: Grant/Contract No. 80NSSC19K0436 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2017-2018 HERO 80JSC017N0001-BPBA Topics in Biological, Physiological, and Behavioral Adaptations to Spaceflight. Appendix C 
Grant/Contract No.: 80NSSC19K0436 
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: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
(2) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
Human Research Program Gaps: (1) Cancer-502:Systematically identify safe and effective countermeasures to reduce radiation carcinogenesis (IRP Rev M)
(2) CVD-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease (IRP Rev L)
(3) CVD-201:Selection of countermeasures and procedures to be tested based on previous objectives (IRP Rev L)
Task Description: The present application seeks to study the long-term consequences of cosmic radiation exposure. Space travel increases solar particle radiation exposure which is significantly elevated once travel moves beyond low Earth orbit. This includes a combination of high-energy protons and heavy ions such as 56Fe, 28Si, and 16O. The adverse risk of radiation-induced heart failure is also evident as a long-term consequence of accidental radiation exposure or cancer treatment. Survivors of cancer are also at risk for other adverse health outcomes including abnormal pulmonary function, endocrine disorders, neurocognitive impairment, and osteoporosis. All of these organ systems are characterized by a low turnover of cells and it is likely that an accelerated cell death and/or the failure of regeneration by the pluripotent cells may be the underlying cause of organ failure. Although this application will focus on heart failure, our findings will have implications for many organ systems.

Our preliminary studies observed degradation of cardiovascular function in a model of cosmic radiation (High-Linear Energy Transfer) exposure. Mice were exposed to 50 cGy (Fe56) at 3 months of age and then studied at 24 months of age. Degradation of cardiac function was evident by significant decreases in myocardial contractility and relaxation. Concomitant with this were significant changes in mitochondrial and stem/progenitor cell function. In the present ground based application, we propose to evaluate the impact of High-Linear Energy Transfer (LET); to identify the pathway to heart failure, and evaluate three distinct protocols as potential countermeasures.

Hypothesis: Radiation-induced cardiomyopathy is the result of a cell specific failure. Cell specific failure is the result of an inability to maintain the balance of repair/replacement that ultimately leads to activation of degradation pathways and accelerated cell loss. This study will utilize both cultured cells as well as Swiss Webster mice to be randomly assigned to control or single heavy ion high-LET exposure groups. Phase 1 will use single exposures to high-LET exposure of 1) 56Fe (50 cGy) or 2) Proton (200 cGy). Phase 2 will utilize a mixed field exposure following the guidelines of the Human Exploration Research Opportunities (HERO) Announcement (80JSC017N0001-BPBA; Appendix C). All exposures will be performed at the NASA Space Radiation Laboratory at Brookhaven National Laboratory. We plan to study three distinct countermeasures including 1) MitoTempo, 2) Metformin, and 3) Lisinopril. MitoTempo is an antioxidant that partitions to the mitochondria. Metformin, an antidiabetic mainstay, has more recently been shown to have significant anticancer properties. Lisinopril, an inhibitor of the angiotensin system, has been shown to mitigate radiation injuries from Low-LET exposure. Evaluations will be made on several levels, to include 1) Determination of cardiovascular function, 2) Identification of cell specific failure, and 3) Intracellular determination of damage focusing on genomic and mitochondrial DNA damage. Cell failure in terms of metabolic failure, accelerated senescence, as well as DNA damage will be determined. A number of investigations in Space Biology are currently ongoing at New York Medical College (NYMC) and collaborations and sharing of resources will enhance the research products derived from funding this application.

Radiation induced cardiomyopathies are observed months or years after exposure. The present application will separate the insult from the consequences. Our preliminary findings demonstrated significant degradation of cardiac function similar to the accelerated aging phenotype observed with chemotherapy. It may not be relevant that any single cell dies but that the balance of cell death and cell replacement is upset. Although focused on the heart, these investigations will have widespread application to other organ systems and collectively serve the long term health and well being of flight crews.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2019 
Task Progress: New project for FY2019.

Bibliography Type: Description: (Last Updated: 02/07/2022) 

Show Cumulative Bibliography Listing
 
 None in FY 2019