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Project Title:  Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome--80NSSC19K1079 Reduce
Images: icon  Fiscal Year: FY 2022 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 04/10/2019  
End Date: 04/09/2023  
Task Last Updated: 03/07/2022 
Download report in PDF pdf
Principal Investigator/Affiliation:   Goukassian, David A M.D., Ph.D. / Icahn School of Medicine at Mount Sinai 
Address:  Zena & Michael A. Weiner Cardiovascular Institute 
One Gustave L. Levy Place, Box 1030 
New York , NY 10029 
Email: david.goukassian@mssm.edu 
Phone: 617-480-3890  
Congressional District: 12 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Icahn School of Medicine at Mount Sinai 
Joint Agency:  
Comments: NOTE: PI moved to Icahn School of Medicine at Mount Sinai from Temple University in October 2018.  
Project Information: Grant/Contract No. 80NSSC19K1079 
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: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC19K1079 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
Human Research Program Gaps: (1) 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)
Flight Assignment/Project Notes: NOTE: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University. (Ed., 2/10/2020)

Task Description: Ed. note 2/10/2020: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921 with the same Principal Investigator Dr. David Goukassian, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University.

During the future Moon, near Earth asteroids, and Mars missions, astronauts will be exposed to higher total doses of space irradiation (IR) (~0.4-0.5 Gy) from galactic cosmic rays (GCR). Most of what we know about harmful effects of IR on cardiovascular (CV) system is from epidemiological studies of long-term survivors of cancer radiotherapy (RT). A recent study of 2,168 women who underwent RT for breast cancer has shown that the rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gy, with no apparent lower or upper threshold. In this study, it was determined that average of the mean doses to the whole heart was 4.9 Gy with the range of 0.03 - 27.72 Gy. Furthermore, metabolomics studies, in patients undergoing hematopoietic stem cell (HSC) transplantation as part of cancer treatment (1.25 Gy total-body irradiated), identified seven urine-based biomarkers with distinct differences between pre- and post-exposure samples. The levels of these markers were found to be gender-dependent suggesting that separate biomarker signatures may exist for males and females.

Hypotheses: Our central hypothesis is that low-dose proton and HZE (high energy) particle IR-induced biological responses are long-lasting, IR type- and dose-dependent and may augment excess relative risk (ERR) estimates for the development of cardiovascular diseases (CVDs) during and after long-duration space missions. In addition, we hypothesize that gender differences could further modify radio-biologically effective (RBE) IR thresholds for CV risk estimates. Gene expression and epigenetic modifications in protein and microRNA (miRNA) in exosomes from the blood (e.g., plasma/serum) may be altered before the onset of the cardiac symptoms, which could be used as potential biomarkers to predict the CVD risks. We will test our hypotheses with the following specific aims:

AIM 1. Determine the longitudinal effect of IR type, dose, and gender on cardiovascular physiology in wild type mice and ApoE null mice after full-body 5-ion simplified mixed field and gamma radiation.

AIM 2. Determine space-type IR mediated modulations in exosomal cargo in the blood, and determine whether these changes are associated with alterations in the heart function, structure, and vasculature before the manifestation of clinical symptoms.

AIM 3. Utilize known and newly identified biomarkers in the blood to develop human-relevant point-of-care tests (POCT) for predicting and monitoring possible CV alterations before and during space flights.

We anticipate that the results of our proposed work may be beneficial for human space exploration and could (1) Determine single whole body mixed field dose-response, radio-biologically effective IR thresholds in the heart and cardiac vasculature, and whether gender differences could modify radio-biologically effective IR thresholds for CV risk estimates; 2) Determine whether space radiation leads to modifications in the circulating exosomal cargo contents and whether IR-induced exosomal cargo modulations are reflective of subclinical changes in the cells and organs of origin; 3) Ascertain if modulations of exosomal cargo may be representative of chronic oxidative stress and inflammation and could serve as early biomarkers of IR-induced CVD initiation and progression; 4) Integrate physiological CV endpoint data sets with gene expression and epigenetic data to identify biomarkers in bio-fluids that could be used for prediction of asymptomatic CVD in the setting of space IR, which will include known early and intermediate biomarkers of cardiac damage, inflammation, and oxidative stress, as well as currently unknown novel radiation-associated cardiac biomarkers.

Research Impact/Earth Benefits: We anticipate that the results of our work could be beneficial for human space exploration as well as for the Earth-based applications on several levels -- (1) determine whether low dose space-type and terrestrial IR may present an increased risk for CVD development during and after prolonged space missions, as well as after conventional and particle cancer radiotherapy; (2) determine the underlying molecular signaling of CV alterations; (3) identify biomarkers in the blood that could be used for prediction of asymptomatic CV disease, which will include known early and intermediate biomarkers of cardiac damage, as well as currently unknown novel cardiac biomarkers; (4) the identification of sub-clinical CV disease biomarkers that could be used for monitoring the effectiveness of mitigating factors for prevention and treatment of IR-induced CVDs in space and in Earth-bound civilian population, in general.

Task Progress & Bibliography Information FY2022 
Task Progress: In late September 2018, we irradiated at the NASA Space Radiation Laboratory (NSRL) and the Brookhaven National Laboratory (BNL) gamma facility 660 ApoE null male mice and 480 C57Bl/6J male mice, the first two cohorts of our longitudinal lifetime studies. We completed and performed cardiac function analyses and harvested tissues and blood for 5 harvesting time points (14, 28, 365, 440, and 660 days post-irradiation). In terms of selection of radiation parameters, we utilized the following doses, energies, and ions, as recommended by Space Radiation Element Management:

(i) Gamma IR - 1, 2, and 4 Gy, using ApoE null MALE mice for all time points indicated above. (ii) 5-Ion Simplified Mixed field IR - 0.5, 1.0 and 1.5 Gy, adjusted to 500 MeV/n, using ApoE null MALE mice for all time points indicated above. (iii) Gamma IR – 1, 2 Gy, using WT-C57BL/6J MALE mice for all time points indicated in section above. (iv) 5-Ion Simplified Mixed field IR - 0.5, 1.0 Gy, adjusted to 500 MeV/n, using WT-C57BL/6J MALE mice for all time points indicated above.

Lifetime tumor burden As part of our study to assess the effects of space radiation on cardiovascular disease (CVD) risks, male mice were systematically examined for tumor development during scheduled tissue collections over 660 days after initial radiation (IR) exposure. We report:

• The incidence of tumors is higher in wild type (WT) compared to ApoE null male mice after the same doses of gamma- and simGCRsim-IR suggesting underlying genotypic variance may attenuate pathways involved in tumorigenesis;

• The highest number of tumors during the lifetime of WT male mice was detected in the no-IR, Western diet-fed (WD-fed) group, suggesting the role of high fat diet in the development of internal organ tumors, especially in the liver;

• In WT male mice, the incidence of IR-induced internal organ tumors was higher in 100 cGy gamma-IR versus 50 cGy simGCRsim-IR, suggesting higher carcinogenic potential of gamma-IR at these doses;

• In WT male mice, the liver is the most affected organ by tumor growth, followed by the spleen, and lung;

• There was a higher incidence of hepatic and splenic tumors in mice fed with WD or exposed to both types of IR in WT mice approaching end of life;

• In ApoE null male mice, the incidence of IR-induced tumors was higher in 50 cGy simCGRsim -IR mice with a higher prevalence of lung tumors.

In October 2020, we have irradiated at the NSL and the BNL gamma facility an additional 160 ApoE null female mice and 300 C57BL/6J female mice. This longitudinal life-time study is designed to have 5 harvesting time points (28, 180, 365, 440, and 660 days). We have already performed cardiac function analyses and harvested tissues for 4 of our harvesting time points (28, 180, 365, and 440 days). The final collecting time point is scheduled for July 2022. In terms of selection of radiation parameters, we utilized the following doses, energies, and ions, as recommended by Space Radiation Element Management:

(i) Gamma IR – 1 Gy, using ApoE null and WT FEMALE mice for all time points indicated above. (ii) 5-Ion Simplified Mixed field IR - 0.5 Gy, adjusted to 500 MeV/n, using ApoE null FEMALE mice. (iii) 5-Ion Simplified Mixed field IR - 0.25, 0.50 cGy adjusted to 500 MeV/n, using WT-C57BL/6J FEMALE mice for all time points indicated above.

Left ventricular (LV) cardiac response to IR.

Cardiac function was assessed non-invasively in all control and irradiated ApoE null and C57BL/6J female mice by transthoracic echocardiography at 28, 180, and 365 days post-IR. Each mouse is microchipped and followed longitudinally.

To briefly summarize our male cohort echocardiography findings:

• A single full-body IR at doses of 100-200 cGy for gamma- IR and 50-100 cGy for simGCRsim-IR decreases global LV systolic function in WT male mice at 14, 28, and 365 days post-IR.

• At 660 days post-IR, 50 cGy simGCRsim-IR WT male mice exhibited increased diastolic stiffness paired with alterations in LV size and mass, suggesting these mice may be exhibiting additional diastolic dysfunction and compensation as a result of pressure overload.

• In ApoE null male mice, global LV systolic function is impaired as early as 14 and 28 days post-IR in both simGCRsim (100, 200, 400 cGy) and gamma- IR (100, 200 cGy) mice. Interestingly, there is no intermediate time point (365, 440 days) where LV dysfunction is noted.

• By 660 days post-IR, gamma-IR ApoE null male mice exhibit significant systolic dysfunction with reduction in Left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and increases in stroke volume (SV), LV mass, and LV dimensions suggesting compensation for likely volume overload. No significant changes in LV function were noted in simGCRsim-IR ApoE null male mice at 660 days.

• No clear dose-response was observed in these studies.

In our female longitudinal cohort:

• A single full-body IR at doses of 100 cGy for gamma-IR and 25 or 50 cGy for simGCRsim-IR decreases the global systolic function of the heart in both ApoE null and WT female mice at 28 days post-IR.

• At later time points (180, 365 days), no significant alterations in global LV systolic function are noted; however, in WT female mice, there is evidence of alterations in LV structure suggesting ongoing remodeling.

• Further work is underway to collect additional data to assess long-term degenerative effects of IR (440, 660 days) in female WT and ApoE null mice. Analysis of additional echocardiography parameters to assess LV remodeling are underway.

These findings do not exclude the possibility of increased acute or degenerative CVD risks at lower doses of space-type IR and/or when combined with other space travel-associated stressors, such as microgravity.

Bibliography Type: Description: (Last Updated: 04/15/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Brojakowska A, Fish K, Khlgatian M, Grano C, Bisserier M, Zhang S, Saffran N, Chepurko V, Chepurko E, Gillespie V, Dai Y, Hadri L, Kishore R, Goukassian D. "Longitudinal evaluation of cardiac function and structure in C57BL/6J mice after gamma and space-type radiation exposure." 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022.

Abstracts. 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022, Abstract #1133-000167. , Feb-2022

Abstracts for Journals and Proceedings Brojakowska A, Bisserier M, Elmas A, Khlgatian M, Zhang S, Gillespie V, Dai Y, Hadri L, Goukassian D. "Lifetime risk of tumor development in C56B1/6J mice fed with Western diet or exposed to a single full body gamma or simGCRsim radiation." 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022.

Abstracts. 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022, Abstract #1133-000425. , Feb-2022

Abstracts for Journals and Proceedings Jackson C, Brojakowska A, Blattnig S, Khlgatian M, Grano C, Fish K, Chepurko V, Chepurko E, Kishore R, Goukassian D. "The comparative effect of gamma and simplified GCR simulation irradiation on cardiac response in ApoE null mice. " NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022.

Abstracts. 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022, Abstract #1133-000142. , Feb-2022

Articles in Peer-reviewed Journals Bisserier M, Saffran N, Brojakowska A, Sebastian A, Evans AC, Coleman MA, Walsh K, Mills PJ, Garikipati VNS, Arakelyan A, Hadri L, Goukassian DA. "Emerging role of exosomal long non-coding RNAs in spaceflight-associated risks in astronauts." Front Genet. 2022 Jan 17;12:812188. https://doi.org/10.3389/fgene.2021.812188 , Jan-2022
Project Title:  Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome--80NSSC19K1079 Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 04/10/2019  
End Date: 04/09/2023  
Task Last Updated: 04/01/2021 
Download report in PDF pdf
Principal Investigator/Affiliation:   Goukassian, David A M.D., Ph.D. / Icahn School of Medicine at Mount Sinai 
Address:  Zena & Michael A. Weiner Cardiovascular Institute 
One Gustave L. Levy Place, Box 1030 
New York , NY 10029 
Email: david.goukassian@mssm.edu 
Phone: 617-480-3890  
Congressional District: 12 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Icahn School of Medicine at Mount Sinai 
Joint Agency:  
Comments: NOTE: PI moved to Icahn School of Medicine at Mount Sinai from Temple University in October 2018.  
Project Information: Grant/Contract No. 80NSSC19K1079 
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: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC19K1079 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
Human Research Program Gaps: (1) 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)
Flight Assignment/Project Notes: NOTE: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University. (Ed., 2/10/2020)

Task Description: Ed. note 2/10/2020: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921 with the same Principal Investigator Dr. David Goukassian, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University.

During the future Moon, near Earth asteroids, and Mars missions, astronauts will be exposed to higher total doses of space irradiation (IR) (~0.4-0.5 Gy) from galactic cosmic rays (GCR). Most of what we know about harmful effects of IR on cardiovascular (CV) system is from epidemiological studies of long-term survivors of cancer radiotherapy (RT). A recent study of 2,168 women who underwent RT for breast cancer has shown that the rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gy, with no apparent lower or upper threshold. In this study, it was determined that average of the mean doses to the whole heart was 4.9 Gy with the range of 0.03 - 27.72 Gy. Furthermore, metabolomics studies, in patients undergoing hematopoietic stem cell (HSC) transplantation as part of cancer treatment (1.25 Gy total-body irradiated), identified seven urine-based biomarkers with distinct differences between pre- and post-exposure samples. The levels of these markers were found to be gender-dependent suggesting that separate biomarker signatures may exist for males and females.

Hypotheses: Our central hypothesis is that low-dose proton and HZE (high energy) particle IR-induced biological responses are long-lasting, IR type- and dose-dependent and may augment excess relative risk (ERR) estimates for the development of CV diseases during and after long-duration space missions. In addition, we hypothesize that gender differences could further modify radio-biologically effective (RBE) IR thresholds for CV risk estimates. Gene expression and epigenetic modifications in protein and microRNA (miRNA) in exosomes from the blood (e.g., plasma/serum) may be altered before the onset of the cardiac symptoms, which could be used as potential biomarkers to predict the CV disease risks. We will test our hypotheses with the following specific aims:

AIM 1. Determine the longitudinal effect of IR type, dose, and gender on cardiovascular physiology in wild type mice and ApoE null mice after full-body 5-ion simplified mixed field and gamma radiation.

AIM 2. Determine space-type IR mediated modulations in exosomal cargo in the blood, and determine whether these changes are associated with alterations in the heart function, structure, and vasculature before manifestation of clinical symptoms.

AIM 3. Utilize known and newly identified bio-markers in the blood to develop human-relevant point-of-care tests (POCT) for predicting and monitoring possible CV alterations before and during the space flights.

We anticipate that the results of our proposed work may be beneficial for human space exploration and could (1) Determine single, low-dose 1H, 56Fe, and mixed field dose-responses, radio-biologically effective IR thresholds in the heart and cardiac vasculature, and whether gender differences could modify radio-biologically effective IR thresholds for CV risk estimates; 2) Determine whether space radiation leads to modifications in the circulating exosomal cargo contents and whether IR-induced exosomal cargo modulations are reflective of subclinical changes in the cells and organs of origin; 3) Ascertain if modulations of exosomal cargo may be representative of chronic oxidative stress and inflammation and could serve as early bio-markers of IR-induced CV disease initiation and progression; 4) Integrate physiological CV endpoint data sets with gene expression and epigenetic data to identify bio-markers in bio-fluids that could be used for prediction of asymptomatic CV disease in the setting of space IR, which will include known early and intermediate bio-markers of cardiac damage, inflammation, and oxidative stress, as well as currently unknown novel radiation-associated cardiac bio-markers.

Research Impact/Earth Benefits: We anticipate that the results of our work could be beneficial for human space exploration as well as for the Earth-based applications on several levels -- (1) determine whether low dose space-type and terrestrial IR may present an increased risks for CV disease development during and after prolonged space missions, as well as after conventional and particle cancer radiotherapy; (2) determine the underlying molecular signaling of CV alterations; (3) identify bio-markers in the blood that could be used for prediction of asymptomatic CV disease, which will include known early and intermediate bio-markers of cardiac damage, as well as currently unknown novel cardiac biomarkers; (4) the identification of sub-clinical CV disease biomarkers that could be used for monitoring the effectiveness of mitigating factors for prevention and treatment of IR-induced CV diseases in space and in Earth-bound civilian population, in general.

Task Progress & Bibliography Information FY2021 
Task Progress: In late September 2018, we irradiated at the NASA Space Radiation Laboratory (NSRL) and the Brookhaven National Laboratory (BNL) gamma facility 660 ApoE null male mice and 480 C57Bl/6J male mice, first two cohorts of our longitudinal lifetime studies. In terms of selection of radiation parameters, we utilized the following doses, energies, and ions, as recommended by Radiation Biology Element Management:

(i) Gamma IR - 100, 200, and 400 cGy, using ApoE null MALE mice for all time points indicated above.

(ii) 5-Ion Simplified Mixed field (simGCRsim) IR – 50, 100, and 150 cGy, adjusted to 500 MeV/n, using ApoE null MALE mice for all time points indicated above.

(iii) Gamma IR – 100 and 200 cGy, using WT-C57BL/6J MALE mice for all time points indicated in section above.

(iv) 5-Ion Simplified Mixed field (simGCRsim) IR – 50 and 100 cGy, adjusted to 500 MeV/n, using WT-C57BL/6J MALE mice for all time points indicated above.

At the time of this report, we have collected functional cardiac echocardiography data as well as various tissues and blood from animals at all five designated time points (14 days and 28 days post IR as well as 12-, 16-, and 22- months post IR). Our updated findings are as follows:

With regards to left ventricular (LV) cardiac function: Cardiac function was assessed non-invasively in all control and irradiated ApoE null and C57Bl/6J mice by transthoracic echocardiography (ECHO) at baseline (before IR) as well as at acute time points post IR (14 and 28 days) and chronic time points (12-, 16- and 22-months post IR). To summarize our findings:

A single full-body IR at doses of 100-400 cGy for gamma- IR and 50-150 cGy for simGCRsim-IR decreases the global systolic function of the heart in both ApoE null and WT mice at 14 and 28 days after exposure. Histological analyses of H&E stained slides at 28 days after radiation showed – (i) multifocal myofiber disarray with mildly increased variation in myofiber diameter; (ii) swollen myocytes; (iii) mild to moderate sarcoplasmic swelling; (iv) minimal multifocal mineralization of few myofibers within papillary muscles. This suggests inducible alterations in cardiac tissues morphology are detectible early on in response to altered LV function.

Our lifetime study reveals that at these doses, cardiac function is significantly affected at 22 months post-IR in both mouse genotypes. Interestingly, WT mice have an intermediate time point (12 months) where impairment in LV function is observed. Our data suggests, WT IR-mice may be exhibiting more diastolic dysfunction and compensation due to pressure overload, while our ApoE null mice LV functional impairment appears more consistent with a volume overloaded system as noted by increased LV dimensions and size. At 22 months, ApoE null gamma-IR mice exhibit significant systolic dysfunction; however, this does not exclude possibility of diastolic dysfunction in remining IR groups and mouse genotypes. Cardiac tissue responses, morphology, structure, and underlying molecular mechanisms are being analyzed for later time points. Overall, these findings do not exclude the possibility of increased acute or degenerative CV disease risks at lower doses of space-type IR and/or when combined with other space travel-associated stressors, such as microgravity.

Vascular plaque burden: We assessed the effects of gamma- and simGCRsim-IR on vascular plaque burden along with fibrosis development and progression in ApoE null mice. We collected the aortic root with ascending aorta, and aortic arch with carotids and descending aorta from ApoE null and WT mice at 14 and 28 days, as well as 12-, 16-, and 22-months post-IR. ApoE null en face aortas were stained with Oil-Red-O to quantify plaque burden.

To summarize our findings, the highest plaque burden is observed in non-IR western diet (WD)-fed mice at 12 months compared to remaining treatment groups. However, there was an ~1.5-fold increase plaque burden in the descending aorta and full aorta from 16 to 22 months in 50 cGy simGCRsim-IR mice. Progression in full aortic and descending aorta plaque burden is also seen in gamma-IR mice from 12 to 22 months, with a 2-fold increase in vascular plaque over a 10-month period. These findings further suggest that simGCRsim- and gamma-IR may accelerate plaque progression and suggest simGCRsim-IR may be doing so at a higher rate compared to gamma-IR. Our data suggests there is potential IR induced acceleration in plaque progression between the 16- and 22-month time points that is possibly more pronounced with simGCRsim-IR, and that could make the long-term effects of IR comparable to that of a WD. Further work is underway for quantification of fibrosis in both the aorta as well as the aortic root for all treatment groups. Further analyses including in WT mice is underway.

Right ventricular (RV) function: We hypothesize that space-type IR may potentiate pulmonary hypertension and lung fibrosis, therefore inducing vascular remodeling and affecting the right ventricular (RV) morphology and function. Thus, we assessed the effects of gamma-IR (100, 200 cGy) and simGCRsim-IR (50, 100, 150 cGy) on the structure and the function of the heart and lungs over a 22-month post-IR follow up.

Our results showed that full-body gamma- and simGCRsim-IR potentiates the mRNA expression of proliferation, oxidative stress, and inflammation gene markers, as well as vascular remodeling and fibrosis in lung tissue as early as 28 days post IR. Compared to controls, morphometric measurements revealed an increase of the intima-media thickness of the distal pulmonary arteries after both types of IR. In addition, there was a significant increase in perivascular inflammatory infiltration in the lung tissue after simGCGsim radiation with a substantial perivascular fibrosis of pulmonary arteries. Concomitantly, compared to controls, a significant increase in right ventricular systolic pressure (RVSP) after exposure to gamma-IR 200 cGy or simGCRsim 100 cGy was observed at 12-month post IR exposure. Echo analyses at 22-months revealed significant increases in RV internal diameter (RVIDs) in ApoE null mice after all doses of simGCRsim, whereas WT mice revealed 2-fold decreases in RV diameter at mid-level after all doses and types of radiation. However, the structural and functional changes such as increases in pulmonary artery diameter and pulmonary valve maximum velocity were detected only in mice exposed to 50 cGy of simGCRsim and 200 cGy of gamma-IR. Collectively, these findings indicate that both types of radiation may have deleterious effects on the RV and lung structure and function that may lead to the development of pulmonary arterial hypertension.

Bibliography Type: Description: (Last Updated: 04/15/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Brojakowska A, Bisserier M, Khlgatian MK, Zhang S. Gillespie V, Dai Y, Hadri, Goukassian DA. "Lifetime risk of tumor development in c57b1/6j mice exposed to a single full body gamma and simGCRsim radiation." 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 Bisserier M, Khlgatian MK, Grano C, Zhang S, Brojakowska A, Fish K, Goukassian DA, Hadri L. "Longitudinal evaluation of right ventricular cardiac function after full space radiation exposure." 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 Fish K, Khlgatian MK, Grano C, Bisserier M, Zhang S, Brojakowska A, Chepurko V, Chepurko E, Gillespie V, Dai Y, Hadri L, Kishore R, Goukassian DA. " Longitudinal evaluation of cardiac function and structure in ApoE null and C57BL/6J mice after gamma and space-type radiation exposure." 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

Articles in Peer-reviewed Journals Garikipati VNS, Arakelyan A, Blakely EA, Chang PY, Truongcao MM, Cimini M, Malaredy V, Bajpai A, Addya S, Bisserier M, Brojakowska A, Eskandari A, Khlgatian MK, Hadri L, Fish K, Kishore R, Goukassian DA. "Long-term effects of very low dose particle radiation on gene expression in the heart: Degenerative disease risks." Cells. 2021 Feb 13;10(2):387. https://doi.org/10.3390/cells10020387 ; PMID: 33668521; PMCID: PMC7917872 , Feb-2021
Project Title:  Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome--80NSSC19K1079 Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 04/10/2019  
End Date: 04/09/2023  
Task Last Updated: 02/21/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Goukassian, David A M.D., Ph.D. / Icahn School of Medicine at Mount Sinai 
Address:  Zena & Michael A. Weiner Cardiovascular Institute 
One Gustave L. Levy Place, Box 1030 
New York , NY 10029 
Email: david.goukassian@mssm.edu 
Phone: 617-480-3890  
Congressional District: 12 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Icahn School of Medicine at Mount Sinai 
Joint Agency:  
Comments: NOTE: PI moved to Icahn School of Medicine at Mount Sinai from Temple University in October 2018.  
Project Information: Grant/Contract No. 80NSSC19K1079 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC19K1079 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
Human Research Program Gaps: (1) 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)
Flight Assignment/Project Notes: NOTE: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University. (Ed., 2/10/2020)

Task Description: Ed. note 2/10/2020: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921 with the same Principal Investigator Dr. David Goukassian, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University.

During the future Moon, near Earth asteroids, and Mars missions, astronauts will be exposed to higher total doses of space irradiation (IR) (~0.4-0.5 Gy) from galactic cosmic rays (GCR). Most of what we know about harmful effects of IR on cardiovascular (CV) system is from epidemiological studies of long-term survivors of cancer radiotherapy (RT). A recent study of 2,168 women who underwent RT for breast cancer has shown that the rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gy, with no apparent lower or upper threshold. In this study, it was determined that average of the mean doses to the whole heart was 4.9 Gy with the range of 0.03 - 27.72 Gy. Furthermore, metabolomics studies, in patients undergoing hematopoietic stem cell (HSC) transplantation as part of cancer treatment (1.25 Gy total-body irradiated), identified seven urine-based biomarkers with distinct differences between pre- and post-exposure samples. The levels of these markers were found to be gender-dependent suggesting that separate biomarker signatures may exist for males and females.

Hypotheses: Our central hypothesis is that low-dose proton and HZE (high energy) particle IR-induced biological responses are long-lasting, IR type- and dose-dependent and may augment excess relative risk (ERR) estimates for the development of CV diseases during and after long-duration space missions. In addition, we hypothesize that gender differences could further modify radio-biologically effective (RBE) IR thresholds for CV risk estimates. Gene expression and epigenetic modifications in protein and microRNA (miRNA) in exosomes from the blood (e.g., plasma/serum) may be altered before the onset of the cardiac symptoms, which could be used as potential biomarkers to predict the CV disease risks. We will test our hypotheses with the following specific aims:

AIM 1. Determine the longitudinal effect of IR type, dose, and gender on cardiovascular physiology in wild type mice and ApoE null mice after full-body 5-ion simplified mixed field and gamma radiation.

AIM 2. Determine space-type IR mediated modulations in exosomal cargo in the blood, and determine whether these changes are associated with alterations in the heart function, structure, and vasculature before manifestation of clinical symptoms.

AIM 3. Utilize known and newly identified bio-markers in the blood to develop human-relevant point-of-care tests (POCT) for predicting and monitoring possible CV alterations before and during the space flights.

We anticipate that the results of our proposed work may be beneficial for human space exploration and could (1) Determine single, low-dose 1H, 56Fe, and mixed field dose-responses, radio-biologically effective IR thresholds in the heart and cardiac vasculature, and whether gender differences could modify radio-biologically effective IR thresholds for CV risk estimates; 2) Determine whether space radiation leads to modifications in the circulating exosomal cargo contents and whether IR-induced exosomal cargo modulations are reflective of subclinical changes in the cells and organs of origin; 3) Ascertain if modulations of exosomal cargo may be representative of chronic oxidative stress and inflammation and could serve as early bio-markers of IR-induced CV disease initiation and progression; 4) Integrate physiological CV endpoint data sets with gene expression and epigenetic data to identify bio-markers in bio-fluids that could be used for prediction of asymptomatic CV disease in the setting of space IR, which will include known early and intermediate bio-markers of cardiac damage, inflammation, and oxidative stress, as well as currently unknown novel radiation-associated cardiac bio-markers.

Research Impact/Earth Benefits: We anticipate that the results of our work could be beneficial for human space exploration as well as for the Earth-based applications on several levels -- (1) determine whether low dose space-type and terrestrial IR may present an increased risks for CV disease development during and after prolonged space missions, as well as after conventional and particle cancer radiotherapy; (2) determine the underlying molecular signaling of CV alterations; (3) identify bio-markers in the blood that could be used for prediction of asymptomatic CV disease, which will include known early and intermediate bio-markers of cardiac damage, as well as currently unknown novel cardiac biomarkers; (4) the identification of sub-clinical CV disease biomarkers that could be used for monitoring the effectiveness of mitigating factors for prevention and treatment of IR-induced CV diseases in space and in Earth-bound civilian population, in general.

Task Progress & Bibliography Information FY2020 
Task Progress: At the time of this report preparation we collected functional cardiovascular data and various tissues for 4 time points – 14, 28 days and 12, 16 months. Within this time points we have established five sub-projects and each is reported here separately as sub-project 1-5. The utilized radiation ions, doses, and energies used in these studies as recommended by Radiation Biology Element of the Human Research Program (HRP) and depicted below:

(i) Gamma IR - 1, 2, and 4 Gy, using ApoE null MALE mice.

(ii) 5-Ion Simplified Mixed field IR - 0.5, 1.0, and 1.5 Gy, adjusted to 500 MeV/n, using ApoE null MALE mice.

(iii) Gamma IR - 1 and 2, using WT-C57BL/6J MALE.

(iv) 5-Ion Simplified Mixed field IR - 0.5 and 1.0 Gy, adjusted to 500 MeV/n, using WT-C57BL/6J MALE mice.

SUB-PROJECT 1. Title - "FULL BODY GAMMA AND 5-ION SIMPLIFIED MIXED ION RADIATION AFFECT CARDIAC FUNCTION AND STRUCTURE IN APOE NULL AND C57BL/6 MICE"

Preliminary Summary: Gamma- and 5-ISMF full body radiation, at doses 100-400 cGy for gamma and 50-150 cGy for 5-ISMF-IR, decrease global systolic function of the heart in both ApoE null and C57Bl/6 mice at 14 and 28 days after exposure. Presence of global systolic dysfunction already by 14 and 28 days post-IR determined by echocardiography (ECHO) and identification of the first detectable changes in the heart tissue only by day 28 after IR, may indicate that alterations in cardiac contractile function could be detected in advance of morphological changes in the heart tissue, suggesting that echocardiography may be one of the early tests to identify CV disease risk development. Compared to control non-irradiated mice, the left ventricular global systolic function continued to deteriorate at 12 and 16 month after exposure, with revealing detectable by echocardiography structural alteration in LV septal wall thickness, as well as other functional ECHO parameters. Additional studies are ongoing to confirm these results and further characterize the functional and histological alterations in cardiac structure and function.

SUB-PROJECT 2. Title - "EFFECTS OF FULL BODY SPACE RADIATION ON RIGHT VENTRICULAR CARDIAC FUNCTION AND DEVELOPMENT OF PULMONARY HYPERTENSION"

Preliminary Summary: At this time, our data suggested that both gamma and 5-ion simplified mix field radiation induce lung damage as characterized by vascular remodeling and increased perivascular fibrosis, proliferation, oxidative stress, and inflammation markers in the lung tissue 28 days and 1 year post radiation. Our results suggested that gamma and 5-ion simplified mix field ion radiation may potentiate fibrosis that could results in pulmonary hypertension.

SUB-PROJECT 3. Title - "FULL BODY GAMMA AND 5-ION SIMPLIFIED MIXED ION RADIATION AFFECT VASCULAR PLAQUE BURDEN IN APOE NULL MICE"

Preliminary Summary: SimGCRsim full body radiation, at a dose of 100cGy in ApoE null mice increase plaque burden at 1 year after exposure. The absence of aortic plaque burden was documented at 14 and 28 days post-IR determined by Oil-Red staining, imaging, and image analyses. Identification of the major detectable changes in the aortas and carotid arteries that was documented at one year after IR may accelerate atherosclerotic plaque development and/or progression when combined with natural aging processes. Further analyses including in vascular cells function/dysfunction in aorta and carotids in Wild Type mice, as well as the extended longitudinal studies in Apoe null mice are ongoing.

SUB-PROJECT 4. Title - "PERIPHERAL BLOOD DERIVED EXOSOMAL miRNA AS BIOMARKERS FOR SPACE RADIATION-ASSOCIATED CARDIOVASCULAR DISEASE DEVELOPMENT"

Preliminary Summary: Results of our studies so far indicate that ionizing radiation alters the miRNA content in peripheral blood derived exosomes of gamma and 5-ISMF full body irradiated mice (both, 100 cGy dose), which can be used as a source of potential biomarkers for cardiac tissue damage. Top five miRNAs were represented by miR223-3p, miR503-3p, miR149-5p (upregulated more than 2-fold after both IRs), and miR1964-3p, miR3068-3p (downregulated more than 2-fold after both IRs). The bioinformatics analyses of miRNA-223-3p and miR-503-3p target mRNAs shared common genes in vascular, cardiac, and metabolic regulatory pathways, e.g., BRINP3, LRP8, SOX11, MEF2C, IL6ST, IGF1R and NTSC1, ADAMTSL1, ABCB1, CCL2, NKAIN2, respectively. Therefore, with further functional and structural validation, exosomal miRNAs could prove to be promising candidate biomarkers for identification and validation of tissue specific damage/pathology for space-type radiation-induced cardiovascular diseases.

SUB-PROJECT 5. Title - "SPACE RADIATION AND HIGH LIPID DIET-ASSOCIATED BRAIN DENDRITIC CELL ACTIVATION: IMPLICATIONS FOR NEUROLOGICAL DISEASE DEVELOPMENT"

Preliminary Summary: Gross examination of brains from irradiated Apo-E mice appears to suggest that 5-Ion Simplified Mix Field-IR (5-ISMF IR) results in increased number of melonocyte-like dendritic cells in western diet-fed and 5-ISMF IR exposed mice meninges. We also detected elevated levels of cells appearing in several pyramidal and granular layers of the cerebral cortex in the 100 cGy 5-IMSF irradiated animals. Congo Red staining for amyloid staining was negative, suggesting that there were no hallmark AD lesions present. Further follow up is needed to confirm these results and further characterize the progression of lesions identified.

Bibliography Type: Description: (Last Updated: 04/15/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Fish K, Khlgatian MK, Bisserier M, Zhang S, Hadri L, Hajjar R, Kishore R, Goukassian DA. "Full body gamma and 5-ion simplified mixed ion radiation affect vascular plaque burden in apoe null mice." Presented at the 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 Bisserier M, Zhang S, Khlgatian MK, Fish K, Goukassian DA, Hadri L. "Effects of full body space radiation on right ventricular cardiac function and development of pulmonary hypertension." Presented at the 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 Khlgatian MK, Bisserier M, Zhang S, Chepurko V, Chepurko V, Gillespie V, Dai Y, Fish K, Hadri L, Hajjar R, Kishore R, Goukassian DA. "Full body gamma and 5-ion simplified mixed ion radiation affect cardiac function and structure in apoe null and c57bl/6 mice." Presented at the 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 Fish K, Bisserier M, Khlgatian MK, Adamiak M, Mathiyalagan P, Hajjar R, Kishore R, Sahoo S, Goukassian DA. "Peripheral blood derived exosomal miRNA as biomarkers for space radiation-associated cardiovascular disease development." Presented at the 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 Fish K, Bisserier MM, Zhang S, Hadri H, Khlgatian MK, Goukassian DA. "Space radiation and high lipid diet-associated brain dendritic cell activation: implications for neurological disease development." Presented at the 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

Project Title:  Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome--80NSSC19K1079 Reduce
Images: icon  Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 04/10/2019  
End Date: 04/09/2023  
Task Last Updated: 02/12/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Goukassian, David A M.D., Ph.D. / Icahn School of Medicine at Mount Sinai 
Address:  Zena & Michael A. Weiner Cardiovascular Institute 
One Gustave L. Levy Place, Box 1030 
New York , NY 10029 
Email: david.goukassian@mssm.edu 
Phone: 617-480-3890  
Congressional District: 12 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Icahn School of Medicine at Mount Sinai 
Joint Agency:  
Comments: NOTE: PI moved to Icahn School of Medicine at Mount Sinai from Temple University in October 2018.  
Project Information: Grant/Contract No. 80NSSC19K1079 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC19K1079 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
Human Research Program Gaps: (1) 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)
Flight Assignment/Project Notes: NOTE: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University. (Ed., 2/10/2020)

Task Description: Ed. note 2/10/2020: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921 with the same Principal Investigator Dr. David Goukassian, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University.

During the future Moon, near Earth asteroids, and Mars missions, astronauts will be exposed to higher total doses of space irradiation (IR) (~0.4-0.5 Gy) from galactic cosmic rays (GCR). Most of what we know about harmful effects of IR on cardiovascular (CV) system is from epidemiological studies of long-term survivors of cancer radiotherapy (RT). A recent study of 2,168 women who underwent RT for breast cancer has shown that the rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gy, with no apparent lower or upper threshold. In this study, it was determined that average of the mean doses to the whole heart was 4.9 Gy with the range of 0.03 - 27.72 Gy. Furthermore, metabolomics studies, in patients undergoing hematopoietic stem cell (HSC) transplantation as part of cancer treatment (1.25 Gy total-body irradiated), identified seven urine-based biomarkers with distinct differences between pre- and post-exposure samples. The levels of these markers were found to be gender-dependent suggesting that separate biomarker signatures may exist for males and females.

Hypotheses: Our central hypothesis is that low-dose proton and HZE (high energy) particle IR-induced biological responses are long-lasting, IR type- and dose-dependent and may augment excess relative risk (ERR) estimates for the development of CV diseases during and after long-duration space missions. In addition, we hypothesize that gender differences could further modify radio-biologically effective (RBE) IR thresholds for CV risk estimates. Gene expression and epigenetic modifications in protein and microRNA (miRNA) in exosomes from the blood (e.g., plasma/serum) may be altered before the onset of the cardiac symptoms, which could be used as potential biomarkers to predict the CV disease risks. We will test our hypotheses with the following specific aims:

AIM 1. Determine the longitudinal effect of IR type, dose, and gender on cardiovascular physiology in wild type mice and ApoE null mice after full-body 5-ion simplified mixed field and gamma radiation.

AIM 2. Determine space-type IR mediated modulations in exosomal cargo in the blood, and determine whether these changes are associated with alterations in the heart function, structure, and vasculature before manifestation of clinical symptoms.

AIM 3. Utilize known and newly identified bio-markers in the blood to develop human-relevant point-of-care tests (POCT) for predicting and monitoring possible CV alterations before and during the space flights.

We anticipate that the results of our proposed work may be beneficial for human space exploration and could (1) Determine single, low-dose 1H, 56Fe, and mixed field dose-responses, radio-biologically effective IR thresholds in the heart and cardiac vasculature, and whether gender differences could modify radio-biologically effective IR thresholds for CV risk estimates; 2) Determine whether space radiation leads to modifications in the circulating exosomal cargo contents and whether IR-induced exosomal cargo modulations are reflective of subclinical changes in the cells and organs of origin; 3) Ascertain if modulations of exosomal cargo may be representative of chronic oxidative stress and inflammation and could serve as early bio-markers of IR-induced CV disease initiation and progression; 4) Integrate physiological CV endpoint data sets with gene expression and epigenetic data to identify bio-markers in bio-fluids that could be used for prediction of asymptomatic CV disease in the setting of space IR, which will include known early and intermediate bio-markers of cardiac damage, inflammation, and oxidative stress, as well as currently unknown novel radiation-associated cardiac bio-markers.

Research Impact/Earth Benefits: We anticipate that the results of our work could be beneficial for human space exploration as well as for the Earth-based applications on several levels -- (1) determine whether low dose space-type and terrestrial IR may present an increased risks for CV disease development during and after prolonged space missions, as well as after conventional and particle cancer radiotherapy; (2) determine the underlying molecular signaling of CV alterations; (3) identify bio-markers in the blood that could be used for prediction of asymptomatic CV disease, which will include known early and intermediate bio-markers of cardiac damage, as well as currently unknown novel cardiac biomarkers; (4) the identification of sub-clinical CV disease biomarkers that could be used for monitoring the effectiveness of mitigating factors for prevention and treatment of IR-induced CV diseases in space and in Earth-bound civilian population, in general.

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

NOTE: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921 with the same Principal Investigator Dr. David Goukassian, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University. See that project for previous reporting. (Added in February 2020 to Task Book when received information on new grant.)

Bibliography Type: Description: (Last Updated: 04/15/2022) 

Show Cumulative Bibliography Listing
 
 None in FY 2019