Responsible Center: NASA JSC
Grant Monitor: Simonsen, Lisa
Solicitation: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics
Grant/Contract No.: 80NSSC19K1079
Project Type: GROUND
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 Gaps:
(1) CV08:Can manifestations of sub-clinical or environmentally induced cardiovascular diseases during spaceflight be predicted?
(2) Degen01:How can tissue specific experimental models be developed for the major degenerative tissue risks, including cardiovascular, lens, digestive, endocrine, and other tissue systems in order to estimate space radiation risks for degenerative diseases? (IRP Rev F)
(3) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
(4) Degen03:What are the progression rates and latency periods for radiation-induced degenerative diseases, and how do progression rates depend on age, sex, radiation type, or other physiological or environmental factors? (IRP Rev F)
|| 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.