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.
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To uncover qualitative differences and determine RBEs for biological damage of proton and HZE particles and mix field exposures compared to terrestrial IR and how this influences CV disease risk, we will compare the biological CV end-points of gamma-IR at 50 and 100 cGy to the end-points after exposure to space relevant doses of protons (5, 15 and 30 cGy, 500 MeV for 1H), iron (1, 5 and 10 cGy, 500 MeV/n for 56Fe) and mix field (10, 25, 50 cGy, where each dose will consist of 60% 1H at 500 MeV; 20% 2He at 250 MeV/n; 10% 12C at 290 MeV/n and 10% 56Fe at 500 MeV/n). At the time of initial IR exposures both male and female mice will be 8-9 months old. At various time-points after IR we will determine whether there may be a difference in the cardiac physiology, survival and function of CM and cardiac ECs. Blood (plasma/serum) will be collected for isolation of circulating exosomes for Next-Gen Sequencing (NGS) and proteomic studies. This will allow us to determine the lowest bio-effective IR dose that may induce alterations in heart function.
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 biomarkers 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.
Crew health and performance is critical to successful human exploration beyond low Earth orbit.
The Human Research Program (HRP) investigates and mitigates the highest risks to human health
and performance, providing essential countermeasures and technologies for human space exploration.
Risks include physiological and performance effects from hazards such as radiation, altered gravity,
and hostile environments, as well as unique challenges in medical support, human factors,
and behavioral health support. The HRP utilizes an Integrated Research Plan (IRP) to identify
the approach and research activities planned to address these risks, which are assigned to specific
Elements within the program. The Human Research Roadmap is the web-based tool for communicating the IRP content.
The Human Research Roadmap is located at: https://humanresearchroadmap.nasa.gov/
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