As a result of galactic cosmic rays (GCR) and solar particle events (SPE) astronauts are exposed to radiation that is composed of high-energy low fluence proton and high atomic number and energy (HZE) nuclei. The effect of prolonged spaceflight on genomic instability in the hematopoietic system has been reported . Presently, space radiation effects on clonal hematopoiesis and how this may influence degenerative CVD and hematologic malignancy risks are unknown. Addressing this question is the objective of the current proposal.
Hypothesis: Space radiation will promote clonal hematopoiesis and thereby impact CVD and leukemogenesis in a radiation- and gene-specific manner.
Significance: This research will evaluate a new quantifiable risk factor for cancer and degenerative disease for individual crew members. These studies will provide insights about molecular targets/pathways for development of mitigating factors to prevent CVD and leukemic morbidity in astronauts. It will also shed light on the mitigation of adverse outcomes in the civilian cancer patient population who are treated with chemotherapies and radiotherapies.
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An experienced team (hematopoiesis, cardiology, oncology, radiation biology) will employ a novel murine adoptive bone marrow transfer approach, developed in the applicants’ labs, to model clonal hematopoiesis induced by somatic mutations in various genes (e.g. TET2, DNMT3A, TP53 and PPM1D). Experiments will examine the consequences of gamma, simulated GCR, and SPE on (1) the rates of hematologic clone expansion, (2) cardiovascular function and (3) leukemogenic/cancer endpoints. DNMT3A, TET2 TP53 and PPM1D genes were selected as possible genes for analysis because they represent the most prevalent driver mutations that contribute to “age-associated clonal hematopoiesis” (DNMT3A and TET2) and “therapy-associated clonal hematopoiesis” (TP53 and PPM1D).
1. Space radiation will increase the rate of hematologic clone expansion and there may be a difference between the expansion of mutant vs. wild type cells.
2. Space radiation will have a detrimental effect on cardiovascular function and this effect may be dependent on the clonal expansion of mutant vs. wild type cells.
3. Space radiation will increase the likelihood of seeing leukemogenic/cancer endpoints and this effect may be dependent on the clonal expansion of mutant vs. wild type cells.