Responsible Center: NASA JSC
Grant Monitor: Stenger, Michael
Center Contact: 281-483-1311
Solicitation / Funding Source: 2019 HERO 80JSC019N0001-FLAGSHIP & OMNIBUS: Human Research Program Crew Health. Appendix A&B
Grant/Contract No.: 80NSSC20K1841
Project Type: GROUND
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|Human Research Program Gaps:
(1) BMed-101:We need to identify, quantify, and validate the key selection factors for astronaut cognitive and behavioral strengths (e.g., resiliency) and operationally-relevant performance threats for increasingly Earth independent, long-duration, autonomous, and/or long-distance exploration missions (IRP Rev L)
(2) Cancer-202:Evaluate the contribution of genetic background/diversity on carcinogenesis risk (IRP Rev M)
(3) IM-104:Evaluate immune dysfunction on missions greater than six months (IRP Rev L)
|| Objectives: Large-scale next-generation sequencing studies have revealed that somatic mutations can be found in blood samples from healthy subjects without evidence of hematologic disease. Such mutations, for example in genes including DNMT3A, TET2, and ASXL1, can lead to clonal expansion of hematopoietic cells and have been termed clonal hematopoiesis (CH). CH is more prevalent with increasing age and can be modulated by exposures encountered in space including radiation. The risks of CH are multiple and include increased risk of cardiovascular mortality as well as increased risk of hematologic malignancies. CH is also a pro-inflammatory condition and is thus likely to exacerbate inflammatory complications due to long-term space flight or return to gravity, as has been described by astronauts returning to Earth following long-term missions in micro-gravity environments. Thus, understanding the association between CH, inflammation, and inflammatory complications -- especially arising from space flight -- is crucial for astronauts. Thus, we plan to identify CH in astronauts and monitor its progression during space flight and return to gravity. We will further assess inflammatory factors and how the presence of CH influences inflammation.
Methods: Genomic DNA from bulk mononuclear cells will be purified and sheared. Illumina sequencing adapters containing unique dual sample indices will be ligated onto fragments according to the Kapa HyperPrep protocol. Targeted enrichment using a custom pool of biotinylated baits directed to 100+ genes involved in clonal hematopoiesis, cancer, and cardiovascular disease will be performed according to the PreCISE-1 protocol, developed by our Englander Institute for Precision Medicine. Sequencing will be performed to >2000x median unique depth of coverage using NovaSeq6000 S4 flowcell chemistry. The median sensitivity of the test is estimated at >95% for mutations present at VAF > 1% (corresponding to 1/50 mutated cells). Mutation calling will be performed as per our previous publication, Desai et al., Nature Medicine 2018.
Significance: A subset of astronauts are likely to launch into space with existing CH and, moreover, radiation exposures are likely to affect the risk of CH. In addition, CH may predict the severity of inflammatory complications arising from long-term space flight. Therefore, developing a detailed understanding of the causes and consequences of CH in astronauts is critical. In particular, this links to the Human Research Program's ongoing efforts for the long-term health studies for astronauts at NASA, aids the work of other space programs, complements the Standard Measures of health for astronauts and the integrated one-year missions (iYMP), and aids the development and application of genetic risk data in space medicine and health monitoring.