Responsible Center: NASA ARC
Grant Monitor: Whitmire, Alexandra
Solicitation / Funding Source: 2018 HERO 80JSC018N0001-Crew Health and Performance (FLAGSHIP, OMNIBUS). Appendix A-Flagship, Appendix B-Omnibus
Grant/Contract No.: Internal Project ; 80NSSC20K0125
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: 1
|Human Research Program Elements:
(1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
|Human Research Program Risks:
(1) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
|Human Research Program Gaps:
(1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
|Flight Assignment/Project Notes:
|| NOTE: End date changed to 09/30/2022 per L. Juliette/JSC (Ed., 5/7/22)
NOTE: End date changed to 12/31/2021 per information in PI report (Ed., 8/19/21)
NOTE: End date changed to 9/30/2021 per F. Hernandez/ARC when PI became civil servant summer 2020 and project extended as internal project at NASA Ames; USRA grant 80NSSC20K0125 has official end date of 6/5/2020 (Ed., 9/2/2020)
|| One of the main risks of human deep space exploration is central nervous system (CNS) damage, which is associated with neuronal damage and neuroinflammation, caused by exposure to space radiation combined with microgravity, and can lead to cognitive and behavioral dysfunction. CNS responses to injuries are strongly regulated by astrocytes, which are a major glial cell type in the brain that has also been shown to control the blood-brain barrier permeability, essential neuronal functions, and inflammation; and thus could serve as a robust CNS-specific target for countermeasure development. Therefore, we propose to investigate the astrocytic regulation of neuronal health in response to simulated space radiation.
We propose to utilize for the first time a novel high-throughput human tissue-on-a-chip model for 3D neuronal/astrocyte cultures. We will investigate the morphological and physiological outcomes as well as gene expression changes after simulated space radiation exposure (5-ion simulation of galactic cosmic rays, 500 mGy) and compare them to the responses to gamma radiation in order to establish the relative biological effectiveness. We will also evaluate the necessity and sufficiency of astrocytes in regulating radiation responses by establishing experimental models where astrocytes are either the only cell type that is irradiated, or the only cell type that escapes irradiation. Finally, we will test whether driving astrocytes more towards A1 (inflammation) or towards A2 (scarring) phenotypes may serve as countermeasures by reducing radiation-mediated neuronal damage.
In summary, we will examine whether astrocytes are necessary and sufficient to protect neurons from damage induced by simulated space radiation and evaluate their effectiveness as a target for further countermeasure development. We will also provide a proof of concept for human tissue-on-a-chip use for studying space radiation effects on the CNS.
Our proposal addresses the Part "B. Basic Investigations Opportunity for Investigators New to NASA" of the Appendix B. The new investigator (Principal Investigator) and experienced investigator (CoInvestigator/Institutional Principal Investigator) have combined expertise in space biology, neuroinflammation astrocyte functions, TGFbeta functions in regulating astrocyte phenotypes, and responses to particle radiation. Thus, we have the capacity to complete this 1-year project at NASA Ames and, given sufficient interest, could easily expand it to a) investigate the outcomes of combined exposures to microgravity, stress, and radiation, and b) design an in vivo follow-up study on astrocytic regulation of CNS responses to spaceflight stressors.
|Research Impact/Earth Benefits:
|| 1. Technological. We have successfully developed human, 3D, multicellular, low footprint, high throughput (40-96 samples per standard 384-well plate) neurovascular model seeded with induced pluripotent stem cells (iPSC)-derived astrocytes and endothelial cells that retain blood-brain barrier properties and last for at least 1 week post irradiation and at least 2 weeks post seeding. This model could be used for personalized medicine approaches using iPSCs derived from specific individuals to test their responses to either therapeutic or space radiation.
2. Scientific. We have discovered that astrocytes are particularly sensitive to ionizing radiation, especially components of galactic cosmic rays. In response to radiation, astrocytes increase oxidative stress and blood-brain barrier permeability and cause immune dysregulation, at least in part via interleukin-1 signaling. These results are important not only for deep space exploration, but also for understanding the outcomes of human central nervous system irradiation for therapeutic purposes (e.g., to treat brain tumors), and results indicate astrocytic interleukin-1 signaling as a potential target for countermeasure/therapeutic development.