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Project Title:  Astrocytes as Key Mediators of Central Nervous System Responses to Space Radiation Reduce
Images: icon  Fiscal Year: FY 2022 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 10/17/2019  
End Date: 09/30/2022  
Task Last Updated: 08/18/2021 
Download report in PDF pdf
Principal Investigator/Affiliation:   Cekanaviciute, Egle  Ph.D. / NASA Ames Research Center 
Address:  Space Biosciences Research Branch 
 
Moffett Field , CA 94035 
Email: egle.cekanaviciute@nasa.gov 
Phone: 415-623-0033  
Congressional District: 18 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Ames Research Center 
Joint Agency:  
Comments: NOTE: PI formerly at Universities Space Research Association at NASA Ames Research Center; became civil servant at NASA Ames in summer 2020. 
Co-Investigator(s)
Affiliation: 
Costes, Sylvain  Ph.D. NASA Ames Research Center 
Key Personnel Changes / Previous PI: NOTE (Ed., 9/2/2020): PI became civil servant at NASA Ames in summer 2020 ; project extended as internal project at NASA Ames and previous USRA grant 80NSSC20K0125 has official end date of 6/5/2020.
Project Information: Grant/Contract No. Internal Project ; 80NSSC20K0125 
Responsible Center: NASA ARC 
Grant Monitor: Whitmire, Alexandra  
Center Contact:  
alexandra.m.whitmire@nasa.gov 
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 
Flight Program:  
TechPort: No 
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 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)

Task Description: 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.

Task Progress & Bibliography Information FY2022 
Task Progress: 1. ASTROCYTES EXACERBATE OXIDATIVE STRESS CAUSED BY SIMULATED DEEP SPACE RADIATION. We have further analyzed the neurovascular model responses to 600 MeV/n 56-Fe irradiation and observed a dose-dependent increase in oxidative stress. The presence of astrocytes exacerbated oxidative stress in irradiated models. Although oxidative stress induced by ionizing radiation, especially high-LET (linear energy transfer) particle radiation, has been extensively studied in CNS models, the relative susceptibility of astrocytes has not been evaluated previously. In combination with the role of astrocytes in exacerbating vascular permeability, this finding further indicates astrocytes as the “weakest link” in neurovascular responses to deep space radiation and a suitable target for countermeasures, and suggests oxidative stress as a key mechanism of radiation-induced damage.

2. ASTROCYTES EXACERBATE IMMUNE DYSFUNCTION CAUSED BY SIMULATED DEEP SPACE RADIATION. One of the main functions of astrocytes is regulating CNS immune responses in health and disease. Therefore, we used astrocyte and mixed endothelial cell-astrocyte neurovascular models to investigate the effects of simulated deep space radiation on astrocyte immunoregulatory characteristics. Secreted immune cytokines revealed a dysfunction in multiple pathways in astrocytes alone and in neurovascular models. Specifically, our results suggest that radiation disrupts astrocyte immunoregulatory functions, which exacerbates the effects of radiation on endothelial cell immune cytokine production, leading to neurovascular leakiness, increased inflammation and immune dysfunction.

3. ONGOING INVESTIGATIONS: NEUROVASCULAR RESPONSES TO 5-ION SIMPLIFIED SIMULATED GALACTIC COSMIC RAYS. Finally, during NASA Space Radiation Laboratory (NSRL) 21B campaign (June 2021), we exposed astrocyte-endothelial cell and astrocyte-neuron-endothelial cell combinations to 5-ion simplified simulated GCRs (SimGCRSim) and repeated 600 MeV/n 56Fe exposure to validate the results obtained during the previous irradiation experiment. Live imaging of neurovascular permeability was performed and samples were collected at different time points days post irradiation. Supernatants were frozen for oxidative stress and immune cytokine measurements, and neurovascular organ models were fixed and stained for immunohistochemistry. All sample analysis is ongoing.

Bibliography Type: Description: (Last Updated: 08/19/2021) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Afshinnekoo E, Scott RT, MacKay MJ, Pariset E, Cekanaviciute E, Barker R, Gilroy S, Hassane D, Smith SM, Zwart SR, Nelman-Gonzalez M, Crucian BE, Ponomarev SA, Orlov OI, Shiba D, Muratani M, Yamamoto M, Richards SE, Vaishampayan PA, Meydan C, Foox J, Myrrhe J, Istasse E, Singh N, Venkateswaran K, Keune JA, Ray HE, Basner M, Miller J, Vitaterna MH, Taylor DM, Wallace D, Rubins K, Bailey SM, Grabham P, Costes SV, Mason CE, Beheshti A. "Fundamental biological features of spaceflight: Advancing the field to enable deep-space exploration." Cell. 2020 Nov 25;183(5):1162-84. Review. https://doi.org/10.1016/j.cell.2020.10.050 ; PMID: 33242416 , Nov-2020
Awards Cekanaviciute E. "Early Career Investigator Spotlight, Radiation Research Society, March 2021. " Mar-2021
Project Title:  Astrocytes as Key Mediators of Central Nervous System Responses to Space Radiation Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 10/17/2019  
End Date: 09/30/2021  
Task Last Updated: 08/13/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Cekanaviciute, Egle  Ph.D. / NASA Ames Research Center 
Address:  Space Biosciences Research Branch 
 
Moffett Field , CA 94035 
Email: egle.cekanaviciute@nasa.gov 
Phone: 415-623-0033  
Congressional District: 18 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Ames Research Center 
Joint Agency:  
Comments: NOTE: PI formerly at Universities Space Research Association at NASA Ames Research Center; became civil servant at NASA Ames in summer 2020. 
Co-Investigator(s)
Affiliation: 
Costes, Sylvain  Ph.D. NASA Ames Research Center 
Key Personnel Changes / Previous PI: NOTE (Ed., 9/2/2020): PI became civil servant at NASA Ames in summer 2020 ; project extended as internal project at NASA Ames and previous USRA grant 80NSSC20K0125 has official end date of 6/5/2020.
Project Information: Grant/Contract No. Internal Project ; 80NSSC20K0125 
Responsible Center: NASA ARC 
Grant Monitor: Lewis, Laura  
Center Contact:  
laura.lewis@nasa.gov 
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 
Flight Program:  
TechPort: No 
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 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 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)

Task Description: 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: So far, my research has demonstrated that astrocytes are particularly sensitive to ionizing radiation, especially particle radiation, by increasing neuroinflammation, oxidative stress, and blood-brain barrier permeability. It is important not only for deep space exploration, but also for understanding the outcomes of human central nervous system irradiation for therapeutic purposes, to treat brain cancer.

Task Progress & Bibliography Information FY2021 
Task Progress: The goal of this project was to investigate the role of astrocytes in regulating central nervous system (CNS) responses to deep space radiation: simulated galactic cosmic rays (GCRs).

We have established a robust and reproducible model of human CNS-on-a-chip that includes blood-brain barrier components in addition to astrocytes. We used this model to discover that GCR components (e.g., 600 MeV/n Fe particles) selectively damage astrocytes and increase blood-brain barrier permeability in an astrocyte-specific manner. In addition, based on our X-ray irradiation experiments, radiation-mediated increase in blood-brain barrier permeability is associated with damage to endothelial cells and tight junctions, release of inflammatory cytokines, and increased oxidative stress.

Our 5-ion simplified simulated GCR exposure experiments were canceled due to Covid-19; therefore, we have requested a costed extension to be able to finish this work once Covid-19 mediated shelter-in-place is over, and to perform additional experiments that aim to demonstrate the molecular and cellular correlates of responses to GCR irradiation, and also evaluate whether astrocytes could be targeted for radioprotection.

Bibliography Type: Description: (Last Updated: 08/19/2021) 

Show Cumulative Bibliography Listing
 
 None in FY 2021
Project Title:  Astrocytes as Key Mediators of Central Nervous System Responses to Space Radiation Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 10/17/2019  
End Date: 04/09/2021  
Task Last Updated: 11/06/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Cekanaviciute, Egle  Ph.D. / NASA Ames Research Center 
Address:  Space Biosciences Research Branch 
 
Moffett Field , CA 94035 
Email: egle.cekanaviciute@nasa.gov 
Phone: 415-623-0033  
Congressional District: 18 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Ames Research Center 
Joint Agency:  
Comments: NOTE: PI formerly at Universities Space Research Association at NASA Ames Research Center; became civil servant at NASA Ames in summer 2020. 
Co-Investigator(s)
Affiliation: 
Costes, Sylvain  Ph.D. NASA Ames Research Center 
Project Information: Grant/Contract No. 80NSSC20K0125 
Responsible Center: NASA ARC 
Grant Monitor: Lewis, Laura  
Center Contact:  
laura.lewis@nasa.gov 
Solicitation / Funding Source: 2018 HERO 80JSC018N0001-Crew Health and Performance (FLAGSHIP, OMNIBUS). Appendix A-Flagship, Appendix B-Omnibus 
Grant/Contract No.: 80NSSC20K0125 
Project Type: GROUND 
Flight Program:  
TechPort: No 
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 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)
Task Description: 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:

Task Progress & Bibliography Information FY2020 
Task Progress: New project for FY2020.

Bibliography Type: Description: (Last Updated: 08/19/2021) 

Show Cumulative Bibliography Listing
 
 None in FY 2020