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Project Title:  Variation in CNS Damage Signaling and Blood Sentinels of Neuropathology After Exposure to Space Radiation Reduce
Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 04/01/2019  
End Date: 04/30/2022  
Task Last Updated: 03/03/2022 
Download report in PDF pdf
Principal Investigator/Affiliation:   Wyrobek, Andrew  Ph.D. / Lawrence Berkeley National Laboratory 
Address:  1 Cyclotron Rd MS: 74R0157 
 
Berkeley , CA 94720-8099 
Email: ajwyrobek@lbl.gov 
Phone: 925-989-4466  
Congressional District: 13 
Web:  
Organization Type: GOVERNMENT 
Organization Name: Lawrence Berkeley National Laboratory 
Joint Agency:  
Comments: For immediate assistance please contact my administrator Caron LaMarsh clamarsh@lbl.gov, 510.486.5317 
Co-Investigator(s)
Affiliation: 
Peterson, Leif  Ph.D. The Methodist Hospital Research Institute 
Bowles, Dawn  Ph.D. Duke University 
Celniker, Susan  Ph.D. Lawrence Berkeley National Laboratory 
Witkowska, Helena  Ph.D. University of California San Francisco - ret 
Key Personnel Changes / Previous PI: March 2020 report: The individuals are co-investigators on this project: Peterson, Leif; Bowles, Dawn; Celniker, Susan; Witkowska, Helena. The following individuals remain as collaborators on this project: Albou, Laurent-Philippe; Mungall, Chris; Fiehn, Oliver; Settles, Matthew; Froenicke, Lutz; Straume, Tore.
Project Information: Grant/Contract No. 80JSC019T0007 
Responsible Center: NASA JSC 
Grant Monitor: Whitmire, Alexandra  
Center Contact:  
alexandra.m.whitmire@nasa.gov 
Solicitation / Funding Source: 2017 HERO 80JSC017N0001-Crew Health and Performance (FLAGSHIP1, OMNIBUS). Appendix A-Flagship1, Appendix B-Omnibus 
Grant/Contract No.: 80JSC019T0007 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
(2) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
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) 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)
(3) 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)
(4) 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)
(5) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes (IRP Rev L)
(6) CVD-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease (IRP Rev L)
Flight Assignment/Project Notes: NOTE: End date changed to 4/30/2022 per PI information (Ed., 2/11/22)

NOTE: End date changed to 12/31/2021 per D. Kulkarni/HRP (Ed., 10/7/21)

NOTE: Period of performance changed to 4/1/2019-3/31/2021 per PI/NASA-LBL interagency agreement; previous information showed 11/28/18-11/27/20 (Ed., 9/5/19)

Task Description: Major objectives of the NASA space radiation research program are to enable human exploration of space without exceeding limits for immediate and persistent risks to the central nervous system (CNS) from space radiation. The proposed research will investigate the CNS subregions of rodents exposed to simulated space radiation for molecular indicators for vascular damage, inflammation, and neurological abnormalities after space radiation. This project will apply multi-omic technologies (proteomics, metabolomics, and bioinformatics) to archived CNS brain subregions from irradiated mouse and rat behavioral models.

The specific aims are:

Aim 1. Characterize the persistence of radiation-induced molecular abnormalities in cortex and hippocampus after low-dose exposures to 56Fe particles, and compare the predictions for CNS tissue damage and late-onset neuropathologies in similarly irradiated mice and rats.

Aim 2. Identify persistent bio-effect markers in peripheral blood and cerebrospinal fluid (CSF) that correlate with molecular damage in CNS vascular or immune functions. Our research plan will provide testable hypotheses of CNS tissue damage and identify molecular targets for susceptible pathways/functions of CNS damage.

This project will also provide proof-of-principle whether CNS damage relevant bio-effect metabolites can be detected in CSF and blood. This project will also identify radiation-sensitive pathways, suitable for future development of biological countermeasures to reduce CNS risks from space radiation. The results of this research are designed to help NASA reduce the uncertainty associated with during mission behavior and CNS risk for astronauts on deep space exploration missions.

Research Impact/Earth Benefits: The predictive model developed in this project will yield numerous hypotheses of mechanisms of CNS radiation damage that are either common or unique to cortex and hippocampus – these hypotheses will be tested in future studies by in situ analyses of archived frozen tissues and fixed contralateral hemispheres that are available from all animals in this proposal. This project will also provide proof-of-principle whether CNS damage relevant bio-effect metabolites can be detected in CSF and blood. This project will also identify radiation-sensitive pathways, suitable for future development of biological countermeasures to reduce CNS risks from space radiation. The results of this research are designed to help NASA reduce the uncertainty associated with during mission behavior and CNS risk for astronauts on deep space exploration missions.

Task Progress & Bibliography Information FY2021 
Task Progress: January 2022 Report:

This 2-year research project was seriously delayed (~18 months) due to the COVID outbreak which imposed badging restrictions to enter institute buildings with a full shutdown of the Wyrobek wet lab from February 2020 to July 2021.

The research consequences of the COVID shutdown: no tissue samples were processed, no multi-omics profiles were generated, and bioinformatic analyses were limited to pre-COVID datasets.

A revised research plan was generated that retained the hypothesis, goals, and the two specific aims of the original plan. NASA granted a No Cost Extension (NCE) to April 30, 2022 to carry out the revised research plan.

Bibliography Type: Description: (Last Updated: 02/08/2018) 

Show Cumulative Bibliography Listing
 
 None in FY 2021
Project Title:  Variation in CNS Damage Signaling and Blood Sentinels of Neuropathology After Exposure to Space Radiation Reduce
Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 04/01/2019  
End Date: 12/31/2021  
Task Last Updated: 03/13/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Wyrobek, Andrew  Ph.D. / Lawrence Berkeley National Laboratory 
Address:  1 Cyclotron Rd MS: 74R0157 
 
Berkeley , CA 94720-8099 
Email: ajwyrobek@lbl.gov 
Phone: 925-989-4466  
Congressional District: 13 
Web:  
Organization Type: GOVERNMENT 
Organization Name: Lawrence Berkeley National Laboratory 
Joint Agency:  
Comments: For immediate assistance please contact my administrator Caron LaMarsh clamarsh@lbl.gov, 510.486.5317 
Co-Investigator(s)
Affiliation: 
Peterson, Leif  Ph.D. The Methodist Hospital Research Institute 
Bowles, Dawn  Ph.D. Duke University 
Celniker, Susan  Ph.D. Lawrence Berkeley National Laboratory 
Witkowska, Helena  Ph.D. University of California San Francisco - ret 
Key Personnel Changes / Previous PI: March 2020 report: The individuals are co-investigators on this project: Peterson, Leif; Bowles, Dawn; Celniker, Susan; Witkowska, Helena. The following individuals remain as collaborators on this project: Albou, Laurent-Philippe; Mungall, Chris; Fiehn, Oliver; Settles, Matthew; Froenicke, Lutz; Straume, Tore.
Project Information: Grant/Contract No. 80JSC019T0007 
Responsible Center: NASA JSC 
Grant Monitor: Williams, Thomas  
Center Contact: 281-483-8773 
thomas.j.will1@nasa.gov 
Solicitation / Funding Source: 2017 HERO 80JSC017N0001-Crew Health and Performance (FLAGSHIP1, OMNIBUS). Appendix A-Flagship1, Appendix B-Omnibus 
Grant/Contract No.: 80JSC019T0007 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
(2) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
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) 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)
(3) 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)
(4) 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)
(5) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes (IRP Rev L)
(6) CVD-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease (IRP Rev L)
Flight Assignment/Project Notes: NOTE: End date changed to 12/31/2021 per D. Kulkarni/HRP (Ed., 10/7/21)

NOTE: Period of performance changed to 4/1/2019-3/31/2021 per PI/NASA-LBL interagency agreement; previous information showed 11/28/18-11/27/20 (Ed., 9/5/19)

Task Description: Major objectives of the NASA space radiation research program are to enable human exploration of space without exceeding limits for immediate and persistent risks to the central nervous system (CNS) from space radiation. The proposed research will investigate the CNS subregions of rodents exposed to simulated space radiation for molecular indicators for vascular damage, inflammation, and neurological abnormalities after space radiation. This project will apply multi-omic technologies (proteomics, metabolomics, and bioinformatics) to archived CNS brain subregions from irradiated mouse and rat behavioral models.

The specific aims are:

Aim 1. Characterize the persistence of radiation-induced molecular abnormalities in cortex and hippocampus after low-dose exposures to 56Fe particles, and compare the predictions for CNS tissue damage and late-onset neuropathologies in similarly irradiated mice and rats.

Aim 2. Identify persistent bio-effect markers in peripheral blood and cerebrospinal fluid (CSF) that correlate with molecular damage in CNS vascular or immune functions. Our research plan will provide testable hypotheses of CNS tissue damage and identify molecular targets for susceptible pathways/functions of CNS damage.

This project will also provide proof-of-principle whether CNS damage relevant bio-effect metabolites can be detected in CSF and blood. This project will also identify radiation-sensitive pathways, suitable for future development of biological countermeasures to reduce CNS risks from space radiation. The results of this research are designed to help NASA reduce the uncertainty associated with during mission behavior and CNS risk for astronauts on deep space exploration missions.

Research Impact/Earth Benefits: The predictive model developed in this project will yield numerous hypotheses of mechanisms of CNS radiation damage that are either common or unique to cortex and hippocampus – these hypotheses will be tested in future studies by in situ analyses of archived frozen tissues and fixed contralateral hemispheres that are available from all animals in this proposal. This project will also provide proof-of-principle whether CNS damage relevant bio-effect metabolites can be detected in CSF and blood. This project will also identify radiation-sensitive pathways, suitable for future development of biological countermeasures to reduce CNS risks from space radiation. The results of this research are designed to help NASA reduce the uncertainty associated with during mission behavior and CNS risk for astronauts on deep space exploration missions.

Task Progress & Bibliography Information FY2020 
Task Progress: This new project will provide NASA with a deeper understanding of the cellular and molecular mechanisms underlying persistent CNS tissue abnormalities and the risks for late-onset neuropathology after exposures to space radiation. This project uses archived tissues from “middle-aged” male rats and mice exposed to space-relevant fluences of 56Fe particle radiation to investigate the persistence of CNS molecular damage across two rodent species and to assess the relevance to astronauts for behavioral deficits during deep-space missions and for neurological risks after return to Earth. Our research plan is to develop a predictive model of the mechanisms of CNS damage and risks for neuropathology. We propose to build this model using high-complexity, multi-omic measurements (proteomics, untargeted metabolomics, complex lipid metabolomics, and 3’TAGseq transcriptomics) in the cortex and hippocampus within animals for which we have blood in all cases and CSF in many. The predictions of the model for CNS damage and neuropathologies will be linked to molecular changes that can be measured in biofluids, and can be verified in situ in archived tissues. The specific aims are:

Aim 1. Characterize the persistence of radiation-induced molecular abnormalities in cortex and hippocampus after low-dose exposures to 56Fe particles, and compare the predictions for CNS tissue damage and late-onset neuro-pathologies in similarly irradiated mice and rats.

Aim1A will use archived CNS tissue from Sprague Dawley (SD) rats collected at 4 and 9 months after low-dose exposures, and generate new transcriptomics (3’TAGseq) and new metabolomics profiles (untargeted metabolism and targeted complex lipids) from cortex and hippocampus. These data will be integrated with prior proteomics profiles from hippocampus at 9 months after exposure to build a predictive model of CNS tissue damage and risks for neuropathology, with emphasis on vascular and immune abnormalities. Aim1B will compare molecular responses in cortex and hippocampus of mice and rats at 9 months after exposure to evaluate cross-species consistency. The predictive model will be built using integrating bioinformatics and biostatistical approaches.

Aim 2. Identify persistent bio-effect markers in peripheral blood and CSF that correlate with molecular damage in CNS vascular or immune functions.

Aim2A will apply targeted metabolite profiling to search in rat CSF and peripheral blood plasma of the 4-month cohort for metabolites that were found in Aim1 to be associated with CNS vascular and immune abnormalities cortex and hippocampus. Aim2B will investigate selected CSF and plasma bio-effects markers of CNS vascular and immune dysfunction in rats that were characterized for high and low anxiety performance on Elevated Plus Maze after exposure.

The predictive model developed in this project will yield numerous hypotheses of mechanisms of CNS radiation damage that are either common or unique to cortex and hippocampus – these hypotheses will be tested in future studies by in situ analyses of archived frozen tissues and fixed contralateral hemispheres that are available from all animals in this proposal. This project will also provide proof-of-principle whether CNS damage relevant bio-effect metabolites can be detected in CSF and blood. This project will also identify radiation-sensitive pathways, suitable for future development of biological countermeasures to reduce CNS risks from space radiation. The results of this research are designed to help NASA reduce the uncertainty associated with during mission behavior and CNS risk for astronauts on deep space exploration missions.

Bibliography Type: Description: (Last Updated: 02/08/2018) 

Show Cumulative Bibliography Listing
 
 None in FY 2020
Project Title:  Variation in CNS Damage Signaling and Blood Sentinels of Neuropathology After Exposure to Space Radiation Reduce
Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 04/01/2019  
End Date: 03/31/2021  
Task Last Updated: 03/04/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Wyrobek, Andrew  Ph.D. / Lawrence Berkeley National Laboratory 
Address:  1 Cyclotron Rd MS: 74R0157 
 
Berkeley , CA 94720-8099 
Email: ajwyrobek@lbl.gov 
Phone: 925-989-4466  
Congressional District: 13 
Web:  
Organization Type: GOVERNMENT 
Organization Name: Lawrence Berkeley National Laboratory 
Joint Agency:  
Comments: For immediate assistance please contact my administrator Caron LaMarsh clamarsh@lbl.gov, 510.486.5317 
Co-Investigator(s)
Affiliation: 
Peterson, Leif  Ph.D. The Methodist Hospital Research Institute 
Project Information: Grant/Contract No. 80JSC019T0007 
Responsible Center: NASA JSC 
Grant Monitor: Williams, Thomas  
Center Contact: 281-483-8773 
thomas.j.will1@nasa.gov 
Solicitation / Funding Source: 2017 HERO 80JSC017N0001-Crew Health and Performance (FLAGSHIP1, OMNIBUS). Appendix A-Flagship1, Appendix B-Omnibus 
Grant/Contract No.: 80JSC019T0007 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
(2) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
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) 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)
(3) 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)
(4) 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)
(5) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes (IRP Rev L)
(6) CVD-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease (IRP Rev L)
Flight Assignment/Project Notes: NOTE: Period of performance changed to 4/1/2019-3/31/2021 per PI/NASA-LBL interagency agreement; previous information showed 11/28/18-11/27/20 (Ed., 9/5/19)

Task Description: Major objectives of the NASA space radiation research program are to enable human exploration of space without exceeding limits for immediate and persistent risks to the central nervous system (CNS) from space radiation. The proposed research will investigate the CNS subregions of rodents exposed to simulated space radiation for molecular indicators for vascular damage, inflammation, and neurological abnormalities after space radiation. This project will apply multi-omic technologies (proteomics, metabolomics, and bioinformatics) to archived CNS brain subregions from irradiated mouse and rat behavioral models.

The specific aims are:

Aim 1. Characterize the persistence of radiation-induced molecular abnormalities in cortex and hippocampus after low-dose exposures to 56Fe particles, and compare the predictions for CNS tissue damage and late-onset neuropathologies in similarly irradiated mice and rats.

AIM 2. Identify persistent bio-effect markers in peripheral blood and cerebrospinal fluid (CSF) that correlate with molecular damage in CNS vascular or immune functions. Our research plan will provide testable hypotheses of CNS tissue damage and identify molecular targets for susceptible pathways/functions of CNS damage.

This project will also provide proof-of-principle whether CNS damage relevant bio-effect metabolites can be detected in CSF and blood. This project will also identify radiation-sensitive pathways, suitable for future development of biological countermeasures to reduce CNS risks from space radiation. The results of this research are designed to help NASA reduce the uncertainty associated with during mission behavior and CNS risk for astronauts on deep space exploration missions.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2019 
Task Progress: New project for FY2019.

Bibliography Type: Description: (Last Updated: 02/08/2018) 

Show Cumulative Bibliography Listing
 
 None in FY 2019