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Project Title:  Identification of Functional Metabolomic Alterations During the Simulated Spaceflight Environment Reduce
Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 03/04/2016  
End Date: 03/31/2020  
Task Last Updated: 07/14/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Rana, Brinda  Ph.D. / University of California, San Diego 
Address:  Psychiatry 
9500 Gilman Dr, MC-0738 
La Jolla , CA 92093-5004 
Email: bkrana@ucsd.edu 
Phone: 858-822-4010  
Congressional District: 49 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of California, San Diego 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Sharma, Kumar  M.D. University of Texas, San Antonio 
Patel, Hemal H Ph.D. University of California, San Diego 
Vaisar, Tomas  Ph.D. University of Washington 
Hoofnagle, Andy  M.D., Ph.D. University of Washington 
Ziegler, Michael  Ph.D. University of California, San Diego 
Darshi, Manjula  Ph.D. University of Texas, San Antonio 
Macias, Brandon  Ph.D. KBR/NASA Johnson Space Center 
Lee, Stuart  Ph.D. KBR/NASA Johnson Space Center 
Smith, Scott  Ph.D. NASA Johnson Space Center 
Stenger, Michael  Ph.D. NASA Johnson Space Center 
Project Information: Grant/Contract No. NNX16AG03G 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-MIXEDTOPICS. Appendix E: Behavioral Health & Human Health Countermeasures Topics 
Grant/Contract No.: NNX16AG03G 
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) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Arrhythmia:Risk of Cardiac Rhythm Problems
(2) Muscle:Risk of Impaired Performance Due to Reduced Muscle Mass, Strength and Endurance
(3) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight (No longer used, July 2020)
(4) SANS:Risk of Spaceflight Associated Neuro-ocular Syndrome (IRP Rev I)
Human Research Program Gaps: (1) CV08:Can manifestations of sub-clinical or environmentally induced cardiovascular diseases during spaceflight be predicted?
(2) M06:Develop pre-flight and in-flight evaluations to determine if muscle fitness standards are met (IRP Rev F)
(3) Osteo05:We need an inflight capability to monitor bone turnover and bone mass changes during spaceflight (IRP Rev E)
(4) SANS03:We need a set of validated and minimally obtrusive diagnostic tools to measure and monitor changes in intracranial pressure, ocular structure, and ocular function (IRP Rev I)
Flight Assignment/Project Notes: NOTE: End date changed to 3/31/2020 per NSSC information (Ed., 4/6/2020)

NOTE: End date changed to 12/31/2019 per NSSC information (Ed., 12/5/19)

NOTE: End date is now 9/30/2019 per NSSC information (Ed., 3/12/19)

NOTE: End date is now 3/03/2019 per NSSC information (Ed., 6/20/18)

Task Description: The goal of the study was to identify serum and urine biomarkers that can be used to improve risk prediction for physiological manifestations due to bed rest beyond current clinical measures and predictors. To accomplish this goal, we proposed to conduct untargeted and targeted metabolomic assays on urine and plasma samples collected longitudinally throughout a 30 day head down tilt bed rest study with elevated CO2 and follow-up these studies with mitochondrial function assays. Our samples consisted of plasma and 24 hour pooled urine samples from 11 subjects who underwent head down tilt (HDT) bed rest for 30 days at :Envihab.

Research Impact/Earth Benefits: Space Research Related Impact: This study has the potential to identify novel biomarkers in plasma and urine to detect the risk for and monitor the progression of physiological outcomes induced by the spaceflight environment.

Research Impact on Earth: The study has potential to identify the sequence of metabolic events leading to disruption of metabolic pathways in individuals experiencing temporary bed rest (e.g., during pregnancy) or permanent bed rest (e.g., due to aging or disabilities). In the future, countermeasures can be developed to target these pathways.

Assay Development: We are optimizing the application of a high throughput mitochondrial flux assay (Seahorse Assay) to detect circulating factors that can alter changes in mitochondrial function (glycolysis and respiration). This assay can then be applied to investigate environmental factors impacting bioenergetics of different tissue and cells for both Earth and Space related research.

Task Progress & Bibliography Information FY2020 
Task Progress: We analyzed plasma and 24 hour collection urine samples from 11 participants of the VaPER study, a 30 day head down tilt bed rest (HDTBR) study with elevated ambient carbon dioxide that was conducted at :Envihab. We collected plasma samples at 8 timepoints including pre-, during, and post-HDTBR. Mass spectrometry (MS) based targeted and untargeted metabolomics were conducted on plasma and urine samples, followed by mitochondrial respiration assays on the plasma samples utilizing the SeaHorse platform. Our aims were expanded within the budget to include an MS based proteomic investigation of the urine samples. The goal of the study was to identify serum and urine biomarkers that can be used to improve risk prediction for physiological manifestations due to bed rest beyond current clinical measures and predictors.

Bibliography Type: Description: (Last Updated: 07/30/2019) 

Show Cumulative Bibliography Listing
 
 None in FY 2020
Project Title:  Identification of Functional Metabolomic Alterations During the Simulated Spaceflight Environment Reduce
Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 03/04/2016  
End Date: 09/30/2019  
Task Last Updated: 01/25/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Rana, Brinda  Ph.D. / University of California, San Diego 
Address:  Psychiatry 
9500 Gilman Dr, MC-0738 
La Jolla , CA 92093-5004 
Email: bkrana@ucsd.edu 
Phone: 858-822-4010  
Congressional District: 49 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of California, San Diego 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Sharma, Kumar  M.D. University of Texas, San Antonio 
Patel, Hemal H Ph.D. University of California, San Diego 
Vaisar, Tomas  Ph.D. University of Washington 
Hoofnagle, Andy  M.D., Ph.D. University of Washington 
Ziegler, Michael  Ph.D. University of California, San Diego 
Darshi, Manjula  Ph.D. University of Texas, San Antonio 
Macias, Brandon  Ph.D. Wyle Cardiovascular 
Lee, Stuart  Ph.D. Wyle Cardiovascular Lab 
Smith, Scott  Ph.D. NASA Johnson Space Center 
Stenger, Michael  Ph.D. NASA Johnson Space Center 
Key Personnel Changes / Previous PI: January 2019: Drs. Saito and Schilling are no longer working on the project. New CoInvestigators Tomas Vaisar and Andy Hoofnagle from the University of Washington, Seattle were brought into the team to conduct mass spectrometry based proteomics on urine samples. This is a new aim that we have added based on findings from the NASA Twins Study. Dr. Ziegler (UC San Diego) was brought into the team to assist with interpreting the metabolomics results in relation with space physiology. Dr. Darshi was formerly a post-doctoral fellow in Dr. Sharma’s lab; she is now a new investigator and is leading the targeted metabolomics assays for the project.
Project Information: Grant/Contract No. NNX16AG03G 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-MIXEDTOPICS. Appendix E: Behavioral Health & Human Health Countermeasures Topics 
Grant/Contract No.: NNX16AG03G 
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) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Arrhythmia:Risk of Cardiac Rhythm Problems
(2) Muscle:Risk of Impaired Performance Due to Reduced Muscle Mass, Strength and Endurance
(3) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight (No longer used, July 2020)
(4) SANS:Risk of Spaceflight Associated Neuro-ocular Syndrome (IRP Rev I)
Human Research Program Gaps: (1) CV08:Can manifestations of sub-clinical or environmentally induced cardiovascular diseases during spaceflight be predicted?
(2) M06:Develop pre-flight and in-flight evaluations to determine if muscle fitness standards are met (IRP Rev F)
(3) Osteo05:We need an inflight capability to monitor bone turnover and bone mass changes during spaceflight (IRP Rev E)
(4) SANS03:We need a set of validated and minimally obtrusive diagnostic tools to measure and monitor changes in intracranial pressure, ocular structure, and ocular function (IRP Rev I)
Flight Assignment/Project Notes: NOTE: End date is now 9/30/2019 per NSSC information (Ed., 3/12/19)

NOTE: End date is now 3/03/2019 per NSSC information (Ed., 6/20/18)

Task Description: The overall goal of the proposed study is to identify serum and urine biomarkers that can be used to improve risk prediction for physiological manifestations due to bed rest beyond current clinical measures and known predictors. Bed rest is a well-accepted model of spaceflight (simulating microgravity) that allows for the study of a larger number of subjects than is available in spaceflight, and thus is well-suited for more rapid evaluation of countermeasures and identification of potential biomarkers associated with deconditioning and countermeasure efficacy. Our study will focus on three physiological manifestations that are prevalent in crew members on long duration spaceflight and are also observed in bed rest and are the target of countermeasures: (1) altered cardiovascular function and potential sub-clinical manifestations of cardiovascular disease; (2) bone loss and increased fracture risk; and (3) muscle atrophy and decreased muscle strength.

To achieve this goal, we are applying two complementary metabolomics approaches, targeted and untargeted, to serum and urine which were collected longitudinally (2 pre-bed rest; 2 during bed rest; 1 post bed rest) from 29 study participants who underwent a 70-day head down tilt bed rest with or without participation in countermeasures (exercise, N=10; exercise plus testosterone supplement, N=9). Because a number of physiological outcomes of bed rest may be attributed to dysregulation of mitochondrial function (e.g., respiration) and mitochondrial related glycolosis, the targeted aims of our study will focus on mitochondrial related metabolic pathways. The strength of our current proposal is to use a combination of untargeted and targeted metabolomics approaches followed by a state-of-the-art metabolomic flux assay which will characterize the functional consequence of the metabolites on mitochondrial related cellular and physiological pathways involved in the homeostasis of metabolomic function.

Research Impact/Earth Benefits: Space Research Related Impact: This study has the potential to identify novel biomarkers in plasma and urine to detect the risk for and monitor the progression of physiological outcomes induced by the spaceflight environment.

Research Impact on Earth: The study has potential to identify the sequence of metabolic events leading to disruption of metabolic pathways in individuals experiencing temporary bed rest (e.g., during pregnancy) or permanent bed rest (e.g., due to aging or disabilities). In the future, countermeasures can be developed to target these pathways.

Assay Development: We are optimizing the application of a high throughput mitochondrial flux assay (Seahorse Assay) to detect circulating factors that can alter changes in mitochondrial function (glycolysis and respiration). This assay can then be applied to investigate environmental factors impacting bioenergetics of different tissue and cells for both Earth and Space related research.

Task Progress & Bibliography Information FY2019 
Task Progress: We have conducted mass spectrometry based untargeted metabolomics assays for primary metabolism on 24 hour pooled urine samples from 29 study participants undergoing a 70 day head down tilt bed rest study. These subjects are from three study arms: 11 bed rest CONTROL subjects, 10 subjects in the EXERCISE arm of the study, and 8 subjects from the COMBINED EXERCISE AND TESTOSTERONE arm. We chose 7 time points representing pre-, during, and post- bed rest (10 and 6 days before bed rest, days 28 and 69 of bed rest, and after bed rest days 0, 2, and 6). Preliminary data analysis has identified the disruption of multiple metabolic pathways during bed rest including pathways involved in the mitochondria, which supplies cellular energy to cells. In addition, as expected the lactic acid increased after bed rest. We are in the process of conducting statistical analysis to assess the relationship between metabolic changes and the treatment of exercise and testosterone.

We are also in the process of conducting targeted mass spectrometry based metabolomics assays, including a panel of targeted mitochondrial pathway metabolites. These metabolomics studies are being complemented by a study designed to measure whether changes in the milieu of factors circulating in the blood as a result of the simulated space environment and countermeasures may affect cellular metabolism. Using the Seahorse Technology (Agilent) we are determining the impact of plasma on mitochondrial respiration on an established skeletal muscle cell line. By examining the trajectory of mitochondrial respiration of L6 cells treated with plasma obtained from bed rest study participants at pre, during, and post time points, we can understand how the body adapts to physical inactivity (on Earth) or microgravity conditions in space.

Bibliography Type: Description: (Last Updated: 07/30/2019) 

Show Cumulative Bibliography Listing
 
 None in FY 2019
Project Title:  Identification of Functional Metabolomic Alterations During the Simulated Spaceflight Environment Reduce
Fiscal Year: FY 2017 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 03/04/2016  
End Date: 03/03/2019  
Task Last Updated: 02/08/2017 
Download report in PDF pdf
Principal Investigator/Affiliation:   Rana, Brinda  Ph.D. / University of California, San Diego 
Address:  Psychiatry 
9500 Gilman Dr, MC-0738 
La Jolla , CA 92093-5004 
Email: bkrana@ucsd.edu 
Phone: 858-822-4010  
Congressional District: 49 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of California, San Diego 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Patel, Hemal  Ph.D. University of California, San Diego 
Sharma, Kumar  M.D. University of California, San Diego 
Patel, Hemal H Ph.D. University of California, San Diego 
Saito, Rintaro  Ph.D. University of California, San Diego 
Schilling, Jan  Ph.D. University of California, San Diego 
Key Personnel Changes / Previous PI: N/A
Project Information: Grant/Contract No. NNX16AG03G 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-MIXEDTOPICS. Appendix E: Behavioral Health & Human Health Countermeasures Topics 
Grant/Contract No.: NNX16AG03G 
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) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Arrhythmia:Risk of Cardiac Rhythm Problems
(2) Muscle:Risk of Impaired Performance Due to Reduced Muscle Mass, Strength and Endurance
(3) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight (No longer used, July 2020)
(4) SANS:Risk of Spaceflight Associated Neuro-ocular Syndrome (IRP Rev I)
Human Research Program Gaps: (1) CV08:Can manifestations of sub-clinical or environmentally induced cardiovascular diseases during spaceflight be predicted?
(2) M06:Develop pre-flight and in-flight evaluations to determine if muscle fitness standards are met (IRP Rev F)
(3) Osteo05:We need an inflight capability to monitor bone turnover and bone mass changes during spaceflight (IRP Rev E)
(4) SANS03:We need a set of validated and minimally obtrusive diagnostic tools to measure and monitor changes in intracranial pressure, ocular structure, and ocular function (IRP Rev I)
Flight Assignment/Project Notes: NOTE: End date is now 3/03/2019 per NSSC information (Ed., 6/20/18)

Task Description: The goal of this proposal is to identify novel early biomarkers in plasma and urine to detect and monitor the progression of a number of physiological disturbances due to prolonged microgravity and CO2 exposure as experienced by crew members on long duration missions. These physiological manifestations include: (1) Visual Impairment/Intracranial Pressure (VIIP); (2) sub-clinical or environmentally induced cardiovascular disease; (3) muscle atrophy and decreased muscle strength; and (4) bone loss. Targeted and untargeted metabolomics will be applied to plasma and urine collected longitudinally from study participants undergoing a 30 day six-degree head-down bed rest combined with ambient 0.5% CO2. We will follow-up metabolomics with a novel cell-based metabolic mammalian organ system assay ("organs on a plate") to address how these metabolites affect physiological processes at the cellular and organ level. The proposed research will directly address the Integrated Research Plan Gaps including CV8, M6, Osteo5, VIIP3, VIIP13, CNS2.

Research Impact/Earth Benefits: Space Research Related Impact: This study has the potential to identify novel biomarkers in plasma and urine to detect the risk for and monitor the progression of physiological outcomes induced by the spaceflight environment.

Research Impact on Earth: The study has potential to identify the sequence of metabolic events leading to disruption of metabolic pathways in individuals experiencing temporary bed rest (e.g., during pregnancy) or permanent bed rest (e.g., due to aging or disabilities). In the future, countermeasures can be developed to target these pathways.

Assay Development: We are optimizing the application of a high throughput mitochondrial flux assay (Seahorse Assay) to detect circulating factors which can alter changes in mitochondrial function (glycolysis and respiration). This assay can then be applied to investigate environmental factors impacting bioenergetics of different tissue and cells for both Earth and Space related research.

Task Progress & Bibliography Information FY2017 
Task Progress: Results: The bed rest study participants are currently under recruitment by :envihab. In the first year, we have obtained NASA and University of California, San Diego IRB (institutional review board) approval to carry out the proposed study, developed an Integrated Data Sharing Plan, and established the blood collection and transportation protocol with :envihab. Metabolomics assays are established and ready to implement upon arrival of the samples. We currently have 86 targeted metabolomics assays developed as well as the protocol in place for conducting untargeted metabolomics. We have been optimizing the Seahorse Metabolic Flux assay to investigate longitudinal changes in circulating factors which may impact mitochondrial function at the cellular level.

Bibliography Type: Description: (Last Updated: 07/30/2019) 

Show Cumulative Bibliography Listing
 
 None in FY 2017
Project Title:  Identification of Functional Metabolomic Alterations During the Simulated Spaceflight Environment Reduce
Fiscal Year: FY 2016 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 03/04/2016  
End Date: 03/03/2018  
Task Last Updated: 05/12/2016 
Download report in PDF pdf
Principal Investigator/Affiliation:   Rana, Brinda  Ph.D. / University of California, San Diego 
Address:  Psychiatry 
9500 Gilman Dr, MC-0738 
La Jolla , CA 92093-5004 
Email: bkrana@ucsd.edu 
Phone: 858-822-4010  
Congressional District: 49 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of California, San Diego 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Patel, Hemal  Ph.D. University of California, San Diego 
Sharma, Kumar  M.D. University of California, San Diego 
Project Information: Grant/Contract No. NNX16AG03G 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: 2015-16 HERO NNJ15ZSA001N-Crew Health (FLAGSHIP, NSBRI, OMNIBUS). Appendix A-Crew Health, Appendix B-NSBRI, Appendix C-Omnibus 
Grant/Contract No.: NNX16AG03G 
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) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Arrhythmia:Risk of Cardiac Rhythm Problems
(2) Muscle:Risk of Impaired Performance Due to Reduced Muscle Mass, Strength and Endurance
(3) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight (No longer used, July 2020)
(4) SANS:Risk of Spaceflight Associated Neuro-ocular Syndrome (IRP Rev I)
Human Research Program Gaps: (1) CV08:Can manifestations of sub-clinical or environmentally induced cardiovascular diseases during spaceflight be predicted?
(2) M06:Develop pre-flight and in-flight evaluations to determine if muscle fitness standards are met (IRP Rev F)
(3) Osteo05:We need an inflight capability to monitor bone turnover and bone mass changes during spaceflight (IRP Rev E)
(4) SANS03:We need a set of validated and minimally obtrusive diagnostic tools to measure and monitor changes in intracranial pressure, ocular structure, and ocular function (IRP Rev I)
Task Description: The goal of this proposal is to identify novel early biomarkers in plasma and urine to detect and monitor the progression of a number of physiological disturbances due to prolonged microgravity and CO2 exposure as experienced by crew members on long duration missions. These physiological manifestations include: (1) Visual Impairment/Intracranial Pressure (VIIP); (2) sub-clinical or environmentally induced cardiovascular disease; (3) muscle atrophy and decreased muscle strength; and (4) bone loss. Targeted and untargeted metabolomics will be applied to plasma and urine collected longitudinally from study participants undergoing a 30 day six-degree head-down bed rest combined with ambient 0.5% CO2. We will follow-up metabolomics with a novel cell-based metabolic mammalian organ system assay ("organs on a plate") to address how these metabolites affect physiological processes at the cellular and organ level. The proposed research will directly address the Integrated Research Plan Gaps including CV8, M6, Osteo5, VIIP3, VIIP13, CNS2.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2016 
Task Progress: New project for FY2016.

Bibliography Type: Description: (Last Updated: 07/30/2019) 

Show Cumulative Bibliography Listing
 
 None in FY 2016