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Project Title:  Astronaut Vision Issues and One Carbon Metabolism: Expanded Polymorphism Evaluation and Evaluation in a Potential Analog Population Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 04/06/2016  
End Date: 09/30/2022  
Task Last Updated: 01/22/2021 
Download report in PDF pdf
Principal Investigator/Affiliation:   Smith, Scott M Ph.D. / NASA Johnson Space Center 
Address:  Biomedical Research and Environmental Sciences Division/SK3 
2101 NASA Pkwy 
Houston , TX 77058-3607 
Email: scott.m.smith@nasa.gov 
Phone: 281-483-7204  
Congressional District: 36 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Johnson Space Center 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Zwart, Sara  Ph.D. University of Texas Medical Branch 
Chang, Alice  M.D. Mayo Clinic, Rochester, MN 
Gregory, Jesse  Ph.D. University of Florida 
Chen, John  M.D., Ph.D. Mayo Clinic, Rochester, MN 
Zeisel, Steven  M.D., Ph.D. University of North Carolina at Chapel Hill 
Gibson, C. Robert  O.D. Coastal Eye Associates 
Mader, Thomas  M.D. U.S. Army (retired) 
Project Information: Grant/Contract No. Directed Research 
Responsible Center: NASA JSC 
Grant Monitor: Stenger, Michael  
Center Contact: 281-483-1311 
michael.b.stenger@nasa.gov 
Solicitation / Funding Source: Directed Research 
Grant/Contract No.: Directed Research 
Project Type: FLIGHT,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) Food and Nutrition:Risk of Performance Decrement and Crew Illness Due to Inadequate Food and Nutrition (IRP Rev L)
(2) SANS:Risk of Spaceflight Associated Neuro-ocular Syndrome (IRP Rev I)
Human Research Program Gaps: (1) N7.3:We need to identify the most important nutritional factors for ocular health (IRP Rev E)
(2) SANS-202:Determine if genetic/metabolic/anatomic dispositions and biomarkers, and sex differences have a contributing role in the development of ocular manifestations (IRP Rev L)
Flight Assignment/Project Notes: NOTE: End date changed to 9/30/22 per C. Ribeiro/HHC HRP (Ed., 6/30/21)

NOTE: End date changed to 10/01/2021 per PI (Ed., 1/7/21)

NOTE: End date changed to 12/31/2020 per PI (Ed., 1/9/2020)

NOTE: Extended to 4/30/2020 per PI (Ed., 1/28/19)

Task Description: Background

We have documented a genetic predisposition for some astronauts to develop ophthalmologic issues. From a limited study of 5 single-nucleotide polymorphisms (SNPs), we found one SNP associated with a greater risk of ophthalmic findings (e.g., choroidal folds, cotton wool spots), and another SNP that was protective against optic disc edema. In light of these findings, we proposed two studies which were combined in this project. Thus, this project has two major goals:

1. To extend the one-carbon pathway SNP assessment as related to astronaut ophthalmologic findings. (One Carbon Expansion study)

2. To evaluate patients with polycystic ovary syndrome (PCOS) and/or Idiopathic intracranial hypertension (IIH) to assess one-carbon biochemistry and genetics and their possible correlation with ophthalmologic findings. (PCOS study)

While these studies alone will not identify the mechanism(s) of astronaut ophthalmologic issues, we aim to clarify the genetic relationship to ophthalmic findings, and to document the utility of PCOS as a clinical population that could be used for studies that may ultimately allow for the definition of the mechanism of and means to prevent or treat these potentially vision-threatening processes in astronauts.

Specific Aims

The study has the following specific aims:

1. Test for multiple SNPs of the 85 major genes involved in one-carbon metabolism in ISS (International Space Station) crewmembers (a total of 523 SNPs), and relate these data to existing one-carbon biochemistry and metabolomic data, along with existing vision and related medical data.

2. Compare the same one-carbon metabolism genetics and biochemistry and ophthalmologic data from patients in one of four treatment groups:

i. women diagnosed with PCOS without IIH

ii. women diagnosed with PCOS and IIH

iii. women diagnosed with IIH without PCOS

iv. controls (neither PCOS nor IIH)

Rationale for HRP Directed Research: This research is directed because it contains highly constrained research. This study has two major goals: 1. To utilize existing samples where possible to extend the scope of the initial One Carbon study. This was initially submitted and reviewed in the NNJ14ZSA001N-OMNIBUS NRA. HRP Management has now asked we submit this as directed research. 2. To add testing to an ongoing clinical trial at the Mayo Clinic. Timing is critical given that study is ongoing. The primary study is a clinical trial of pharmaceutical treatment for PCOS. We propose to extend this study by collecting a blood sample for one carbon biochemical and genetic testing, along with ophthalmologic exams, with the aim of documenting the utility of this population as an analog group for future VIIP research.

Research Impact/Earth Benefits: While much research is in progress to understand vision issues in astronauts, a key question remains as to why only some individuals are affected. Our preliminary data suggest that some individuals may have a genetic predisposition for vision issues, related to one-carbon metabolism. Our initial study was intentionally constrained given our concerns about it being the first study involving individual genetic testing at NASA. In light of the crewmember response to that study (>97% participation) and the initial findings from that effort, we now propose to evaluate a wider range of one-carbon metabolism SNPs, to help clarify and verify that one-carbon metabolism is indeed the source of this effect, and to identify possible associations with ethnicity. The results of this study could be profound, and may have significant implications for the direction of NASA vision countermeasure research, for operational decisions regarding treatment of affected astronauts, and for informing the general medical and scientific communities, where research is ongoing to understand the role of one-carbon metabolism genetics in other cerebrovascular issues.

Task Progress & Bibliography Information FY2021 
Task Progress: One Carbon Expansion data analysis is underway.

PCOS (polycystic ovary syndrome) Study-- recruitment was halted due to the pandemic, and sample and data analysis are underway.

Bibliography Type: Description: (Last Updated: 05/25/2021)  Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Patel ZS, Brunstetter TJ, Tarver WJ, Whitmire AM, Zwart SR, Smith SM, Huff JL. "Red risks for a journey to the red planet: the highest priority human health risks for a mission to Mars." NPJ Microgravity. 2020 Nov 5;6(1):33. https://doi.org/10.1038/s41526-020-00124-6 ; PMID: 33298950; PMCID: PMC7645687 , Nov-2020
Articles in Peer-reviewed Journals Shelhamer M, Bloomberg J, LeBlanc A, Prisk GK, Sibonga J, Smith SM, Zwart SR, Norsk P. "Selected discoveries from human research in space that are relevant to human health on Earth." npj Microgravity. 2020 Feb 12;6(1):5. https://doi.org/10.1038/s41526-020-0095-y ; PMID: 32128361; PMCID: PMC7016134 , Feb-2020
Project Title:  Astronaut Vision Issues and One Carbon Metabolism: Expanded Polymorphism Evaluation and Evaluation in a Potential Analog Population Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 04/06/2016  
End Date: 12/31/2020  
Task Last Updated: 01/23/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Smith, Scott M Ph.D. / NASA Johnson Space Center 
Address:  Biomedical Research and Environmental Sciences Division/SK3 
2101 NASA Pkwy 
Houston , TX 77058-3607 
Email: scott.m.smith@nasa.gov 
Phone: 281-483-7204  
Congressional District: 36 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Johnson Space Center 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Zwart, Sara  Ph.D. University of Texas Medical Branch 
Chang, Alice  M.D. Mayo Clinic, Rochester, MN 
Gregory, Jesse  Ph.D. University of Florida 
Chen, John  M.D., Ph.D. Mayo Clinic, Rochester, MN 
Zeisel, Steven  M.D., Ph.D. University of North Carolina at Chapel Hill 
Gibson, C. Robert  O.D. Coastal Eye Associates 
Mader, Thomas  M.D. U.S. Army (retired) 
Project Information: Grant/Contract No. Directed Research 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: Directed Research 
Grant/Contract No.: Directed Research 
Project Type: FLIGHT,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) Food and Nutrition:Risk of Performance Decrement and Crew Illness Due to Inadequate Food and Nutrition (IRP Rev L)
(2) SANS:Risk of Spaceflight Associated Neuro-ocular Syndrome (IRP Rev I)
Human Research Program Gaps: (1) N7.3:We need to identify the most important nutritional factors for ocular health (IRP Rev E)
(2) SANS-202:Determine if genetic/metabolic/anatomic dispositions and biomarkers, and sex differences have a contributing role in the development of ocular manifestations (IRP Rev L)
Flight Assignment/Project Notes: NOTE: End date changed to 12/31/2020 per PI (Ed., 1/9/2020)

NOTE: Extended to 4/30/2020 per PI (Ed., 1/28/19)

Task Description: Background

We have documented a genetic predisposition for some astronauts to develop ophthalmologic issues. From a limited study of 5 single-nucleotide polymorphisms (SNPs), we found one SNP associated with a greater risk of ophthalmic findings (e.g., choroidal folds, cotton wool spots), and another SNP that was protective against optic disc edema. In light of these findings, we proposed two studies which were combined in this project. Thus, this project has two major goals:

1. To extend the one-carbon pathway SNP assessment as related to astronaut ophthalmologic findings. (One Carbon Expansion study)

2. To evaluate patients with polycystic ovary syndrome (PCOS) and/or Idiopathic intracranial hypertension (IIH) to assess one-carbon biochemistry and genetics and their possible correlation with ophthalmologic findings. (PCOS study)

While these studies alone will not identify the mechanism(s) of astronaut ophthalmologic issues, we aim to clarify the genetic relationship to ophthalmic findings, and to document the utility of PCOS as a clinical population that could be used for studies that may ultimately allow for the definition of the mechanism of and means to prevent or treat these potentially vision-threatening processes in astronauts.

Specific Aims

The study has the following specific aims:

1. Test for multiple SNPs of the 85 major genes involved in one-carbon metabolism in ISS (International Space Station) crewmembers (a total of 523 SNPs), and relate these data to existing one-carbon biochemistry and metabolomic data, along with existing vision and related medical data.

2. Compare the same one-carbon metabolism genetics and biochemistry and ophthalmologic data from patients in one of four treatment groups:

i. women diagnosed with PCOS without IIH

ii. women diagnosed with PCOS and IIH

iii. women diagnosed with IIH without PCOS

iv. controls (neither PCOS nor IIH)

Rationale for HRP Directed Research: This research is directed because it contains highly constrained research. This study has two major goals: 1. To utilize existing samples where possible to extend the scope of the initial One Carbon study. This was initially submitted and reviewed in the NNJ14ZSA001N-OMNIBUS NRA. HRP Management has now asked we submit this as directed research. 2. To add testing to an ongoing clinical trial at the Mayo Clinic. Timing is critical given that study is ongoing. The primary study is a clinical trial of pharmaceutical treatment for PCOS. We propose to extend this study by collecting a blood sample for one carbon biochemical and genetic testing, along with ophthalmologic exams, with the aim of documenting the utility of this population as an analog group for future VIIP research.

Research Impact/Earth Benefits: While much research is in progress to understand vision issues in astronauts, a key question remains as to why only some individuals are affected. Our preliminary data suggest that some individuals may have a genetic predisposition for vision issues, related to one-carbon metabolism. Our initial study was intentionally constrained given our concerns about it being the first study involving individual genetic testing at NASA. In light of the crewmember response to that study (>97% participation) and the initial findings from that effort, we now propose to evaluate a wider range of one-carbon metabolism SNPs, to help clarify and verify that one-carbon metabolism is indeed the source of this effect, and to identify possible associations with ethnicity. The results of this study could be profound, and may have significant implications for the direction of NASA vision countermeasure research, for operational decisions regarding treatment of affected astronauts, and for informing the general medical and scientific communities, where research is ongoing to understand the role of one-carbon metabolism genetics in other cerebrovascular issues.

Task Progress & Bibliography Information FY2020 
Task Progress: We continue with subject recruitment for both studies, and are nearing completion. Sample analysis has been initiated, and for the flight study, initial data analysis is underway. A spin off study examining data from a bed rest study in Germany (VaPER) was published. The Twins Study was also published, which included data related to the One Carbon Study [Ed. note: Twins Study article in Science was reported in FY2019 report].

Bibliography Type: Description: (Last Updated: 05/25/2021)  Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Zwart SR, Laurie SS, Chen J, Macias B, Lee SMC, Stenger M, Grantham B, Carey K, Young M, Smith SM. "Association of genetics and B vitamin status with magnitude of optic disc edema during 30-day strict head-down tilt bed rest." JAMA Ophthalmology. 2019;137(10):1195-200. https://doi.org/10.1001/jamaophthalmol.2019.3124 ; PubMed PMID: 31415055; PubMed Central PMCID: PMC6696878 , Oct-2019
Project Title:  Astronaut Vision Issues and One Carbon Metabolism: Expanded Polymorphism Evaluation and Evaluation in a Potential Analog Population Reduce
Images: icon  Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 04/06/2016  
End Date: 04/30/2020  
Task Last Updated: 03/04/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Smith, Scott M Ph.D. / NASA Johnson Space Center 
Address:  Biomedical Research and Environmental Sciences Division/SK3 
2101 NASA Pkwy 
Houston , TX 77058-3607 
Email: scott.m.smith@nasa.gov 
Phone: 281-483-7204  
Congressional District: 36 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Johnson Space Center 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Zwart, Sara  Ph.D. University of Texas Medical Branch 
Chang, Alice  M.D. Mayo Clinic, Rochester, MN 
Gregory, Jesse  Ph.D. University of Florida 
Chen, John  M.D., Ph.D. Mayo Clinic, Rochester, MN 
Zeisel, Steven  M.D., Ph.D. University of North Carolina at Chapel Hill 
Gibson, C. Robert  O.D. Coastal Eye Associates 
Mader, Thomas  M.D. U.S. Army (retired) 
Project Information: Grant/Contract No. Directed Research 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: Directed Research 
Grant/Contract No.: Directed Research 
Project Type: FLIGHT,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) Food and Nutrition:Risk of Performance Decrement and Crew Illness Due to Inadequate Food and Nutrition (IRP Rev L)
(2) SANS:Risk of Spaceflight Associated Neuro-ocular Syndrome (IRP Rev I)
Human Research Program Gaps: (1) N7.3:We need to identify the most important nutritional factors for ocular health (IRP Rev E)
(2) SANS-202:Determine if genetic/metabolic/anatomic dispositions and biomarkers, and sex differences have a contributing role in the development of ocular manifestations (IRP Rev L)
Flight Assignment/Project Notes: NOTE: Extended to 4/30/2020 per PI (Ed., 1/28/19)

Task Description: Background

We have documented a genetic predisposition for some astronauts to develop ophthalmologic issues. From a limited study of 5 single-nucleotide polymorphisms (SNPs), we found one SNP associated with a greater risk of ophthalmic findings (e.g., choroidal folds, cotton wool spots), and another SNP that was protective against optic disc edema. In light of these findings, we proposed two studies which were combined in this project. Thus, this project has two major goals:

1. To extend the one-carbon pathway SNP assessment as related to astronaut ophthalmologic findings. (One Carbon Expansion study)

2. To evaluate patients with polycystic ovary syndrome (PCOS) and/or Idiopathic intracranial hypertension (IIH) to assess one-carbon biochemistry and genetics and their possible correlation with ophthalmologic findings. (PCOS study)

While these studies alone will not identify the mechanism(s) of astronaut ophthalmologic issues, we aim to clarify the genetic relationship to ophthalmic findings, and to document the utility of PCOS as a clinical population that could be used for studies that may ultimately allow for the definition of the mechanism of and means to prevent or treat these potentially vision-threatening processes in astronauts.

Specific Aims

The study has the following specific aims:

1. Test for multiple SNPs of the 85 major genes involved in one-carbon metabolism in ISS (International Space Station) crewmembers (a total of 523 SNPs), and relate these data to existing one-carbon biochemistry and metabolomic data, along with existing vision and related medical data.

2. Compare the same one-carbon metabolism genetics and biochemistry and ophthalmologic data from patients in one of four treatment groups:

i. women diagnosed with PCOS without IIH

ii. women diagnosed with PCOS and IIH

iii. women diagnosed with IIH without PCOS

iv. controls (neither PCOS nor IIH)

Rationale for HRP Directed Research: This research is directed because it contains highly constrained research. This study has two major goals: 1. To utilize existing samples where possible to extend the scope of the initial One Carbon study. This was initially submitted and reviewed in the NNJ14ZSA001N-OMNIBUS NRA. HRP Management has now asked we submit this as directed research. 2. To add testing to an ongoing clinical trial at the Mayo Clinic. Timing is critical given that study is ongoing. The primary study is a clinical trial of pharmaceutical treatment for PCOS. We propose to extend this study by collecting a blood sample for one carbon biochemical and genetic testing, along with ophthalmologic exams, with the aim of documenting the utility of this population as an analog group for future VIIP research.

Research Impact/Earth Benefits: While much research is in progress to understand vision issues in astronauts, a key question remains as to why only some individuals are affected. Our preliminary data suggest that some individuals may have a genetic predisposition for vision issues, related to one-carbon metabolism. Our initial study was intentionally constrained given our concerns about it being the first study involving individual genetic testing at NASA. In light of the crewmember response to that study (>97% participation) and the initial findings from that effort, we now propose to evaluate a wider range of one-carbon metabolism SNPs, to help clarify and verify that one-carbon metabolism is indeed the source of this effect, and to identify possible associations with ethnicity. The results of this study could be profound, and may have significant implications for the direction of NASA vision countermeasure research, for operational decisions regarding treatment of affected astronauts, and for informing the general medical and scientific communities, where research is ongoing to understand the role of one-carbon metabolism genetics in other cerebrovascular issues.

Task Progress & Bibliography Information FY2019 
Task Progress: Both projects continue to proceed, albeit slowly. Subject recruitment for both projects continues, and initial analyses have been conducted. In FY19, we begin data analysis with initial findings, with more complete work to be completed in FY20. One carbon study findings were also included in the Twins Study reporting.

Bibliography Type: Description: (Last Updated: 05/25/2021)  Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Garrett-Bakelman FE, Darshi M, Green SJ, Gur RC, Lin L, Macias BR, McKenna MJ, Meydan C, Mishra T, Nasrini J, Piening BD, Rizzardi LF, Sharma K, Siamwala JH, Taylor L, Vitaterna MH, Afkarian M, Afshinnekoo E, Ahadi S, Ambati A, Arya M, Bezdan D, Callahan CM, Chen S, Choi A, Chlipala GE, Contrepois KP, Covington M, Crucian BE, De Vivo I, Dinges DF, Ebert DJ, Feinberg J, Gandara J, George K, Goutsias J, Grills GS, Hargens AR, Heer M, Hillary RP, Hoofnagle AN, Hook VYH, Jenkinson G, Jiang P, Keshavarzian A, Laurie SS, Lee-McMullen B, Lumpkins S, Maienschein-Cline MG, MacKay M, Melnick A, Moore TM, Nakahira K, Patel HH, Pietrzyk R, Rao V, Saito R, Salins D, Schilling JM, Sears DD, Sheridan C, Stenger MB, Tryggvadottir R, Urban AE, Vaisar T, Van Espen B, Zhang J, Ziegler MG, Zwart SR, Charles JB, Kundrot C, Scott G, Bailey SM, Basner M, Feinberg AP, Lee SMC, Mason CE, Mignot E, Rana BK, Smith SM, Snyder M, Turek FW. "The NASA Twins Study: A multi-dimensional analysis of a year-long human spaceflight." Science. 2019 Apr 12;364(6436):eaau8650. https://science.sciencemag.org/content/364/6436/eaau8650 ; PubMed PMID: 30975860 , Apr-2019
Articles in Peer-reviewed Journals Smith SM, Zwart SR. "Spaceflight-related ocular changes: the potential role of genetics, and the potential of B vitamins as a countermeasure." Curr Opin Clin Nutr Metab Care. 2018 Nov;21(6):481-8. https://doi.org/10.1097/MCO.0000000000000510 ; PubMed PMID: 30169456 , Nov-2018
Project Title:  Astronaut Vision Issues and One Carbon Metabolism: Expanded Polymorphism Evaluation and Evaluation in a Potential Analog Population Reduce
Images: icon  Fiscal Year: FY 2018 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 04/06/2016  
End Date: 04/30/2020  
Task Last Updated: 01/29/2018 
Download report in PDF pdf
Principal Investigator/Affiliation:   Smith, Scott M Ph.D. / NASA Johnson Space Center 
Address:  Biomedical Research and Environmental Sciences Division/SK3 
2101 NASA Pkwy 
Houston , TX 77058-3607 
Email: scott.m.smith@nasa.gov 
Phone: 281-483-7204  
Congressional District: 36 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Johnson Space Center 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Zwart, Sara  Ph.D. University of Texas Medical Branch 
Chang, Alice  M.D. Mayo Clinic, Rochester, MN 
Gregory, Jesse  Ph.D. University of Florida 
Chen, John  M.D., Ph.D. Mayo Clinic, Rochester, MN 
Zeisel, Steven  M.D., Ph.D. University of North Carolina at Chapel Hill 
Gibson, C. Robert  O.D. Coastal Eye Associates 
Mader, Thomas  M.D. U.S. Army (retired) 
Project Information: Grant/Contract No. Directed Research 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: Directed Research 
Grant/Contract No.: Directed Research 
Project Type: FLIGHT,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) Food and Nutrition:Risk of Performance Decrement and Crew Illness Due to Inadequate Food and Nutrition (IRP Rev L)
(2) SANS:Risk of Spaceflight Associated Neuro-ocular Syndrome (IRP Rev I)
Human Research Program Gaps: (1) N7.3:We need to identify the most important nutritional factors for ocular health (IRP Rev E)
(2) SANS-202:Determine if genetic/metabolic/anatomic dispositions and biomarkers, and sex differences have a contributing role in the development of ocular manifestations (IRP Rev L)
Flight Assignment/Project Notes: NOTE: Extended to 4/30/2020 per PI (Ed., 1/28/19)

Task Description: Background

We have documented a genetic predisposition for some astronauts to develop ophthalmologic issues. From a limited study of 5 single-nucleotide polymorphisms (SNPs), we found one SNP associated with a greater risk of ophthalmic findings (e.g., choroidal folds, cotton wool spots), and another SNP that was protective against optic disc edema. In light of these findings, we proposed two studies which were combined in this project. Thus, this project has two major goals:

1. To extend the one-carbon pathway SNP assessment as related to astronaut ophthalmologic findings. (One Carbon Expansion study)

2. To evaluate patients with polycystic ovary syndrome (PCOS) and/or Idiopathic intracranial hypertension (IIH) to assess one-carbon biochemistry and genetics and their possible correlation with ophthalmologic findings. (PCOS study)

While these studies alone will not identify the mechanism(s) of astronaut ophthalmologic issues, we aim to clarify the genetic relationship to ophthalmic findings, and to document the utility of PCOS as a clinical population that could be used for studies that may ultimately allow for the definition of the mechanism of and means to prevent or treat these potentially vision- threatening processes in astronauts.

Specific Aims

The study has the following specific aims:

1. Test for multiple SNPs of the 85 major genes involved in one-carbon metabolism in ISS (International Space Station) crewmembers (a total of 523 SNPs), and relate these data to existing one-carbon biochemistry and metabolomic data, along with existing vision and related medical data.

2. Compare the same one-carbon metabolism genetics and biochemistry and ophthalmologic data from patients in one of four treatment groups:

i. women diagnosed with PCOS without IIH

ii. women diagnosed with PCOS and IIH

iii. women diagnosed with IIH without PCOS

iv. controls (neither PCOS nor IIH)

Rationale for HRP Directed Research: This research is directed because it contains highly constrained research. This study has two major goals: 1. To utilize existing samples where possible to extend the scope of the initial One Carbon study. This was initially submitted and reviewed in the NNJ14ZSA001N-OMNIBUS NRA. HRP Management has now asked we submit this as directed research. 2. To add testing to an ongoing clinical trial at the Mayo Clinic. Timing is critical given that study is ongoing. The primary study is a clinical trial of pharmaceutical treatment for PCOS. We propose to extend this study by collecting a blood sample for one carbon biochemical and genetic testing, along with ophthalmologic exams, with the aim of documenting the utility of this population as an analog group for future VIIP research.

Research Impact/Earth Benefits: While much research is in progress to understand vision issues in astronauts, a key question remains as to why only some individuals are affected. Our preliminary data suggest that some individuals may have a genetic predisposition for vision issues, related to one-carbon metabolism. Our initial study was intentionally constrained given our concerns about it being the first study involving individual genetic testing at NASA. In light of the crewmember response to that study (>97% participation) and the initial findings from that effort, we now propose to evaluate a wider range of one-carbon metabolism SNPs, to help clarify and verify that one-carbon metabolism is indeed the source of this effect, and to identify possible associations with ethnicity. The results of this study could be profound, and may have significant implications for the direction of NASA vision countermeasure research, for operational decisions regarding treatment of affected astronauts, and for informing the general medical and scientific communities, where research is ongoing to understand the role of one-carbon metabolism genetics in other cerebrovascular issues.

Task Progress & Bibliography Information FY2018 
Task Progress: For the 1Carbon Expansion effort, crewmember consenting was initiated in May 2017 and continues.

For the PCOS study, subject recruitment and screening was initiated in November 2016. As of January 2018, 25 subjects have completed sample and data collection, 4 more are enrolled, and 28 have passed the pre-screening. Recruitment and sample/data collection continues. The first batch of sample analysis for both studies is planned for spring 2018.

Bibliography Type: Description: (Last Updated: 05/25/2021)  Show Cumulative Bibliography Listing
 
Articles in Other Journals or Periodicals Smith SM, Zwart SR. "Genetics, vitamins, and astronaut eyes." Retina Specialist. 2017 Nov:32-5. http://www.retina-specialist.com/article/genetics-vitamins-and-astronaut-eyes , Nov-2017
Articles in Peer-reviewed Journals Zwart SR, Gibson CR, Gregory JF, Mader TH, Stover PJ, Zeisel SH, Smith SM. "Astronaut ophthalmic syndrome." FASEB J. 2017 Sep;31(9):3746-56. Epub 2017 May 25. https://doi.org/10.1096/fj.201700294 ; PubMed PMID: 28546443 , Sep-2017
Articles in Peer-reviewed Journals Laurie SS, Vizzeri G, Taibbi G, Ferguson CR, Hu X, Lee SMC, Ploutz-Snyder R, Smith SM, Zwart SR, Stenger MB. "Effects of short-term mild hypercapnia during head-down tilt on intracranial pressure and ocular structures in healthy human subjects." Physiological Reports. 2017 Jun;5(11). https://doi.org/10.14814/phy2.13302 ; PubMed PMID: 28611153; PubMed Central PMCID: PMC5471441 , Jun-2017
Journal/Magazine covers Smith SM, Zwart SR. "Cover highlight of article 'Genetics, vitamins, and astronaut eyes.' " Retina Specialist. 2017 Nov:32-5. http://www.retina-specialist.com/article/genetics-vitamins-and-astronaut-eyes , Nov-2017
Journal/Magazine covers Zwart SR, Gibson CR, Gregory JF, Mader TH, Stover PJ, Zeisel SH, Smith SM. "Journal cover including figure from paper for article 'Astronaut ophthalmic syndrome.' " FASEB J. 2017 Sep;31(9):3746-56. http://www.fasebj.org/doi/abs/10.1096/fj.201700294?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed ; PubMed PMID: 28546443 , Sep-2017
Significant Media Coverage Laurie et al. American Physiological Society. "APS Press release for CO2 study: Laurie SS, Vizzeri G, Taibbi G, Ferguson CR, Hu X, Lee SMC, Ploutz-Snyder R, Smith SM, Zwart SR, Stenger MB. Effects of short-term mild hypercapnia during head-down tilt on intracranial pressure and ocular structures in healthy human subjects. Physiol Rep. 2017 Jun;5(11):e13302." American Physiological Society press release highlighting article, June 29, 2017. http://www.the-aps.org/mm/hp/Audiences/Public-Press/2017/36.html ; https://www.sciencedaily.com/releases/2017/06/170630090354.htm , Sep-2017
Project Title:  Astronaut Vision Issues and One Carbon Metabolism: Expanded Polymorphism Evaluation and Evaluation in a Potential Analog Population Reduce
Images: icon  Fiscal Year: FY 2017 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 04/06/2016  
End Date: 04/30/2019  
Task Last Updated: 01/11/2017 
Download report in PDF pdf
Principal Investigator/Affiliation:   Smith, Scott M Ph.D. / NASA Johnson Space Center 
Address:  Biomedical Research and Environmental Sciences Division/SK3 
2101 NASA Pkwy 
Houston , TX 77058-3607 
Email: scott.m.smith@nasa.gov 
Phone: 281-483-7204  
Congressional District: 36 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Johnson Space Center 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Zwart, Sara  University of Texas Medical Branch 
Chang, Alice  M.D. Mayo Clinic, Rochester, MN 
Gregory, Jesse  University of Florida 
Chen, John  Mayo Clinic, Rochester, MN 
Zeisel, Steven  University of North Carolina at Chapel Hill 
Gibson, C. Robert  O.D. Coastal Eye Associates 
Mader, Thomas  M.D. U.S. Army (retired) 
Project Information: Grant/Contract No. Directed Research 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: Directed Research 
Grant/Contract No.: Directed Research 
Project Type: FLIGHT,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) Food and Nutrition:Risk of Performance Decrement and Crew Illness Due to Inadequate Food and Nutrition (IRP Rev L)
(2) SANS:Risk of Spaceflight Associated Neuro-ocular Syndrome (IRP Rev I)
Human Research Program Gaps: (1) N7.3:We need to identify the most important nutritional factors for ocular health (IRP Rev E)
(2) SANS-202:Determine if genetic/metabolic/anatomic dispositions and biomarkers, and sex differences have a contributing role in the development of ocular manifestations (IRP Rev L)
Task Description: 1. We have documented a genetic predisposition for some astronauts to develop ophthalmologic findings as described in 2011 by NASA’s Space Medicine Division (1) known as VIIP (vision impairment/intracranial pressure). From a limited study of 5 single-nucleotide polymorphisms (SNPs), we found one SNP associated with a greater risk of ophthalmic findings (e.g., choroidal folds, cotton wool spots), and another SNP that was protective against optic disc edema. In light of these findings, we propose to evaluate a wider range of SNPs from the same metabolic pathway, to clarify and verify the relationship of genetics in some astronauts that may predispose to ophthalmic anomalies. Furthermore, we have identified a clinical population -- patients with polycystic ovary syndrome (PCOS) -- with several characteristics similar to those described in astronauts. The clinical findings shared by PCOS patients and astronauts with ophthalmic anomalies include higher homocysteine, increased retinal nerve fiber layer, increased incidence of white matter hyperintensities on MRI, increased androgen concentrations (or responses), and altered carbohydrate metabolism. PCOS patients have not been evaluated in detail regarding the occurrence of other anomalies observed in astronauts including choroidal folds, optic disc edema, and cotton wool spots as well as changes in cycloplegic refraction, and optic nerve sheath diameter. While researchers have evaluated one-carbon metabolism pathway polymorphisms re: PCOS, and initial studies show an association with certain one-carbon polymorphisms, none have looked at the complete set of SNPs we propose here. Thus, this study has two major goals: 1. To extend the one-carbon pathway SNP assessment as related to astronaut ophthalmologic findings. 2. To evaluate patients with PCOS and/or Idiopathic intracranial hypertension (IIH) to assess one-carbon biochemistry and genetics and their possible correlation with ophthalmologic findings. While these studies alone will not identify the mechanism(s) of VIIP, we aim to clarify the genetic relationship to ophthalmic findings, and to document the utility of PCOS as a clinical population that could be used for studies that may ultimately allow for the definition of the mechanism of and means to prevent or treat these potentially vision-threatening processes in astronauts.

Specific Aims

1. Test for multiple SNPs of the 85 major genes involved in one-carbon metabolism in ISS (International Space Station) crewmembers (a total of 523 SNPs), and relate these data to existing one-carbon biochemistry and metabolomic data, along with existing vision and related medical data.

a. A secondary aim is to gather ethnicity data from the crewmembers, and characterize the extent to which ethnicity is predictive of ophthalmic issues after long-duration space flight.

b. Another secondary aim is to evaluate the data collected in this (and the initial) one carbon metabolism genetics studies and cardiovascular data. To this end, we will request VO2 max (pre, in, post), Framingham Risk Score, resting heart rate and blood pressure (pre, in, post) diastolic and systolic, exercise heart rate and blood pressure (pre, in, post) diastolic and systolic, Vascular Compliance data share (heart rate, blood pressure, cardiac output and stroke volume), medications, diagnoses, BMI, and % body fat data from the Lifetime Surveillance of Astronaut Health project for evaluation relative to the one carbon genetic and biochemical data.

2. Compare the same one-carbon metabolism genetics and biochemistry and ophthalmologic data from patients in one of four treatment groups:

i. women diagnosed with PCOS without IIH

ii. women diagnosed with PCOS and IIH

iii. women diagnosed with IIH without PCOS

iv. controls (neither PCOS nor IIH)

Subjects will be matched by age and body mass index (BMI). Statistical analyses will be used to evaluate the independent and shared contributions of age, body mass (BMI), and genetics on biochemical, and ophthalmologic outcomes, with False Discovery Rate adjustments to account for multiple comparisons.

3. A secondary aim is to combine the patient and control data from this study with ISS crewmember data in order to help inform us on whether or not these two cohorts (VIIP, PCOS) share similar associations among one-carbon metabolism genetics and biochemistry and ophthalmologic data identified in our earlier analyses.

Rationale for HRP Directed Research: This research is directed because it contains highly constrained research. This study has two major goals: 1. To utilize existing samples where possible to extend the scope of the initial One Carbon study. This was initially submitted and reviewed in the NNJ14ZSA001N-OMNIBUS NRA. HRP Management has now asked we submit this as directed research. 2. To add testing to an ongoing clinical trial at the Mayo Clinic. Timing is critical given that study is ongoing. The primary study is a clinical trial of pharmaceutical treatment for PCOS. We propose to extend this study by collecting a blood sample for one carbon biochemical and genetic testing, along with ophthalmologic exams, with the aim of documenting the utility of this population as an analog group for future VIIP research.

Research Impact/Earth Benefits: While much research is in progress to understand vision issues in astronauts, a key question remains as to why only some individuals are affected. Our preliminary data suggest that some individuals may have a genetic predisposition for vision issues, related to one-carbon metabolism. Our initial study was intentionally constrained given our concerns about it being the first study involving individual genetic testing at NASA. In light of the crewmember response to that study (>97% participation) and the initial findings from that effort, we now propose to evaluate a wider range of one-carbon metabolism SNPs, to help clarify and verify that one-carbon metabolism is indeed the source of this effect, and to identify possible associations with ethnicity. The results of this study could be profound, and may have significant implications for the direction of NASA vision countermeasure research, for operational decisions regarding treatment of affected astronauts, and for informing the general medical and scientific communities, where research is ongoing to understand the role of one-carbon metabolism genetics in other cerebrovascular issues.

Task Progress & Bibliography Information FY2017 
Task Progress: For the flight study: we have obtained IRB (Institutional Review Board) approval, and Human Research Program (HRP) select for flight approval. We are currently waiting for International Space Station Medical Projects (ISSMP) element to determine if we can consent crewmembers by email.

For the PCOS study: we obtained IRB approvals at Johnson Space Center (JSC) and Mayo Clinic. Subject recruitment, screening, and data collection have been initiated.

Bibliography Type: Description: (Last Updated: 05/25/2021)  Show Cumulative Bibliography Listing
 
 None in FY 2017
Project Title:  Astronaut Vision Issues and One Carbon Metabolism: Expanded Polymorphism Evaluation and Evaluation in a Potential Analog Population Reduce
Images: icon  Fiscal Year: FY 2016 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 04/06/2016  
End Date: 04/30/2019  
Task Last Updated: 06/09/2016 
Download report in PDF pdf
Principal Investigator/Affiliation:   Smith, Scott M Ph.D. / NASA Johnson Space Center 
Address:  Biomedical Research and Environmental Sciences Division/SK3 
2101 NASA Pkwy 
Houston , TX 77058-3607 
Email: scott.m.smith@nasa.gov 
Phone: 281-483-7204  
Congressional District: 36 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Johnson Space Center 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Zwart, Sarah  Ph.D. Universities Space Research Association 
Chang, Alice  M.D. Mayo Clinic, Rochester, MN 
Gregory, Jesse  Ph.D. University of Florida 
Chen, John  M.D., Ph.D. Mayo Clinic, Rochester, MN 
Zeisel, Steven  M.D., Ph.D. University of North Carolina at Kannapolis 
Gibson, C. Robert  O.D. Coastal Eye Associates 
Mader, Thomas  M.D. U.S. Army (retired) 
Project Information: Grant/Contract No. Directed Research 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: Directed Research 
Grant/Contract No.: Directed Research 
Project Type: FLIGHT,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) Food and Nutrition:Risk of Performance Decrement and Crew Illness Due to Inadequate Food and Nutrition (IRP Rev L)
(2) SANS:Risk of Spaceflight Associated Neuro-ocular Syndrome (IRP Rev I)
Human Research Program Gaps: (1) N7.3:We need to identify the most important nutritional factors for ocular health (IRP Rev E)
(2) SANS-202:Determine if genetic/metabolic/anatomic dispositions and biomarkers, and sex differences have a contributing role in the development of ocular manifestations (IRP Rev L)
Task Description: 1. We have documented a genetic predisposition for some astronauts to develop ophthalmologic findings as described in 2011 by NASA’s Space Medicine Division (1) known as VIIP (vision impairment/intracranial pressure). From a limited study of 5 single-nucleotide polymorphisms (SNPs), we found one SNP associated with a greater risk of ophthalmic findings (e.g., choroidal folds, cotton wool spots), and another SNP that was protective against optic disc edema. In light of these findings, we propose to evaluate a wider range of SNPs from the same metabolic pathway, to clarify and verify the relationship of genetics in some astronauts that may predispose to ophthalmic anomalies. Furthermore, we have identified a clinical population -- patients with polycystic ovary syndrome (PCOS) -- with several characteristics similar to those described in astronauts. The clinical findings shared by PCOS patients and astronauts with ophthalmic anomalies include higher homocysteine, increased retinal nerve fiber layer, increased incidence of white matter hyperintensities on MRI, increased androgen concentrations (or responses), and altered carbohydrate metabolism. PCOS patients have not been evaluated in detail regarding the occurrence of other anomalies observed in astronauts including choroidal folds, optic disc edema and cotton wool spots as well as changes in cycloplegic refraction, and optic nerve sheath diameter. While researchers have evaluated one-carbon metabolism pathway polymorphisms re: PCOS, and initial studies show an association with certain one-carbon polymorphisms, none have looked at the complete set of SNPs we propose here. Thus, this study has two major goals: 1. To extend the one-carbon pathway SNP assessment as related to astronaut ophthalmologic findings. 2. To evaluate patients with PCOS and/or Idiopathic intracranial hypertension (IIH) to assess one-carbon biochemistry and genetics and their possible correlation with ophthalmologic findings. While these studies alone will not identify the mechanism(s) of VIIP, we aim to clarify the genetic relationship to ophthalmic findings, and to document the utility of PCOS as a clinical population that could be used for studies that may ultimately allow for the definition of the mechanism of and means to prevent or treat these potentially vision-threatening processes in astronauts.

Specific Aims

1. Test for multiple SNPs of the 85 major genes involved in one-carbon metabolism in ISS (International Space Station) crewmembers (a total of 523 SNPs), and relate these data to existing one-carbon biochemistry and metabolomic data, along with existing vision and related medical data.

a. A secondary aim is to gather ethnicity data from the crewmembers, and characterize the extent to which ethnicity is predictive of ophthalmic issues after long-duration space flight.

b. Another secondary aim is to evaluate the data collected in this (and the initial) one carbon metabolism genetics studies and cardiovascular data. To this end, we will request VO2 max (pre, in, post), Framingham Risk Score, resting heart rate and blood pressure (pre, in, post) diastolic and systolic, exercise heart rate and blood pressure (pre, in, post) diastolic and systolic, Vascular Compliance data share (heart rate, blood pressure, cardiac output and stroke volume), medications, diagnoses, BMI, and % body fat data from the Lifetime Surveillance of Astronaut Health project for evaluation relative to the one carbon genetic and biochemical data.

2. Compare the same one-carbon metabolism genetics and biochemistry and ophthalmologic data from patients in one of four treatment groups:

i. women diagnosed with PCOS without IIH

ii. women diagnosed with PCOS and IIH

iii. women diagnosed with IIH without PCOS

iv. controls (neither PCOS nor IIH)

Subjects will be matched by age and body mass index (BMI). Statistical analyses will be used to evaluate the independent and shared contributions of age, body mass (BMI), and genetics on biochemical, and ophthalmologic outcomes, with False Discovery Rate adjustments to account for multiple comparisons.

3. A secondary aim is to combine the patient and control data from this study with ISS crewmember data in order to help inform us on whether or not these two cohorts (VIIP, PCOS) share similar associations among one-carbon metabolism genetics and biochemistry and ophthalmologic data identified in our earlier analyses.

Rationale for HRP Directed Research: This research is directed because it contains highly constrained research. This study has two major goals: 1. To utilize existing samples where possible to extend the scope of the initial One Carbon study. This was initially submitted and reviewed in the NNJ14ZSA001N-OMNIBUS NRA. HRP Management has now asked we submit this as directed research. 2. To add testing to an ongoing clinical trial at the Mayo Clinic. Timing is critical given that study is ongoing. The primary study is a clinical trial of pharmaceutical treatment for PCOS. We propose to extend this study by collecting a blood sample for one carbon biochemical and genetic testing, along with ophthalmologic exams, with the aim of documenting the utility of this population as an analog group for future VIIP research.

Research Impact/Earth Benefits:

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

Bibliography Type: Description: (Last Updated: 05/25/2021)  Show Cumulative Bibliography Listing
 
 None in FY 2016