Menu

 


Project Title:  Exercise Countermeasures for Knee and Hip Joint Degradation during Spaceflight Expand All
Images: icon  Fiscal Year: FY 2020 
Division: Space Biology 
Research Discipline/Element:
Cell & Molecular Biology | Animal Biology: Vertebrate 
Start Date: 10/28/2014  
End Date: 03/31/2020  
Task Last Updated: 08/29/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Willey, Jeffrey S. Ph.D. / Wake Forest University 
Address:  Radiation Biology Section 
Medical Center Blvd, 4th Floor NRC Building 
Winston-Salem , NC 27157-0001 
Email: jwilley@wakehealth.edu 
Phone: 336-713-7637  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Wake Forest University 
Comments: NOTE: PI formerly at Clemson University when NSBRI Postdoctoral Fellow Feb 2008-Oct 2010 (Ed., 12/18/2014) 
Key Personnel Changes / Previous PI: August 2019 report: Dr. Ted Bateman added as CoInvestigator as of July 2017, and continued until April 2018. Dr. Tom Smith retired in 2018 and is no longer CoInvestigator on the project.
Co-Investigator(s) / Affiliation:  Bateman, Ted  Ph.D./ University of North Carolina Chapel Hill 
Project Information: Grant/Contract No. NNX15AB50G 
Responsible Center: NASA ARC 
Grant Monitor: Sato, Kevin  
Center Contact: 650-604-1104 
kevin.y.sato@nasa.gov 
Solicitation: 2014 Space Biology Flight NNH14ZTT001N 
Grant/Contract No.: NNX15AB50G 
Project Type: FLIGHT  
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:  
Space Biology Element: (1) Cell & Molecular Biology
(2) Animal Biology: Vertebrate
Space Biology Cross-Element Discipline: (1) Musculoskeletal Biology
Space Biology Special Category: (1) Translational (Countermeasure) Potential
Task Description: Maintaining musculoskeletal health during long-duration spaceflight is crucial for ensuring both mission success and full skeletal recovery upon returning to weight-bearing. Clinical and preclinical evidence indicates that cartilage degradation in the hip and knee joints occurs with reduced weight-bearing. Less well characterized are the damaging effects of spaceflight-relevant radiation on cartilage, including exposure to solar particle events (SPE). Deterioration of the hip and knee joint during prolonged spaceflight has the potential to reduce an astronaut’s performance during a mission, cause arthritis, and negatively impact the astronaut’s long-term quality of life (QOL). Our study will test the hypothesis that mouse hip and knee joints exposed to microgravity on the International Space Station (ISS) or from reduced weight bearing via tail-suspended with or without exposure to spaceflight-relevant doses of radiation in Definition Phase studies will exhibit profound tissue degradation. Additionally, this degradation can be recovered using aerobic (running) and resistance (climbing) exercise countermeasures.

To study these problems, we will determine the hip and knee joint damage that occurs in mice that will fly in space on the International Space Station for 30 days. This damage will be compared to the hip and knee joint damage in another group of mice kept on Earth that also will not have weight on the hip and knee joints for 30 days, with or without receiving radiation exposure that simulates a solar flare. Damage to the hip and knee joint structures will be determined using imaging techniques, engineering devices to measure tissue strength, stained tissue sections, and identification of the molecules that cause the damage. The ability to walk normally after 30 days of weightlessness will also be determined. Finally, we will determine if treadmill running or climbing can reverse any of the hip and knee joint damage caused by being in the weightless space environment.

Our goal is to determine, 1] if hip and knee joint damage occurs in the weightless space environment, and 2] if recovery from this damage is possible with exercise.

 

Flight Assignment/Project Notes: ISS Rodent Research-9

NOTE: End date changed to 3/31/2020 per F. Hernandez/ARC (Ed., 6/23/17)

 

Research Impact/Earth Benefits: From these studies, we also will gain insights into how arthritis and joint failure develop in both patients that receive radiation therapy for the treatment for cancer, and in patients with limited mobility (cancer patients, wheel-chair bound spinal cord injury patients, or after limb surgery), and how this can be prevented.

 

Task Progress & Bibliography Information FY2020 
Task Progress: Summary of Progress to Date

We have met 3 main milestones during the past year. i] We have completed the ground-based Definition Phase portion for Specific Aim 1 and have published that portion in the journal Radiation Research, which examines the combined effect of reduced weight-bearing (HLU--hindlimb unloading) with/without exposure to one of 3 low dose radiation scenarios (0.1, 0.5, or 1 Gy) in regards to whole joint health. ii] We have completed the flight experiment. The data from the gait assessment has been submitted for publication; we have resubmitted our revisions. iii] Additionally, we have finished analyzing the spaceflight data and have started writing up a publication (combining these results with results from STS-135).

Progress to date includes:

A. Results from Specific Aim 1 Definition Phase – a ground based study in which we examined the individual and combined effects of low dose radiation and reduced weight bearing via tail suspension in mice: Both reduced weight bearing and low dose radiation as independent challenges cause degradation of knee cartilage and increases arthritic, catabolic signaling pathways in cartilage that can lead to arthritis.

B. Flight study RR-9: Our mouse payload has been launched as part of the Rodent Research-9 mission aboard SpaceX-12 to the International Space Station. Our two primary aims were to examine if knee joint degradation (e.g., articular cartilage and menisci) occurred after spaceflight; and if gait alterations occurred that could indicate pathology in the joint or otherwise.

B1. Knee joint findings. Articular cartilage volume lining the medial tibial plateau in FLIGHT mice measured from microCT was significantly lower than controls. Cartilage thinning was localized to the weight-bearing tibial-femoral contact point, which is the point of the greatest weight bearing within the knee. Thus loss of cartilage was greatest where the loading is the generally the greatest -- reducing pressure across the knee during flight had the biggest negative impact at that location. Within the knee cartilage, enzymes capable of breaking down cartilage (MMPs) were increased in the spaceflight FLIGHT cartilage. Additionally, the molecules that provide the spongy, compressive properties of cartilage were lower after spaceflight. The meniscus is a tissue in the knee that stabilizes the structure. We found that Meniscal volume was significantly lower than controls after flight. Additionally, the same molecules (proteoglycans) that provide the compressive properties in cartilage were also lower in the menisci of FLIGHT mice. This pattern was similar to results from the STS-135 space shuttle flight flight, in which proteoglycans were lower in menisci from left (-11%; p<0.05) and right (-9%; p=.1) knees vs controls. We also found that within the menisci, the "control pathways" that can lead to damage or arthritis were activated, specifically ones that can result in a decrease in meniscal volume. Many proteins associated with building new cartilage and meniscal tissues were lower after flight, and this could be due to lowered defenses against free radicals.

SUMMARY: Degradation of knee soft tissues occurred after flights on ISS. Cartilage loss localized to the highest weight-bearing location across the knees. Excess oxidative stress is a known cause for meniscal and cartilage degradation; our data indicate this as potentially a contributor to the observed joint degradation.

B2. Gait Assessment Findings. We have submitted our gait For FLIGHT mice; many of the evaluated gait characteristics in the hind limbs were significantly changed, including: stride width variability; stride length and variance; stride, swing, and stance duration; paw angle and area at peak stance; and step angle, among others. Gait characteristics that decreased included stride frequency, and others. Moreover, numerous forelimb gait characteristics in the FLIGHT mice were changed at post-flight measures relative to pre-flight. We also sought to identify gait alterations that are reflective of joint (cartilage) degradation, a known response of knees to reduced weight bearing. Some patterns of gait change in rodents reflect musculoskeletal deficits, a well-described consequence of prolonged periods of reduced weight bearing in mice. For instance, an arthritic gait in rodents may display increased stride duration and reduced stride length and/or increased stride width, with related pain. Increased stride duration was observed in the flight animals, but as noted the stride length was significantly increased and stride width was unaltered, which is in contrast to what one might expect with painful arthritis. Thus while cartilage degradation was noted from anatomic and proteomic assessment, the reponse may not be painful at the point of tissue harvest.

B3. Muscle Metabolomic findings. We examined how metabolism was changed in the gastrocnemius, and the quadriceps femoris (“quadriceps”) muscles, and was conducted at Georgetown University by Dr. Willey’s collaborator, Dr. Lia Laiakis. Results demonstrate the increased responsiveness of gastrocnemius to spaceflight compared to quadricep in the metabolomic level. All the data suggest that microgravity and spaceflight have a direct effect on the metabolomic profiles of muscle tissues. However, some muscles appear to be more responsive compared to others, or some have the ability to reprogram efficiently upon return to Earth.

 

Bibliography Type: Description: (Last Updated: 09/02/2019)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Mao XW, Nishiyama NC, Willey JS, Delp M, Pecaut MJ. "Acute effect of spaceflight on ocular structure, intraocular pressure and retina." Podium. 34th Annual Meeting of the American Society for Gravitational and Space Biology, Bethesda, MD, October 31-November 3, 2018.

ASGSR Program Book. 34th Annual Meeting of the American Society for Gravitational and Space Biology, Bethesda, MD, October 31-November 3, 2018. , Oct-2018

Abstracts for Journals and Proceedings Delp M, Ghosh P, Cullen A, Park H, Goldsmith J, Maraj J, Evenson K, Mao XW, Willey J, Behnke B, Zawieja DC. "Effects of Spaceflight on Jugular Venomotor Responses in Mice." Podium. 34th Annual Meeting of the American Society for Gravitational and Space Research, Bethesda, MD, October 31-November 3, 2018.

ASGSR Program Book. 34th Annual Meeting of the American Society for Gravitational and Space Research, Bethesda, MD, October 31-November 3, 2018. , Oct-2018

Abstracts for Journals and Proceedings Laiakis EC, Kwok A, Delp M, Zawieja DC, Mao XW, Livingston E, Bateman TA, Willey JS. "Metabolomic alterations associated with spaceflight and microgravity in gastrocnemius and quadriceps muscle murine samples." Podium. 2019 International Space Station Research and Development Conference (ISSRDC), Atlanta, GA, July 29-August 1, 2019.

ISS R&D Program Book. 2019 International Space Station Research and Development Conference (ISSRDC), Atlanta, GA, July 29-August 1, 2019. , Jul-2019

Abstracts for Journals and Proceedings Willey JS, Kwok A, Moore JE, Rosas S. "Knee and hip soft tissue damage occurs from reduced weight bearing and/or low dose radiation exposure." Poster. 64th Annual Meeting of the Radiation Research Society, Chicago, IL, September 23-26, 2018.

Radiation Research Program Book. 64th Annual Meeting of the Radiation Research Society, Chicago, IL, September 23-26, 2018. , Sep-2018

Abstracts for Journals and Proceedings Kwok A, Moore JE, Livingston E, Rosas S, Delp M, Mao XW, Willey JS. "Impaired Gait Patterns in Mice After 30 Days of Spaceflight." Poster. 34th Annual Meeting of the American Society for Gravitational and Space Research, Bethesda, MD, October 31-November 3, 2018.

ASGSR Program Book. 34th Annual Meeting of the American Society for Gravitational and Space Research, Bethesda, MD, October 31-November 3, 2018. , Oct-2018

Abstracts for Journals and Proceedings Nishiyama NC, Pecaut MJ, Willey J, Delp M, Mao XW. "The Impact of Spaceflight on Circulating Blood Cell Populations." Poster. 34th Annual Meeting of the American Society for Gravitational and Space Research, Bethesda, MD, October 31-November 3, 2018.

ASGSR Program Book. 34th Annual Meeting of the American Society for Gravitational and Space Research, Bethesda, MD, October 31-November 3, 2018. , Oct-2018

Abstracts for Journals and Proceedings Willey JS, Kwok A, Delp MD, Zawieja DC, Mao X, Livingston E, Rosas S. "Gait pattern changes after 33 days aboard ISS reflect neuromotor deficits primarily in the hind limbs of mice." Poster6. 2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

HRP IWS Program Book. 2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019. , Jan-2019

Abstracts for Journals and Proceedings Kwok A, Rosas S, Moore JE, Delp MD, Mao X, Bateman TA, Willey JS. "34 Days of Spaceflight Altered Gait Patterns In Mice." Poster. NC Space Symposium, Raleigh, NC, April 4-5, 2019.

NC Space Symposium Program Book. NC Space Symposium, Raleigh, NC, April 4-5, 2019. , Apr-2019

Articles in Peer-reviewed Journals Kwok AT, Moore JE, Rosas S, Kerr BA, Andrews RN, Nguyen CM, Lee J, Furdui CM, Collins BE, Munley MT, Willey JS. "Knee and hip joint cartilage damage from combined spaceflight hazards of low-dose radiation less than 1 Gy and prolonged hindlimb unloading." Radiat Res. 2019 Jun;191(6):497-506. https://doi.org/10.1667/RR15216.1 ; PubMed PMID: 30925135; PubMed Central PMCID: PMC6599637 , Jun-2019
Articles in Peer-reviewed Journals Mao XW, Nishiyama NC, Byrum SD, Stanbouly S, Jones T, Drew A, Sridharan V, Boerma M, Tackett AJ, Zawieja D, Willey JS, Delp M, Pecaut MJ. "Characterization of mouse ocular response to a 35-day spaceflight mission: Evidence of blood-retinal barrier disruption and ocular adaptations." Scientific Reports. 2019 Jun 3;9(1):8215. https://doi.org/10.1038/s41598-019-44696-0 ; PubMed PMID: 31160660; PubMed Central PMCID: PMC6547757 , Jun-2019
Project Title:  Exercise Countermeasures for Knee and Hip Joint Degradation during Spaceflight Expand All
Images: icon  Fiscal Year: FY 2019 
Division: Space Biology 
Research Discipline/Element:
Cell & Molecular Biology | Animal Biology: Vertebrate 
Start Date: 10/28/2014  
End Date: 03/31/2020  
Task Last Updated: 08/30/2018 
Download report in PDF pdf
Principal Investigator/Affiliation:   Willey, Jeffrey S. Ph.D. / Wake Forest University 
Address:  Radiation Biology Section 
Medical Center Blvd, 4th Floor NRC Building 
Winston-Salem , NC 27157-0001 
Email: jwilley@wakehealth.edu 
Phone: 336-713-7637  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Wake Forest University 
Comments: NOTE: PI formerly at Clemson University when NSBRI Postdoctoral Fellow Feb 2008-Oct 2010 (Ed., 12/18/2014) 
Key Personnel Changes / Previous PI: August 2017 report: Dr. Ted Bateman added as CoInvestigator as of July 2017.
Co-Investigator(s) / Affiliation:  Smith, Thomas  Ph.D./ Wake Forest University Health Sciences  Bateman, Ted  Ph.D./ University of North Carolina Chapel Hill 
Project Information: Grant/Contract No. NNX15AB50G 
Responsible Center: NASA ARC 
Grant Monitor: Sato, Kevin  
Center Contact: 650-604-1104 
kevin.y.sato@nasa.gov 
Solicitation: 2014 Space Biology Flight NNH14ZTT001N 
Grant/Contract No.: NNX15AB50G 
Project Type: FLIGHT  
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:  
Space Biology Element: (1) Cell & Molecular Biology
(2) Animal Biology: Vertebrate
Space Biology Cross-Element Discipline: (1) Musculoskeletal Biology
Space Biology Special Category: (1) Translational (Countermeasure) Potential
Task Description: Maintaining musculoskeletal health during long-duration spaceflight is crucial for ensuring both mission success and full skeletal recovery upon returning to weight-bearing. Clinical and preclinical evidence indicates that cartilage degradation in the hip and knee joints occurs with reduced weight-bearing. Less well characterized are the damaging effects of spaceflight-relevant radiation on cartilage, including exposure to solar particle events (SPE). Deterioration of the hip and knee joint during prolonged spaceflight has the potential to reduce an astronaut’s performance during a mission, cause arthritis, and negatively impact the astronaut’s long-term quality of life (QOL). Our study will test the hypothesis that mouse hip and knee joints exposed to microgravity on the International Space Station (ISS) or from reduced weight bearing via tail-suspended with or without exposure to spaceflight-relevant doses of radiation in Definition Phase studies will exhibit profound tissue degradation. Additionally, this degradation can be recovered using aerobic (running) and resistance (climbing) exercise countermeasures.

To study these problems, we will determine the hip and knee joint damage that occurs in mice that will fly in space on the International Space Station for 30 days. This damage will be compared to the hip and knee joint damage in another group of mice kept on Earth that also will not have weight on the hip and knee joints for 30 days, with or without receiving radiation exposure that simulates a solar flare. Damage to the hip and knee joint structures will be determined using imaging techniques, engineering devices to measure tissue strength, stained tissue sections, and identification of the molecules that cause the damage. The ability to walk normally after 30 days of weightlessness will also be determined. Finally, we will determine if treadmill running or climbing can reverse any of the hip and knee joint damage caused by being in the weightless space environment.

Our goal is to determine, 1] if hip and knee joint damage occurs in the weightless space environment, and 2] if recovery from this damage is possible with exercise.

 

Flight Assignment/Project Notes: ISS Rodent Research-9

NOTE: End date changed to 3/31/2020 per F. Hernandez/ARC (Ed., 6/23/17)

 

Research Impact/Earth Benefits: From these studies, we also will gain insights into how arthritis and joint failure develop in both patients that receive radiation therapy for the treatment for cancer, and in patients with limited mobility (cancer patients, wheel-chair bound spinal cord injury patients, or after limb surgery), and how it can be prevented.

 

Task Progress & Bibliography Information FY2019 
Task Progress: 1. We finished all the tail suspension +/- simulated spaceflight radiation studies and have submitted a paper for publication. Mice were either hindlimb unloaded (HLU) (n=40) or remained full weight-bearing as Ground mice (n=40). Within each of these groups, mice either received no radiation, or 1 of 3 low-dose, spaceflight-relevant radiation scenarios. We measured cartilage and joint damage on Day 30 after initiating HLU.

Primary Results: Contrast-enhanced microCT demonstrated decreased in volume and thickness at the site of primary weight-bearing in the knee (e.g., the femoral-tibial cartilage-cartilage contact point) in all treatment groups vs. GROUND-SHAM. Interestingly and importantly, damage was localized to the sites of most weight bearing; cartilage is senstiive to loading. Within the knee cartilage, the protein collagen was reduced, and collagen type II-degrading matrix metalloproteinase-13 (MMP-13) were greater in all groups vs. controls indicating that cartilage degraded after both radiation and reduced weight bearing. Circulating serum cartilage oligomeric matrix proteins (sCOMP), biomarker for ongoing cartilage degradation, was increased in all of the irradiated groups vs. GROUND-SHAM, regardless of unloading. Mass spectrometry, combined with Ingenuity Pathway Analysis (IPA), of the cartilage lining the femoral head showed decrease in cartilage compositional proteins, increased osteoarthritic pathways, and decreased cell survival by increased apoptosis and oxidative stress. Our findings demonstrate that both individually and combined HLU and spaceflight-relevant doses of irradiation lead to cartilage degradation of the knee and hip with expression of an arthritic phenotype. Moreover, early administration of low dose irradiation (0.1 Gy, 0.5 Gy, or 1 Gy) causes an active catabolic response in cartilage 24 days post irradiation. IMp

2. Flight study: Our mouse payload has been launched aboard the SpaceX-12 mission to the International Space Station. We successfully brought our Digigait treadmill down to the Kennedy Space Center, performed an initial gait assessment on all mice; grouped the mice; and after launch collected the baseline tissues for ourselves and for biospecimen sharing program (BSP). We traveled to Loma Linda University, where we repeated the gait assessment on the flight animals upon return, a new Cohort Control group of mice, and again collected tissues for our primary science and for BSP. We have analyzed how gait is altered post flight. Analysis of tissues is ongoing.

Primary results: Gait data were acquired over ~1.5 minutes/mouse. Several patterns of gait changes were noted post-flight. Stride width variance increased in both forelimbs (p<0.05) and hind limbs (p<0.001), indicating an increased risk of falling. Increased swing phase duration observed in the hind limbs post-flight (p < 0.05) characterizes an arthritic gait. Step angle widened in hind limbs post-flight, suggesting impaired CNS motor centers with ataxia (p < 0.01). Paw area variability at peak stance increased in hind limbs (p < 0.01), reflecting impaired neuromotor control. Importantly, while many gait patterns indicated neuromotor deficits, most remained unaltered. Our data indicates that longitudinal gait analysis of rodents provides a non-invasive assay to measure functional responses to spaceflight. The mobile DigiGait system permits identification of gait changes in rodents suggestive of functional impairment. The majority of deficits from RR-9 mice were noted as sensorimotor in nature. Deficits were more pronounced in hind limbs vs. forelimbs, which could be related to locomotor habits in the Rodent Habitats on ISS (e.g., grabbing wire mesh).

 

Bibliography Type: Description: (Last Updated: 09/02/2019)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Kwok A, Moore JE, Collins B, Pecaut M, Nishiyama N, Mao XW, Willey JS. "Knee and Hip Joint Damage from Reduced Weight-Bearing and/or Spaceflight Radiation. Knee and Hip Joint Damage from Reduced Weight-Bearing and/or Spaceflight Radiation." Session: LS Systems V: Musculoskeletal System II - Bone. Presented at 33rd Annual Meeting of the American Society for Gravitational and Space Research, Seattle, WA, October 25-28, 2017.

33rd Annual Meeting of the American Society for Gravitational and Space Research, Seattle, WA, October 25-28, 2017. , Oct-2017

Abstracts for Journals and Proceedings Mao XW, Nishiyama N, Pecaut M, Willey JS. "Retinal oxidative damage in low-dose radiated and hindlimb unloaded mice." Poster. 33rd Annual Meeting of the American Society for Gravitational and Space Research, Seattle, WA, October 25-28, 2017.

33rd Annual Meeting of the American Society for Gravitational and Space Research, Seattle, WA, October 25-28, 2017. , Oct-2017

Abstracts for Journals and Proceedings Willey JS, Kwok A, Moore JE, Mao XW, Collins BE. "Knee And Hip Joint Degradation from Reduced Weight-Bearing and/or Low-Dose Radiation." Rodent models. 2018 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2018.

2018 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2018. , Jan-2018

Articles in Peer-reviewed Journals Farris M, McTyre ER, Okoukoni C, Dugan G, Johnson BJ, Blackstock AW, Munley MT, Bourland JD, Cline JM, Willey JS. "Cortical thinning and structural bone changes in non-human primates after single-fraction whole-chest irradiation." Radiat Res. 2018 Jul;190(1):63-71. Epub 2018 May 8. https://doi.org/10.1667/RR15007.1 ; PubMed PMID: 29738279; PubMed Central PMCID: PMC6036641 , Jul-2018
Project Title:  Exercise Countermeasures for Knee and Hip Joint Degradation during Spaceflight Expand All
Images: icon  Fiscal Year: FY 2018 
Division: Space Biology 
Research Discipline/Element:
Cell & Molecular Biology | Animal Biology: Vertebrate 
Start Date: 10/28/2014  
End Date: 03/31/2020  
Task Last Updated: 08/29/2017 
Download report in PDF pdf
Principal Investigator/Affiliation:   Willey, Jeffrey S. Ph.D. / Wake Forest University 
Address:  Radiation Biology Section 
Medical Center Blvd, 4th Floor NRC Building 
Winston-Salem , NC 27157-0001 
Email: jwilley@wakehealth.edu 
Phone: 336-713-7637  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Wake Forest University 
Comments: NOTE: PI formerly at Clemson University when NSBRI Postdoctoral Fellow Feb 2008-Oct 2010 (Ed., 12/18/2014) 
Key Personnel Changes / Previous PI: August 2017 report: Dr. Ted Bateman added as CoInvestigator as of July 2017.
Co-Investigator(s) / Affiliation:  Smith, Thomas  Ph.D./ Wake Forest University Health Sciences  Bateman, Ted  Ph.D./ Universy of North Carolina Chapel Hill 
Project Information: Grant/Contract No. NNX15AB50G 
Responsible Center: NASA ARC 
Grant Monitor: Sato, Kevin  
Center Contact: 650-604-1104 
kevin.y.sato@nasa.gov 
Solicitation: 2014 Space Biology Flight NNH14ZTT001N 
Grant/Contract No.: NNX15AB50G 
Project Type: FLIGHT  
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:
Space Biology Element: (1) Cell & Molecular Biology
(2) Animal Biology: Vertebrate
Space Biology Cross-Element Discipline: (1) Musculoskeletal Biology
Space Biology Special Category: (1) Translational (Countermeasure) Potential
Task Description: Maintaining musculoskeletal health during long-duration spaceflight is crucial for ensuring both mission success and full skeletal recovery upon returning to weight-bearing. Clinical and preclinical evidence indicates that cartilage degradation in the hip and knee joints occurs with reduced weight-bearing. Less well characterized are the damaging effects of spaceflight-relevant radiation on cartilage, including exposure to solar particle events (SPE). Deterioration of the hip and knee joint during prolonged spaceflight has the potential to reduce an astronaut’s performance during a mission, cause arthritis, and negatively impact the astronaut’s long-term quality of life (QOL). Our study will test the hypothesis that mouse hip and knee joints exposed to microgravity on the International Space Station (ISS) or from reduced weight bearing via tail-suspended with or without exposure to spaceflight-relevant doses of radiation in Definition Phase studies will exhibit profound tissue degradation. Additionally, this degradation can be recovered using aerobic (running) and resistance (climbing) exercise countermeasures.

To study these problems, we will determine the hip and knee joint damage that occurs in mice that will fly in space on the International Space Station for 30 days. This damage will be compared to the hip and knee joint damage in another group of mice kept on Earth that also will not have weight on the hip and knee joints for 30 days, with or without receiving radiation exposure that simulates a solar flare. Damage to the hip and knee joint structures will be determined using imaging techniques, engineering devices to measure tissue strength, stained tissue sections, and identification of the molecules that cause the damage. The ability to walk normally after 30 days of weightlessness will also be determined. Finally, we will determine if treadmill running or climbing can reverse any of the hip and knee joint damage caused by being in the weightless space environment.

Our goal is to determine, 1] if hip and knee joint damage occurs in the weightless space environment, and 2] if recovery from this damage is possible with exercise.

 

Flight Assignment/Project Notes: ISS Rodent Research-9

NOTE: End date changed to 3/31/2020 per F. Hernandez/ARC (Ed., 6/23/17)

 

Research Impact/Earth Benefits: From these studies, we also will gain insights into how arthritis and joint failure develop in both patients that receive radiation therapy for the treatment for cancer, and in patients with limited mobility (cancer patients, wheel-chair bound spinal cord injury patients, or after limb surgery), and how it can be prevented.

 

Task Progress & Bibliography Information FY2018 
Task Progress: Our work to date has identified that 30 days of reduced weight-bearing with/without exposure to spaceflight-relevant radiation in ground-based models increased biomarkers of arthritis local to both the knee and hip joints, and systemically. Our mice have launched to the International Space Station, and we will measure how spaceflight changes joint health (e.g., degradation of cartilage, menisci, ligaments) and how these changes are associated with alterations in normal walking performance.

Specific progress includes:

1. We finished all the tail suspension +/- simulated spaceflight radiation studies. Mice were either hindlimb unloaded (HLU) (n=40) or remained full weight-bearing as Ground mice (n=40). Within each of these groups, mice either received no radiation, or 1 of 3 low-dose, spaceflight-relevant radiation scenarios. We measured cartilage and joint damage on Day 30 after initiating HLU.

3. From our ground-based studies, we noted from our advanced imaging analysis that both reduced weight bearing and low dose radiation can cause loss of cartilage and molecular changes characteristic of arthritis. The volume and thickness of cartilage lining the medial tibial plateau (knee cartilage) was lower in the HLU groups than the GROUND mice whether or not the mice were irradiated. There was not a combined effect; therefore, both reduced weight bearing and radiation can cause loss of cartilage volume. Also, we noted an increase in the presence of enzymes and molecules that are associated with a breakdown of cartilage in the hip cartilage after HLU and irradiation. A specific change in two cell signaling pathways was observed in the femoral head cartilage that is strongly associated with cartilage catabolism and arthritis. Inflammation may have been increased in the HLU mice as indicated by serum IL-6 levels; increased IL-6 is associated with arthritis. Finally, there was an overall reduction in the amount of normal proteins that make up the femoral head cartilages. Taken together, both HLU and radiation can damage cartilage and joints.

4. In preparation for our flight study, we performed a rodent study in which we compared the walking gait of mice before and after 30 days of reduced weight bearing via tail suspension (HLU) with those that were not unloaded (GROUND). We utilized our Digigait system to measure the walking gait. Analysis has not been performed as of yet, as we began preparation for our flight investigation.

5. Flight study: Our mouse payload has been launched aboard the SpaceX-12 mission to the International Space Station, and is currently in orbit. We measured the walking gait of the mice before launch. We plan to recover the mice in September 2017.

 

Bibliography Type: Description: (Last Updated: 09/02/2019)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Willey JS, Kwok A, Moore JE, Ma X, Zabarsky Z, Jinnah A, Luo T, Collins B, Smith T. "Arthritic Responses in the Knee and Hip Joint from Reduced Weight-Bearing and/or Low Dose Radiation." 2017 International Space Station (ISS) Research and Development Conference, Washington, DC, July 17-20, 2017.

2017 International Space Station (ISS) Research and Development Conference, Washington, DC, July 17-20, 2017. , Jul-2017

Abstracts for Journals and Proceedings Binaco PJ, Ayala S, Howe D, Pecaut MJ, Nishiyama NC, Mao XM, Rodriguez D, Kwok A, Bateman TA, Chapes SK, Willey JS, Lau AG. "Effects of Low Dose Radiation and Tetanus Toxoid on the Strength of Bone." Biomedical Engineering Society (BMES) Annual Meeting 2016, Minneapolis, MN, October 5-8, 2016.

Biomedical Engineering Society (BMES) Annual Meeting 2016, Minneapolis, MN, October 5-8, 2016. BMES annual program book. , Oct-2016

Project Title:  Exercise Countermeasures for Knee and Hip Joint Degradation during Spaceflight Expand All
Images: icon  Fiscal Year: FY 2017 
Division: Space Biology 
Research Discipline/Element:
Cell & Molecular Biology | Animal Biology: Vertebrate 
Start Date: 10/28/2014  
End Date: 03/31/2020  
Task Last Updated: 08/25/2016 
Download report in PDF pdf
Principal Investigator/Affiliation:   Willey, Jeffrey S. Ph.D. / Wake Forest University 
Address:  Radiation Biology Section 
Medical Center Blvd, 4th Floor NRC Building 
Winston-Salem , NC 27157-0001 
Email: jwilley@wakehealth.edu 
Phone: 336-713-7637  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Wake Forest University 
Comments: NOTE: PI formerly at Clemson University when NSBRI Postdoctoral Fellow Feb 2008-Oct 2010 (Ed., 12/18/2014) 
Co-Investigator(s) / Affiliation:  Smith, Thomas  Ph.D./ Wake Forest University Health Sciences 
Project Information: Grant/Contract No. NNX15AB50G 
Responsible Center: NASA ARC 
Grant Monitor: Sato, Kevin  
Center Contact: 650-604-1104 
kevin.y.sato@nasa.gov 
Solicitation: 2014 Space Biology Flight NNH14ZTT001N 
Grant/Contract No.: NNX15AB50G 
Project Type: FLIGHT  
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:  
Space Biology Element: (1) Cell & Molecular Biology
(2) Animal Biology: Vertebrate
Space Biology Cross-Element Discipline: (1) Musculoskeletal Biology
Space Biology Special Category: (1) Translational (Countermeasure) Potential
Task Description: Maintaining musculoskeletal health during long-duration spaceflight is crucial for ensuring both mission success and full skeletal recovery upon returning to weight-bearing. Clinical and preclinical evidence indicates that cartilage degradation in the hip and knee joints occurs with reduced weight-bearing. Less well characterized are the damaging effects of spaceflight-relevant radiation on cartilage, including exposure to solar particle events (SPE). Deterioration of the hip and knee joint during prolonged spaceflight has the potential to reduce an astronaut’s performance during a mission, cause arthritis, and negatively impact the astronaut’s long-term quality of life (QOL). Our study will test the hypothesis that mouse hip and knee joints exposed to microgravity on the International Space Station (ISS) or from reduced weight bearing via tail-suspended with or without exposure to spaceflight-relevant doses of radiation in Definition Phase studies will exhibit profound tissue degradation. Additionally, this degradation can be recovered using aerobic (running) and resistance (climbing) exercise countermeasures.

To study these problems, we will determine the hip and knee joint damage that occurs in mice that will fly in space on the International Space Station for 30 days. This joint damage will be compared to the hip and knee joint damage in another group of mice kept on Earth that also will not have weight on the hip and knee joints for 30 days, with or without receiving radiation exposure that simulates a solar flare. Damage to the hip and knee joint structures will be determined using imaging techniques, engineering devices to measure tissue strength, stained tissue sections, and identification of the molecules that cause the damage. The ability to walk normally after 30 days of weightlessness will also be determined. Finally, we will determine if treadmill running or climbing can reverse any of the hip and knee joint damage caused by being in the weightless space environment.

Our goal is to determine, 1] if hip and knee joint damage occurs in the weightless space environment, and 2] if recovery from this damage is possible with exercise.

 

Flight Assignment/Project Notes: NOTE: End date changed to 3/31/2020 per F. Hernandez/ARC (Ed., 6/23/17)

 

Research Impact/Earth Benefits: From these studies, we also will gain insights into how arthritis and joint failure develop in both patients that receive radiation therapy for the treatment for cancer, and in wheel-chair bound spinal cord injury patients or after limb surgery, and how it can be prevented.

 

Task Progress & Bibliography Information FY2017 
Task Progress: Progress to date includes:

A. We developed a chamber that lets us simulate the spaceflight and near weightless radiation environment at the same time. We can place mice into this this chamber and expose them to a similar dose of radiation that astronauts can face while in orbit, all while the mice are exposed to reduced weight bearing. This setup can be used at nearly all academic medical centers. These animals do not require anesthesia during the procedure. Thus this chamber improves and expands our ability to perform ground-based research that simulates the challenges of the spaceflight environment

B. We have identified that periods of reduced weight-bearing causing thinning of the cartilage lining the tibial plateau. Using resources that were allocated prior to full implementation, we developed an ultra-high resolution nano-computed tomography (nanoCT) method of measuring cartilage changes after periods of hindlimb unloading (HLU). The medial plateau in particular is important as this is the region of the knee with the highest amount of weight-bearing, and is often the region most susceptible to arthritis.

D. Indicators of arthritis are increased within the femoral head cartilage after periods of reduced weight-bearing. Specifically, the genes that drive degradation of cartilage during the process of arthritis are increased after 21 days of HLU. The pattern of altered gene expression in the femoral heads after 21 days of HLU are highly indicative of a specific type of intracellular signaling (Wnt-signaling) in cartilage that contributes to cartilage damage and arthritis.

 

Bibliography Type: Description: (Last Updated: 09/02/2019)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Willey JS, Moore J, Black P, Payne V, Kwok A, Yammani R, Lindburg C, Munley MT, Olson J. "Reduced Weight-Bearing Combined with Spaceflight Radiation Causes Persistent Pre-Arthritic Damage in Rat Knee Articular Cartilage." Presented at the 31st Annual Meeting of the American Society for Gravitational and Space Research, Alexandria, VA, November 11-14, 2015.

31st Annual Meeting of the American Society for Gravitational and Space Research, Alexandria, VA, November 11-14, 2015. Conference Program Book listed in Concurrent Session #20 (Rodent 1): https://asgsr.org/index.php/2015-abstracts , Nov-2015

Abstracts for Journals and Proceedings Kwok A, Moore JE, Payne V, Livingston E, Lau A, Bateman TA, Willey JS. "Unloading induces cartilage degradation and biomarkers of arthritis in the knee and hip joints." Presented at the 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. Abstract Book #7214. , Feb-2016

Project Title:  Exercise Countermeasures for Knee and Hip Joint Degradation during Spaceflight Expand All
Images: icon  Fiscal Year: FY 2016 
Division: Space Biology 
Research Discipline/Element:
Cell & Molecular Biology | Animal Biology: Vertebrate 
Start Date: 10/28/2014  
End Date: 10/27/2017  
Task Last Updated: 08/28/2015 
Download report in PDF pdf
Principal Investigator/Affiliation:   Willey, Jeffrey S. Ph.D. / Wake Forest University 
Address:  Radiation Biology Section 
Medical Center Blvd, 4th Floor NRC Building 
Winston-Salem , NC 27157-0001 
Email: jwilley@wakehealth.edu 
Phone: 336-713-7637  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Wake Forest University 
Comments: NOTE: PI formerly at Clemson University when NSBRI Postdoctoral Fellow Feb 2008-Oct 2010 (Ed., 12/18/2014) 
Co-Investigator(s) / Affiliation:  Smith, Thomas  Ph.D./ Wake Forest University Health Sciences 
Project Information: Grant/Contract No. NNX15AB50G 
Responsible Center: NASA ARC 
Grant Monitor: Taylor, Elizabeth  
Center Contact: 650.604.1783 
elizabeth.taylor-23@nasa.gov 
Solicitation: 2014 Space Biology Flight NNH14ZTT001N 
Grant/Contract No.: NNX15AB50G 
Project Type: FLIGHT  
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:  
Space Biology Element: (1) Cell & Molecular Biology
(2) Animal Biology: Vertebrate
Space Biology Cross-Element Discipline: (1) Musculoskeletal Biology
Space Biology Special Category: (1) Translational (Countermeasure) Potential
Task Description: This project will study the risk of damaging both the hip and knee joints because of exposure to weightlessness during long spaceflights. The knee joint contains cartilage lining the bone, the meniscus which distributes weight through the joint, and the ligaments which join the bones. The hip joint contains cartilage lining the bone. Weightlessness during long spaceflights has the potential to damage these structures, increasing the risk of developing arthritis or bone fractures either during spaceflight or after returning to Earth. However, the extent and cause of damage to these joint structures during spaceflight has not been studied. It is also not known if these joint tissues can recover from weightlessness-related damage.

To study these problems, we will determine the hip and knee joint damage that occurs in mice that will fly in space on the International Space Station for 30 days. This joint damage will be compared to the hip and knee joint damage in another group of mice kept on Earth that also will not have weight on the hip and knee joints for 30 days. Damage to the hip and knee joint structures will be determined using imaging techniques, engineering devices to measure tissue strength, stained tissue sections, and identification of the molecules that cause the damage. The ability to walk normally after 30 days of weightlessness will also be determined. Finally, we will determine if treadmill running or climbing can reverse any of the hip and knee joint damage caused by being in the weightless space environment.

Our goal is to determine, 1] if hip and knee joint damage occurs in the weightless space environment, and 2] if recovery from this damage is possible with exercise. From these studies, we also will gain insights into how arthritis develops in wheel-chair bound spinal cord injury patients or after limb surgery, and how it can be prevented.

 

Research Impact/Earth Benefits: From these studies, we also will gain insights into how arthritis develops in wheel-chair bound spinal cord injury patients or after limb surgery, and how it can be prevented.

 

Task Progress & Bibliography Information FY2016 
Task Progress: The progress on our grant was limited during the past year as full funding was not made available. The funding that was made available permitted us to travel to NASA Ames and present our work to other investigators funded in this soliciation and to the management team. However, a positive outcome from this meeting was the formation of a new collaboration between my lab and two other funded investigators, specifically Dr. Michael Pecaut and Dr. Vivien Mao, both from Loma Linda Medical Center. We have enrolled in a tissue sharing opportunity, in which I am now analyzing the knee joints from mice enrolled in their studies examining the consequences of spaceflight on other body systems (e.g., immune system). We are using our unique small animal imaging approach to describe the arthritis in these joints, and thus we will maximize the productivity, publications, and impact through collaborative work.

 

Bibliography Type: Description: (Last Updated: 09/02/2019)  Show Cumulative Bibliography Listing
 
 None in FY 2016
Project Title:  Exercise Countermeasures for Knee and Hip Joint Degradation during Spaceflight Expand All
Images: icon  Fiscal Year: FY 2015 
Division: Space Biology 
Research Discipline/Element:
Cell & Molecular Biology | Animal Biology: Vertebrate 
Start Date: 10/28/2014  
End Date: 10/27/2017  
Task Last Updated: 12/18/2014 
Download report in PDF pdf
Principal Investigator/Affiliation:   Willey, Jeffrey S. Ph.D. / Wake Forest University 
Address:  Radiation Biology Section 
Medical Center Blvd, 4th Floor NRC Building 
Winston-Salem , NC 27157-0001 
Email: jwilley@wakehealth.edu 
Phone: 336-713-7637  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Wake Forest University 
Comments: NOTE: PI formerly at Clemson University when NSBRI Postdoctoral Fellow Feb 2008-Oct 2010 (Ed., 12/18/2014) 
Co-Investigator(s) / Affiliation:  Smith, Thomas  Ph.D./ Wake Forest University Health Sciences 
Project Information: Grant/Contract No. NNX15AB50G 
Responsible Center: NASA ARC 
Grant Monitor: Smith, Jeffrey  
Center Contact: 650-604-0880 
jeffrey.d.smith2@nasa.gov 
Solicitation: 2014 Space Biology Flight NNH14ZTT001N 
Grant/Contract No.: NNX15AB50G 
Project Type: FLIGHT  
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:  
Space Biology Element: (1) Cell & Molecular Biology
(2) Animal Biology: Vertebrate
Space Biology Cross-Element Discipline: (1) Musculoskeletal Biology
Space Biology Special Category: (1) Translational (Countermeasure) Potential
Task Description: This project will study the risk of damaging both the hip and knee joints because of exposure to weightlessness during long spaceflights. The knee joint contains cartilage lining the bone, the meniscus which distributes weight through the joint, and the ligaments which join the bones. The hip joint contains cartilage lining the bone. Weightlessness during long spaceflights has the potential to damage these structures, increasing the risk of developing arthritis or bone fractures either during spaceflight or after returning to Earth. However, the extent and cause of damage to these joint structures during spaceflight has not been studied. It is also not known if these joint tissues can recover from weightlessness-related damage.

To study these problems, we will determine the hip and knee joint damage that occurs in mice that will fly in space on the International Space Station for 30 days. This joint damage will be compared to the hip and knee joint damage in another group of mice kept on Earth that also will not have weight on the hip and knee joints for 30 days. Damage to the hip and knee joint structures will be determined using imaging techniques, engineering devices to measure tissue strength, stained tissue sections, and identification of the molecules that cause the damage. The ability to walk normally after 30 days of weightlessness will also be determined. Finally, we will determine if treadmill running or climbing can reverse any of the hip and knee joint damage caused by being in the weightless space environment.

Our goal is to determine, 1] if hip and knee joint damage occurs in the weightless space environment, and 2] if recovery from this damage is possible with exercise. From these studies, we also will gain insights into how arthritis develops in wheel-chair bound spinal cord injury patients or after limb surgery, and how it can be prevented.

 

Research Impact/Earth Benefits: From these studies, we also will gain insights into how arthritis develops in wheel-chair bound spinal cord injury patients or after limb surgery, and how it can be prevented.

 

Task Progress & Bibliography Information FY2015 
Task Progress: New project for FY2015.

 

Bibliography Type: Description: (Last Updated: 09/02/2019)  Show Cumulative Bibliography Listing
 
 None in FY 2015