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Fiscal Year: FY 2016  Task Last Updated:  03/10/2017 
PI Name: Globus, Ruth  Ph.D. 
Project Title: Simulated Space Radiation and Weightlessness: Vascular-Bone Coupling Mechanisms to Preserve Skeletal Health 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Musculoskeletal Alterations Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight
Human Research Program Gaps: (1) Osteo04:We do not know the contribution of each risk factor on bone loss and recovery of bone strength, and which factors are the best targets for countermeasure application (IRP Rev E)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: Ruth.K.Globus@nasa.gov  Fax:   
PI Organization Type: NASA CENTER  Phone: 650-604-5247  
Organization Name: NASA Ames Research Center 
PI Address 1: Bone and Signaling Laboratory 
PI Address 2: Space Biosciences Research Branch 
PI Web Page:  
City: Moffett Field  State: CA 
Zip Code: 94035-1000  Congressional District:  18 
Comments:  
Project Type: GROUND  Solicitation:  2010 Crew Health NNJ10ZSA003N 
Start Date: 10/01/2011  End Date:  09/30/2016 
No. of Post Docs: No. of PhD Degrees: 
No. of PhD Candidates: No. of Master' Degrees: 
No. of Master's Candidates: No. of Bachelor's Degrees: 
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment: NOTE: End date changed to 9/30/2016, per NSBRI (Ed., 8/26/15)

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Alwood, Joshua   ( NASA Ames Research Center )
Castillo, Alesha   ( Veterans Affairs Palo Alto Health Care System )
Delp, Michael   ( Florida State University )
Limoli, Charles   ( University of California, Irvine ) 
Grant/Contract No.: NCC 9-58-MA02501 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: Astronauts may develop bone loss in space as a result of environmental challenges such as exposure to weightlessness and ionizing radiation. Oxidative stress results from an imbalance between production of free radicals and the ability of cells to counteract their harmful effects at the molecular level. To date, little is known about the combined effects of weightlessness and space radiation on the musculoskeletal system, the cardiovascular system, and how these two systems interact in maintaining bone health. The overall objectives of our National Space Biomedical Research Institute (NSBRI)-supported research project were to define mechanisms and risks of bone loss in space, to explore the relationship between microvessel function and bone loss due to weightlessness and radiation exposure, and to help develop effective ways to prevent bone loss.

Our NSBRI-supported research project can be considered quite productive--seven peer-reviewed primary papers have been published to date, one published review article, and numerous talks and posters were presented at national and international scientific conferences. Two of the published papers garnered considerable public interest and exposure in the popular press, while one was the subject of both a commentary and a recent article in JAMA. A new manuscript is now in review at a journal (Radiation Research). Three additional primary research papers acknowledging this grant's support are still in preparation (all experimental work complete), and a review article is also being prepared that integrates both our new findings over the life of this project and the contributions of others to this field of research. In the course of this project, two NASA postdoctoral fellowships (funded by the Space Biology program, 3-yr in duration) were awarded to perform work related to this grant. Further, results obtained in the course of executing this grant's research contributed key preliminary results to two new grants that were awarded recently by NASA. Thus, considerable scientific advances and leverage were realized as a consequence of this NSBRI award.

Using mice to simulate weightlessness and space-relevant radiation, results from the series of studies supported by this grant demonstrate that both of these environmental conditions interact to induce early impairment of endothelium-dependent vasodilation and cancellous bone loss. However, the only sustained vascular endothelial cell dysfunction is that mediated by exposure to High-Z-High Energy ions (HZE) and not by simulated weightlessness. If such results translate to the human condition, then long-term dysfunction of the vascular endothelium induced by HZE particles could be a major contributor to the development of atherosclerotic cardiovascular disease in astronauts, as well as contribute to the long-term bone loss.

We find that simulated weightlessness causes decrements in both slow-turnover cortical bone tissue and high turnover cancellous tissue, whereas ionization radiation (0.5-2Gy) causes decrements only in cancellous tissue. Whereas the radiation-induced deficits in skeletal microarchitecture diminish over a period of 6-7 months due to age-related bone loss in control animals, dysfunction in cell populations persists. HZE but not protons or gamma (<2Gy) cause defects in osteoblastogenesis from bone marrow derived stem cells and progenitors. This defect can be attributed to persistent deficits in progenitor cell proliferation and colony growth, whereas the capacity to differentiate into osteoblast-like cells and mineralize an extracellular matrix (the hallmark of osteoblasts) is retained. In addition, bones from HZE-irradiated animals can respond later to anabolic loading stimulus with improved bone formation, although there is some evidence from analyses by dynamic histomorphometry and gene expression that there may be persistent defects in osteoprogenitor cell populations localized to regions adjacent to the periosteal surfaces of bone tissue. Together, these findings on marrow-derived progenitors and periosteal cell behavior lead us to predict that fracture healing and perhaps other wound healing processes that depend mesenchymal stem cells derived from the marrow and/or periosteal bone surfaces are deficient after exposure to HZE at space relevant doses. This prediction is both consistent with a few reports in the scientific literature and may have relevance to regenerative medicine in space, thus represents a potentially important area for future study. With respect to prevention, either mechanical stimulation (resembling vigorous exercise) or feeding a diet containing dried plum, can improve bone structure despite prior exposure to HZE. In contrast, treatment with antioxidants that have displayed at least some radioprotective properties (lipoic acid injections, anti-oxidant cocktail, or treatment with an anti-inflammatory (Ibuprofen)) failed to prevent radiation-induced bone loss. These findings imply treatment with antioxidants alone are unlikely to prove fully protective to the skeleton exposed to ionizing radiation.

In sum, findings from our studies show that in the short term, ionizing radiation and simulated weightlessness cause greater deficits in blood vessels when combined compared to either challenge alone. In the long term, HZE but not unloading, can lead to persistent, adverse consequences for bone cell and vessel function, possibly due to oxidative stress-related pathways. Novel countermeasures to radiation-induced damage to the skeleton identified in the course of this project include both mechanical stimulation and a dietary supplement.

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: A better understanding of the mechanisms and long-term risks posed by exposure to weightlessness and radiation in space is needed to help protect the skeletal health of astronauts during and after long duration, exploration class missions. We hypothesize that countermeasures to unloading and radiation-induced bone loss that target cells responsible for bone formation and bone's vascular supply will be useful for limiting continued bone loss in space and preserving subsequent recovery. Cellular and molecular mechanisms that contribute to the formation of new bone (stem cells, osteoprogenitors, and osteoblasts) will be defined, using ground-based rodent models for simulating space radiation and weightlessness.

On the basis of the mechanistic insight gained, potential anti-oxidant countermeasures will be tested in the following specific aims. Aim 1: Determine how prolonged weightlessness and space radiation (simulated spaceflight) cause functional and structural changes in skeletal vasculature and bone. Aim 2. Determine the extent to which specific countermeasures protect against weightlessness and space radiation-induced bone loss and vascular dysfunction. Aim 3. Determine how low dose space radiation influences later skeletal recovery from prolonged weightlessness. Aim 4. Determine if transient treatment with countermeasures protects from bone loss caused by weightlessness and radiation during subsequent aging. These studies will provide important new insight into the bone loss that is caused by musculoskeletal disuse and radiation at the molecular, cell, and tissue level, with biomedical applications to Earth (e.g., radiotherapy, accidental exposures), as well as space.

 

Task Progress: Astronauts may develop bone loss in space as a result of environmental challenges, such as exposure to weightlessness and ionizing radiation. Oxidative stress results from an imbalance between production of free radicals and the ability of cells to counteract their harmful effects at the molecular level. The overall objectives of our research are to define the mechanisms and risks of bone loss in space and to help develop effective ways to prevent that bone loss. We hypothesize weightlessness and radiation together cause oxidative stress, adversely affecting both bone and the blood vessels that feed muscle and bone.

This last year, four published papers describe results from our experiments with mice testing various aspects of our hypothesis. We examined the effects of radiation and/or simulated weightlessness by hindlimb unloading on bone and blood vessel function either after a short period or at a later time after transient exposures. In short term studies the combination of weightlessness and heavy ion radiation together cause worse deficits in blood vessel function than either factor alone, and these deficits appear to be mediated via free radical-related pathways. In contrast, long-term studies show that bones and vessels can recover from exposure to transient simulated weightlessness, but cannot recover fully from heavy ion radiation. With respect to prevention, either mechanical stimulation (resembling vigorous exercise) or feeding a diet containing dried plum, can improve bone structure despite prior exposure to heavy ion radiation. In sum, recent findings from our studies show that in the short term, ionizing radiation and simulated weightlessness cause greater deficits in blood vessels when combined compared to either challenge alone. In the long term, heavy ion radiation, but not unloading, can lead to persistent, adverse consequences for bone and vessel function, possibly due to oxidative stress-related pathways.

 

Bibliography Type: Description: (Last Updated: 07/15/2019) Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Ghosh P, Behnke BJ, Stabley JN, Kilar CR, Park Y, Narayanan A, Alwood JS, Shirazi-Fard Y, Schreurs AS, Globus RK, Delp MD. "Effects of high-LET radiation exposure and hindlimb unloading on skeletal muscle resistance artery vasomotor properties and cancellous bone microarchitecture in mice." Radiat Res. 2016 Mar;185(3):257-66. http://dx.doi.org/10.1667/RR4308.1 ; PubMed PMID: 26930379 , Mar-2016
Articles in Peer-reviewed Journals Delp MD, Charvat JM, Limoli CL, Globus RK, Ghosh P. "Apollo lunar astronauts show higher cardiovascular disease mortality: Possible deep space radiation effects on the vascular endothelium." Sci Rep. 2016 Jul 28;6:29901. http://dx.doi.org/10.1038/srep29901 ; PubMed PMID: 27467019; PubMed Central PMCID: PMC4964660 , Jul-2016
Articles in Peer-reviewed Journals Globus RK, Morey-Holton E. "Hindlimb unloading: rodent analog for microgravity." J Appl Physiol (1985). 2016 May 15;120(10):1196-206. Review. http://dx.doi.org/10.1152/japplphysiol.00997.2015 ; PubMed PMID: 26869711 , May-2016
Articles in Peer-reviewed Journals Alwood JS, Shahnazari M, Chicana B, Schreurs AS, Kumar A, Bartolini A, Shirazi-Fard Y, Globus RK. "Ionizing radiation stimulates expression of pro-osteoclastogenic genes in marrow and skeletal tissue." J Interferon Cytokine Res. 2015 Jun;35(6):480-7. http://dx.doi.org/10.1089/jir.2014.0152 ; PubMed PMID: 25734366; PubMed Central PMCID: PMC4490751 , Jun-2015
Articles in Peer-reviewed Journals Prisby RD, Alwood JS, Behnke BJ, Stabley JN, McCullough DJ, Ghosh P, Globus RK, Delp MD. "Effects of hindlimb unloading and ionizing radiation on skeletal muscle resistance artery vasodilation and its relation to cancellous bone in mice." J Appl Physiol (1985). 2016 Jan 15;120(2):97-106. Epub 2015 Oct 15. http://dx.doi.org/10.1152/japplphysiol.00423.2015 ; PubMed PMID: 26472865 , Jan-2016
Articles in Peer-reviewed Journals Prisby RD, Behnke BJ, Allen MR, Delp MD. "Effects of skeletal unloading on the vasomotor properties of the rat femur principal nutrient artery." Journal of Applied Physiology. 2015 Apr 15;118(8):980-8. Epub 2015 Jan 29. http://dx.doi.org/10.1152/japplphysiol.00576.2014 ; PubMed PMID: 25635000; PubMed Central PMCID: PMC4398884 , Apr-2015
Articles in Peer-reviewed Journals Schreurs AS, Shirazi-Fard Y, Shahnazari M, Alwood JS, Truong TA, Tahimic CG, Limoli CL, Turner ND, Halloran B, Globus RK. "Dried plum diet protects from bone loss caused by ionizing radiation." Sci Rep. 2016 Feb 11;6:21343. http://dx.doi.org/10.1038/srep21343 ; PubMed PMID: 26867002; PubMed Central PMCID: PMC4750446 , Feb-2016
Articles in Peer-reviewed Journals Shirazi-Fard Y, Alwood JS, Schreurs AS, Castillo AB, Globus RK. "Mechanical loading causes site-specific anabolic effects on bone following exposure to ionizing radiation." Bone. 2015 Dec;81:260-9. Epub 2015 Jul 18. http://dx.doi.org/10.1016/j.bone.2015.07.019 ; PubMed PMID: 26191778 , Dec-2015
Articles in Peer-reviewed Journals Alwood JS, Tran LH, Schreurs AS, Shirazi-Fard Y, Kumar A, Hilton D, Tahimic CGT, Globus RK. "Dose- and ion-dependent effects in the oxidative stress response to space-like radiation exposure in the skeletal system." Int J Mol Sci. 2017 Oct 10;18(10):E2117. https://doi.org/10.3390/ijms18102117 ; PubMed PMID: 28994728; PubMed Central PMCID: PMC5666799 , Oct-2017
Awards Schreurs A-S. "American Society for Bone and Mineral Research (ASBMR) young investigator travel award, September 2016." Sep-2016
Awards Schreurs A-S. "HRP-IWS (Human Research Program-Investigators' Workshop), travel award, February 2016." Feb-2016
Awards Globus R. "NASA Ames Honor Award, September 2016." Sep-2015
Awards Globus R. "NASA Scientific Achievement Medal, July 2015." Jul-2015
Awards Shirazi-Fard Y. "American Society of Bone and Mineral Research Young Investigator Travel Grant, September 2015." Sep-2015
Awards Shirazi-Fard Y. "Radiation Research Society Scholar in Training Travel Award, September 2016." Sep-2016
Significant Media Coverage Kaplan S. "Studying heart disease in astronauts yields clues but not conclusive evidence. Coverage of PI Globus' paper: Delp MD, Charvat JM, Limoli CL, Globus RK, Ghosh P. Apollo lunar astronauts show higher cardiovascular disease mortality: Possible deep space radiation effects on the vascular endothelium. Sci Rep. 2016 Jul 28;6:29901. " Washington Post feature article, July 28, 2016. https://www.washingtonpost.com/news/speaking-of-science/wp/2016/07/28/studying-heart-disease-in-astronauts-yields-clues-but-not-conclusive-evidence/ , Jul-2016
Download in PDF pdf     
Fiscal Year: FY 2015  Task Last Updated:  10/14/2014 
PI Name: Globus, Ruth  Ph.D. 
Project Title: Simulated Space Radiation and Weightlessness: Vascular-Bone Coupling Mechanisms to Preserve Skeletal Health 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Musculoskeletal Alterations Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight
Human Research Program Gaps: (1) Osteo04:We do not know the contribution of each risk factor on bone loss and recovery of bone strength, and which factors are the best targets for countermeasure application (IRP Rev E)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: Ruth.K.Globus@nasa.gov  Fax:   
PI Organization Type: NASA CENTER  Phone: 650-604-5247  
Organization Name: NASA Ames Research Center 
PI Address 1: Bone and Signaling Laboratory 
PI Address 2: Space Biosciences Research Branch 
PI Web Page:  
City: Moffett Field  State: CA 
Zip Code: 94035-1000  Congressional District:  18 
Comments:  
Project Type: GROUND  Solicitation:  2010 Crew Health NNJ10ZSA003N 
Start Date: 10/01/2011  End Date:  09/30/2016 
No. of Post Docs: No. of PhD Degrees: 
No. of PhD Candidates: No. of Master' Degrees: 
No. of Master's Candidates: No. of Bachelor's Degrees: 
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment: NOTE: End date changed to 9/30/2016, per NSBRI (Ed., 8/26/15)

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Alwood, Joshua   ( NASA Ames Research Center )
Castillo, Alesha   ( Veterans Affairs Palo Alto Health Care System )
Delp, Michael   ( Florida State University )
Limoli, Charles   ( University of California, Irvine ) 
Grant/Contract No.: NCC 9-58-MA02501 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: (1) Original project aims/objectives. Long term spaceflight leads to extensive changes in the musculoskeletal system attributable to unloading in microgravity, although with future exploration outside the protection of Earth's magnetosphere, space radiation also may have adverse, long term effects. Acute, whole body irradiation at high doses can cause significant depletion of stem/progenitor cell pools throughout the body as well as inflammation associated with prompt tissue degradation. To date, little is known about the combined effects of weightlessness and space radiation on the musculoskeletal system and its associated vasculature. Radiation can increase cancellous osteoclasts, leading to rapid bone loss, which can be mitigated in the short term by treatment with a potent anti-oxidant (alpha-lipoic acid). Furthermore, simulated weightlessness in adult mice exacerbates the adverse effects of space-relevant radiation on cancellous tissue, mechanical properties, and osteoprogenitors, as well as long-term responses during recovery from disuse. If weightlessness undermines the capacity to mount radio-protective mechanisms, then potentially irreversible oxidative injury and persistent skeletal damage to stem and progenitor populations may ensue. Deficits in vascular-perfusion coupling also can lead to profound bone loss and may contribute to spaceflight-induced osteopenia. Together, these findings support a two-pronged approach for countermeasure development; one focusing on preventing acute bone loss and another on protecting cell populations needed for skeletal remodeling in the long term. Our long term goals are twofold--define the mechanisms and risk of bone loss in the spaceflight environment and facilitate the development of effective countermeasures if needed. Our working hypothesis is that prolonged musculoskeletal disuse and radiation together cause cumulative, adverse changes in the structure and function of bone and its vasculature resulting from oxidative stress, and prevent recovery from unloading by damaging the stem and progenitor cells needed for subsequent recovery. The rationale for this research is that a better understanding of the mechanisms and long-term risks posed by exposure to weightlessness and space radiation will improve the development and application of countermeasures for future exploration-class missions.

(2) Key findings were:

• Both weightlessness and ionizing radiation) caused rapid but transient increase in skeletal expression levels of the global antioxidant transcription factor, nrf2 expression, indicating that weightlessness and radiation pose an acute oxidative challenge to skeletal tissue.

• Total-body irradiation (gamma or heavy-ion) caused temporal, concerted regulation of gene expression within both marrow and mineralized tissue for select, osteoclastogenic cytokines and markers of bone resorption; this is likely to account for the rapid and progressive deterioration of cancellous microarchitecture observed following exposure to ionizing radiation.

• A dietary countermeasure with high antioxidant activity showed an impressive ability to maintain the integrity of their bone structure after high LET irradiation, making it a strong candidate to mitigate radiation-induced tissue damage.

• High LET radiation did not completely impair ability of the bone to respond to a potent anabolic mechanical stimulus, rest-inserted axial loading.

• Simulated weightlessness and iron radiation each impaired peak endothelium-dependent vasodilation and the combination of HU and IR further impaired endothelium-dependent vasodilation.

(3) Impact of key findings on hypotheses, technology requirements, objectives, and specific aims of the original proposal.

• Further experiments and analysis of tissues from the dietary intervention and mechanical stimulation experiments needed.

• Results from the iron radiation experiment support the theory of a bone-vascular coupling for bone remodeling in response to simulated spaceflight.

(4) Proposed research plan for the coming year. In the coming year, we plan to complete analysis of tissues and bones from recent extensive experimentation conducted at NASA Space Radiation Laboratory/Brookhaven National Lab (Aim 1 and 2). We also will conduct experiments at both NSRL/BNL and ARC for this coming year that will: 1) evaluate the effects of the new dietary intervention on vascular reactivity and bone structure following 2 wks of simulated weightlessness alone and combined with simulated space radiation (protons + iron) (Aim 2); 2) define the ability of bone and vascular responses to recover over the long term (2-6 mos) from the adverse effects of protons + iron on a standard vs. supplemented diet (Aim 2, 3) determine the time- and radiation- dependence of anabolic mechanical loading during recovery from simulated space radiation (Aim 1, 3).

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: Our research project focuses on the effects of spaceflight environmental factors, such as microgravity and irradiation, on the skeleton. Through use of an antioxidant as a potential countermeasure to the effects of spaceflight could provide Earth-based benefits in areas including radioprotection, mitigation of oxidative stress, disuse osteoporosis, and fracture healing. Findings are relevant to biomedical concerns including skeletal degeneration such as those caused by radiotherapy, spinal cord injury, or prolonged bedrest.

 

Task Progress: We are entering the last year of our four-year grant. We have successfully completed the majority of the first two Aims of the grant, and this coming year will focus on recovery and countermeasures. By the grant completion, our results will inform the design of a flight experiment utilizing antioxidants or dietary supplements as a countermeasure to spaceflight-induced bone loss and established the relevance of changes in vascular reactivity to simulated spaceflight-induced bone loss. We are also using models of mechanical loading as an anabolic stimulus to bone after exposure to ionizing radiation.

 

Bibliography Type: Description: (Last Updated: 07/15/2019) Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Prisby RD, BehnkeBJ, Allen MR, Delp MD. "Effects of skeletal unloading on the vasomotor properties of the rat femur principal nutrient artery." Journal of Applied Physiology. Pending review as of August 2014. , Aug-2014
Awards Schreurs A-S. "NASA Postdoctoral Program (NPP) Fellowship, Year 2, August 2014." Aug-2014
Awards Schreurs A-S. "Travel grant awarded to attend Association of Radiation Research, 6/29-7/2/2014 Brighton, UK, June 2014." Jun-2014
Awards Alwood J. "2012 Presidential Early Career Award for Scientists and Engineers (PECASE), announced Dec. 23, 2013." Dec-2013
Download in PDF pdf     
Fiscal Year: FY 2014  Task Last Updated:  10/16/2013 
PI Name: Globus, Ruth  Ph.D. 
Project Title: Simulated Space Radiation and Weightlessness: Vascular-Bone Coupling Mechanisms to Preserve Skeletal Health 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Musculoskeletal Alterations Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight
Human Research Program Gaps: (1) Osteo04:We do not know the contribution of each risk factor on bone loss and recovery of bone strength, and which factors are the best targets for countermeasure application (IRP Rev E)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: Ruth.K.Globus@nasa.gov  Fax:   
PI Organization Type: NASA CENTER  Phone: 650-604-5247  
Organization Name: NASA Ames Research Center 
PI Address 1: Bone and Signaling Laboratory 
PI Address 2: Space Biosciences Research Branch 
PI Web Page:  
City: Moffett Field  State: CA 
Zip Code: 94035-1000  Congressional District:  18 
Comments:  
Project Type: GROUND  Solicitation:  2010 Crew Health NNJ10ZSA003N 
Start Date: 10/01/2011  End Date:  09/30/2015 
No. of Post Docs: No. of PhD Degrees: 
No. of PhD Candidates: No. of Master' Degrees: 
No. of Master's Candidates: No. of Bachelor's Degrees: 
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment:

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Alwood, Joshua   ( NASA Ames Research Center )
Castillo, Alesha   ( Veterans Affairs Palo Alto Health Care System )
Delp, Michael   ( University of Florida )
Limoli, Charles   ( University of California, Irvine ) 
Grant/Contract No.: NCC 9-58-MA02501 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: (1) Original project aims/objectives. Long term spaceflight leads to extensive changes in the musculoskeletal system attributable to unloading in microgravity, although with future exploration outside the protection of Earth's magnetosphere, space radiation also may have adverse, long term effects. Acute, whole body irradiation at high doses can cause significant depletion of stem/progenitor cell pools throughout the body as well as inflammation associated with prompt tissue degradation. To date, little is known about the combined effects of weightlessness and space radiation on the musculoskeletal system and its associated vasculature. Radiation can increase cancellous osteoclasts, leading to rapid bone loss, which can be mitigated in the short term by treatment with a potent anti-oxidant (alpha-lipoic acid). Furthermore, simulated weightlessness in adult mice exacerbates the adverse effects of space-relevant radiation on cancellous tissue, mechanical properties, and osteoprogenitors, as well as long-term responses during recovery from disuse. If weightlessness undermines the capacity to mount radio-protective mechanisms, then potentially irreversible oxidative injury and persistent skeletal damage to stem and progenitor populations may ensue. Deficits in vascular-perfusion coupling also can lead to profound bone loss and may contribute to spaceflight-induced osteopenia. Together, these findings support a two-pronged approach for countermeasure development; one focusing on preventing acute bone loss and another on protecting cell populations needed for skeletal remodeling in the long term. Our long term goals are twofold; define the mechanisms and risk of bone loss in the spaceflight environment and facilitate the development of effective countermeasures if needed. Our working hypothesis is that prolonged musculoskeletal disuse and radiation together cause cumulative, adverse changes in the structure and function of bone and its vasculature resulting from oxidative stress, and prevent recovery from unloading by damaging the stem and progenitor cells needed for subsequent recovery. The rationale for this research is that a better understanding of the mechanisms and long-term risks posed by exposure to weightlessness and space radiation will improve the development and application of countermeasures for future exploration-class missions.

(2) Key Findings. Substantial progress was made in completing Aims 1 and 2 of the original proposal. A standard protocol for simulating the spaceflight factors of space radiation (dual-ion; proton+iron) and weightlessness (hindlimb unloading) was established, and the influence of possible nutritional countermeasures (antioxidant cocktail and flaxseed) tested. The following provides a summary of key findings.

• Dietary supplementation of male, 16wk old C57Bl/6J mice with an antioxidant cocktail or flaxseed did not prevent decrements in cancellous bone volume and microarchitecture caused by exposure to ionizing radiation.

• Gamma irradiation and hindlimb unloading each reduced endothelium-dependent vasodilation of the gastrocnemius feed artery, which correlated well with cancellous tissue decrements. Signaling pathways in addition to those related to nitric oxide (NO) release may contribute to observed changes in vascular reactivity during simulated spaceflight.

(3) Impact of key findings on hypotheses, technology requirements, objectives, and specific aims of the original proposal.

• Further analysis of tissues and results from the dietary intervention strategies tested to date are needed before definitive conclusions can be drawn and impact on hypotheses and aims determined. Results obtained to date lead us to focus on evaluating tissues at the mRNA and biochemical levels for evidence of both oxidative damage and the impact of the dietary countermeasures.

• Results from the gamma radiation experiment support the theory of a bone-vascular coupling for bone remodeling in response to simulated spaceflight.

(4) Proposed research plan for the coming year. In the coming year, we plan to complete analysis of tissues and bones from the dietary countermeasure experiments using ionizing radiation (Aim 1 and 2). We also will conduct experiments at both NSRL/BNL and ARC for this coming year that will: continue analysis of tissues and data from vascular reactivity experiments using simulated space radiation at NSRL/BNL with Dr. Delp's team and perform additional in-depth experiments to evaluate vascular responses (Aim 1); analyze skeletal gene expression after exposure to simulated space radiation (Aim 1 and 2); determine the influence of dietary antioxidants on skeletal responses to simulated weightlessness (Aim 2); assess the ability of axial loading to stimulate bone formation after exposure of the mice to simulated space radiation in recovery experiments (Aim 3); perform additional follow-on experiments to determine the ability of dietary countermeasures to prevent bone loss caused by simulated spaceflight (Aim 2, 3).

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: Our research project focuses on the effects of spaceflight environmental factors, such as microgravity and irradiation, on the skeleton. Through use of an antioxidant as a potential countermeasure to the effects of spaceflight our research could provide Earth-based benefits in areas including radioprotection, mitigation of oxidative stress, and disuse osteoporosis. Findings are relevant to biomedical concerns including skeletal degeneration such as those caused by radiotherapy, spinal cord injury, or prolonged bedrest.

 

Task Progress: During this reporting period, we performed series of experiments at the NASA Space Radiation Laboratory at Brookhaven, NSRL-BNL, using iron (56Fe) or a sequential exposure to protons / iron / protons, and separate experiments at NASA Ames Research Center (ARC), using 137Cs. Analysis of samples is still in progress from the recent NSRL experiments, which focused on dietary and mechanical countermeasures to radiations and skeletal unloading. Analysis of an experiment that focused on the effects of gamma irradiation and disuse on the vascular reactivity showed impaired vasodilation in gastrocnemius muscle feed arteries. It is likely that both skeletal disuse and radiation causes diminished vascular capacity. Initial results revealed that dietary interventions (an antioxidant cocktail or flaxseed) did not protect cancellous tissue from ionizing radiation; further experiments are in progress.

 

Bibliography Type: Description: (Last Updated: 07/15/2019) Show Cumulative Bibliography Listing
 
Download in PDF pdf     
Fiscal Year: FY 2013  Task Last Updated:  11/16/2012 
PI Name: Globus, Ruth  Ph.D. 
Project Title: Simulated Space Radiation and Weightlessness: Vascular-Bone Coupling Mechanisms to Preserve Skeletal Health 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Musculoskeletal Alterations Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight
Human Research Program Gaps: (1) Osteo04:We do not know the contribution of each risk factor on bone loss and recovery of bone strength, and which factors are the best targets for countermeasure application (IRP Rev E)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: Ruth.K.Globus@nasa.gov  Fax:   
PI Organization Type: NASA CENTER  Phone: 650-604-5247  
Organization Name: NASA Ames Research Center 
PI Address 1: Bone and Signaling Laboratory 
PI Address 2: Space Biosciences Research Branch 
PI Web Page:  
City: Moffett Field  State: CA 
Zip Code: 94035-1000  Congressional District:  18 
Comments:  
Project Type: GROUND  Solicitation:  2010 Crew Health NNJ10ZSA003N 
Start Date: 10/01/2011  End Date:  09/30/2015 
No. of Post Docs: No. of PhD Degrees: 
No. of PhD Candidates: No. of Master' Degrees: 
No. of Master's Candidates: No. of Bachelor's Degrees: 
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment:

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Alwood, Joshua   ( NASA Ames Research Center )
Castillo, Alesha   ( Veterans Affairs Palo Alto Health Care System )
Delp, Michael   ( University of Florida )
Limoli, Charles   ( University of California, Irvine ) 
Grant/Contract No.: NCC 9-58-MA02501 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: (1) Original project aims/objectives. Long term spaceflight leads to extensive changes in the musculoskeletal system attributable to unloading in microgravity, although with future exploration outside the protection of Earth's magnetosphere space radiation also may have adverse, long term effects. Acute, whole body irradiation at high doses can cause significant depletion of stem/progenitor cell pools throughout the body as well as inflammation associated with prompt tissue degradation. To date, little is known about the combined effects of weightlessness and space radiation on the musculoskeletal system and its associated vasculature. Radiation can increase cancellous osteoclasts, leading to rapid bone loss, which can be mitigated in the short term by treatment with a potent anti-oxidant (a-lipoic acid). Furthermore, simulated weightlessness in adult mice exacerbates the adverse effects of space-relevant radiation on cancellous tissue, mechanical properties and osteoprogenitors, as well as long-term responses during recovery from disuse. If weightlessness undermines the capacity to mount radio-protective mechanisms, then potentially irreversible oxidative injury and persistent skeletal damage to stem and progenitor populations may ensue. Deficits in vascular-perfusion coupling also can lead to profound bone loss and may contribute to spaceflight-induced osteopenia. Together, these findings support a two-pronged approach for countermeasure development; one focusing on preventing acute bone loss and another on protecting cell populations needed for skeletal remodeling in the long term. Our long term goals are twofold; define the mechanisms and risk of bone loss in the spaceflight environment and facilitate the development of effective countermeasures if needed. Our working hypothesis is that prolonged musculoskeletal disuse and radiation together cause cumulative, adverse changes in the structure and function of bone and its vasculature resulting from oxidative stress, and prevent recovery from unloading by damaging the stem and progenitor cells needed for subsequent recovery. The rationale for this research is that a better understanding of the mechanisms and long-term risks posed by exposure to weightlessness and space radiation will improve the development and application of countermeasures for future exploration-class missions.

(2) Key Findings. Progress has been made on multiple fronts during the first year of the grant. We have confirmed structural and cellular phenotypes with previous results. Work remains to study the cellular and molecular mechanisms in more detail and to investigate how antioxidants can effectively modulate skeletal radioresponses. The following provides a summary of key findings.

Bone Structure and Vascular Reactivity Acute Effects

• Radiation-induced bone loss results above a cumulative dose of 100 cGy from low- or high-LET ion constituents

• Vasodilation responses to acetylcholine were diminished in gastrocnemius muscle feed arteries in hindlimb unloaded and irradiated mice relative to that in control animals. The combined effects of hindlimb unloading and irradiation did not further depress endothelium-dependent vasodilation.

Simulated Spaceflight Effects on Osteoblast Cell Cultures

• These results suggest that osteoprogenitor growth from marrow progenitors may be impaired above a threshold dose of heavy-ions between 20 and 50 cGy

(3) These experiments inform the radiation doses and duration of hindlimb unloading to be utilized in future work, as part of Milestone 1, 2, and 3 of our grant proposal, and to establish treatment schedules to modulate bone structure and vascular reactivity

(4) In the coming year, we plan to test antioxidant countermeasures to radiation-induced bone loss and to protect osteoprogenitors. Pilot studies will be conducted at ARC and NSRL/BNL to establish the efficacy of different antioxidant compounds and additional experiments will be conducted to investigate if simulated space-irradiation affects vascular reactivity, responses to unloading, and oxidative mechanisms.

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: Our research project focuses on the effects of spaceflight environmental factors, such as microgravity and irradiation, on the skeleton. Through use of an antioxidant as a potential countermeasure to the effects of spaceflight, our research could provide Earth-based benefits in areas including radioprotection, mitigation of oxidative stress and disuse osteoporosis.

 

Task Progress: During this reporting period, we performed two series of experiments at the NASA Space Radiation Laboratory at Brookhaven, NSRL-BNL, (using iron (56Fe) or a sequential exposure to protons / iron / protons), and separate experiments at NASA Ames Research Center (ARC), (using 137Cs). Analysis of samples is still in progress from the recent NSRL experiments, which focused on acute effects of sequential radiation exposure in combination with disuse. Analysis of the experiment conducted at NASA ARC which focused on the acute effects of gamma irradiation and disuse on the vascular reactivity is nearing completion. The first series of experiments at NSRL/BNL and NASA ARC were conducted to identify the timing and extent of radiation and unloading effects on bone structure and function. Our results suggest unloading and irradiation affected skeletal structure of adult mice to a similar extent and the sequential beam exposure had similar effects as exposure to iron alone within a 2-week time frame. Vasodilation responses to acetylcholine were diminished in gastrocnemius muscle feed arteries in hindlimb unloaded and irradiated mice relative to controls. The combined effects of hindlimb unloading and irradiation did not further depress endothelium-dependent vasodilation. Results from separate, related experiments demonstrate that altered redox defense mechanisms and sensitivity to DNA-damage in osteoprogenitors and precursors persist long after acute exposure to heavy-ion irradiation. These results inform the radiation doses and duration of unloading to be utilized in future work, as part of Milestone 1, 2, and 3 of our grant proposal, and help establish treatment schedules to investigate the responses of bone structure and vascular reactivity to both radiation and simulated weightlessness. Thus, substantive progress has been made on multiple fronts during the first year of the grant. Work remains to study the cellular and molecular mechanisms in greater detail and to investigate how and which antioxidants effectively modulate skeletal changes in response to simulated spaceflight.

ESTIMATED % COMPLETION PER AIM: AIM 1: ~75% complete AIM 2: ~10% complete. AIM 3: ~2% complete As outlined in our proposal, we have been actively involved with several Education & Outreach activities, including the STEM Teacher And Researcher (STAR), the Education Associates' Program (EAP) programs, and the Space Settlement Design Contest.

 

Bibliography Type: Description: (Last Updated: 07/15/2019) Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Alwood JS, Limoli CL, Delp MD, Castillo AB, Globus RK. "Simulated space radiation and weightlessness: vascular-bone coupling mechanisms to preserve skeletal health." 2012 NASA Human Research Program Investigators’ Workshop, Houston, TX, February 14-16, 2012.

2012 NASA Human Research Program Investigators’ Workshop, Houston, TX, February 14-16, 2012. , Feb-2012

Abstracts for Journals and Proceedings Globus RK, Alwood JS, Kumar A, Limoli CL. "Hypothesis: Space Radiation-Induced Bone Loss as Collateral Damage." 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8-11, 2012.

23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8-11, 2012. , Jul-2012

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Fiscal Year: FY 2012  Task Last Updated:  10/05/2011 
PI Name: Globus, Ruth  Ph.D. 
Project Title: Simulated Space Radiation and Weightlessness: Vascular-Bone Coupling Mechanisms to Preserve Skeletal Health 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Musculoskeletal Alterations Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight
Human Research Program Gaps: (1) Osteo04:We do not know the contribution of each risk factor on bone loss and recovery of bone strength, and which factors are the best targets for countermeasure application (IRP Rev E)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: Ruth.K.Globus@nasa.gov  Fax:   
PI Organization Type: NASA CENTER  Phone: 650-604-5247  
Organization Name: NASA Ames Research Center 
PI Address 1: Bone and Signaling Laboratory 
PI Address 2: Space Biosciences Research Branch 
PI Web Page:  
City: Moffett Field  State: CA 
Zip Code: 94035-1000  Congressional District:  18 
Comments:  
Project Type: GROUND  Solicitation:  2010 Crew Health NNJ10ZSA003N 
Start Date: 10/01/2011  End Date:  09/30/2015 
No. of Post Docs:   No. of PhD Degrees:   
No. of PhD Candidates:   No. of Master' Degrees:   
No. of Master's Candidates:   No. of Bachelor's Degrees:   
No. of Bachelor's Candidates:   Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment:

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Alwood, Joshua   ( NASA Ames Research Center )
Castillo, Alesha   ( Veterans Affairs Palo Alto Health Care System )
Delp, Michael   ( University of Florida )
Limoli, Charles   ( University of California, Irvine ) 
Grant/Contract No.: NCC 9-58-MA02501 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: Astronauts develop bone loss as a result of spaceflight environmental conditions, including increased ionizing radiation, microgravity with ensuing fluid shifts and altered forces on muscles and bones, confinement, and stress. The objectives of our proposal are twofold; define the mechanisms and risk of bone loss in the spaceflight environment and facilitate the development of effective countermeasures, if needed. Our working hypothesis is that prolonged disuse and radiation together cause cumulative, adverse changes in the structure and function of bone and its vasculature resulting from oxidative stress, and prevent recovery from unloading by damaging the stem and progenitor cells needed for subsequent recovery.

Our plan has three aims.

AIM 1: Determine the functional and structural consequences of prolonged weightlessness and space radiation (simulated spaceflight) for bone and skeletal vasculature in the context of bone cell function and oxidative stress.

AIM 2: Determine the extent to which an anti-oxidant protects against weightlessness and space radiation-induced bone loss and vascular dysfunction.

AIM 3: Determine how space radiation influences later skeletal and vascular recovery from prolonged weightlessness and the potential of anti-oxidants to improve or prevent this recovery.

This proposal addresses the current research announcement and NASA's HRP-Integrated Research Plan risks for the bone system by defining mechanisms and countermeasures designed to prevent the effects of combined unloading and radiation on bone, with the goal of enabling human space exploration.

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: 0

 

Task Progress: New project for FY2012.

 

Bibliography Type: Description: (Last Updated: 07/15/2019) Show Cumulative Bibliography Listing