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Project Title:  Human endothelial cells in 2-D and 3-D systems; non-cancer effects and space-related radiations Reduce
Fiscal Year: FY 2011 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2005  
End Date: 09/30/2011  
Task Last Updated: 06/03/2013 
Download report in PDF pdf
Principal Investigator/Affiliation:   Geard, Charles Ray Ph.D. / Columbia University 
Address:  Center for Radiological Research 
VC 11-206, 630 W 168TH ST 
New York , NY 10032-3702 
Email: crg4@columbia.edu  
Phone: 212-305-5662   
Congressional District: 15 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Columbia University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Grabham, Peter  Columbia University 
Hu, Burong  Columbia University 
Ponnaiya, Brian  Columbia University 
Project Information: Grant/Contract No. NNJ05HI37G 
Responsible Center: NASA JSC 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2004 Radiation Biology NNH04ZUU005N 
Grant/Contract No.: NNJ05HI37G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Degen01:How can tissue specific experimental models be developed for the major degenerative tissue risks, including cardiovascular, lens, digestive, endocrine, and other tissue systems in order to estimate space radiation risks for degenerative diseases? (IRP Rev F)
(2) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
Flight Assignment/Project Notes: NOTE: Change in Gaps per HRR information (Ed., 9/26/2011)

NOTE: Received no-cost extension to 9/30/2011 per C. Guidry/JSC (10/2010)

NOTE: Received no-cost extension to 9/30/2010 per J. Dardano/JSC (8/09)

Task Description: Though not prone to carcinogenic change the endothelial cell is of critical importance to the normal functioning of all tissues and organs of the body. Endothelial cells constitute the linings of the blood circulatory system, and disruption of this function can lead to multiple changes, from minor to catastrophic. Cardio-vascular diseases are the leading cause of death in developed societies. Endothelial cells have been studied in monolayers [2-dimensional ] for many years, however it is clear that cell behavior in the third dimension [tissue-like structures] is not necessarily well represented by such studies. Recognizing the crucial role of the endothelial cell we studied the radiation sensitivity of the chromosomes of normal human umbilical vein endothelial cells [HUVEC] to low LET radiation. It was determined that chromatid-type aberrations in late G2 cells were exquisitely linearly sensitive to radiation doses in the range 0.0125 to 0.8 Gy. This response was ~ 3 times more sensitive than that of early-mid G2 cellls, and ~15 times more sensitive than for chromosome-type aberrations in non-cycling G1 cells [dose range, 0.5-8.0 Gy]. Recently we have obtained 3-dimensional capillary like tubular structures from the culture of HUVECs in collagen gel matrices. We propose to irradiate 2D [cell monolayers] and 3D [capillary-like cell structures] with Fe ions at 1GeV with doses where a bystander effect may apply [< 0.1 Gy] to doses where multiple traversals are expected [up to 1Gy]. We will compare responses to low LET X-rays and to alpha particles at the same LET as the Fe ions, where delta rays are less likely to be influential. Chromosomal changes using G2-PCC`s and state of the art m-FISH, micronuclei, apoptosis and cell-cell, cell-matrix interacting proteins will be quantified. We hypothesize that 2D versus 3D culture results in no difference in the responsiveness of human endothelial cells. We further hypothesize that space related radiations are not more effective than low LET radiations for these cells with their crucial role in the maintenance of normal bodily functions.

We have successfully developed 3-D human micro-vasculature models from normal human umbilical vein endothelial cells. These structures have been characterized by multi- photon microscopy and have been irradiated with high energy iron ions and protons. Irradiation of mature vessels led to a breakdown of the vessels after low doses of iron ions [<1 Gy] but no effect of protons out to 3.2 Gray. Monitoring vessel structures over time led to the observation that the 3-D mature vessel network is essentially restored by 12 days, even after 3.2 Gy of iron ions. By contrast the irradiation of developing vessels showed that both protons and iron ions at 1GeV similarly disrupt network vessel development, with ~50% loss of intact vessel length [relative to control] at 3 days after 0.8 Gy. The full pattern of vessel recovery remains to be determined.

DNA damage foci [53BP-1] formation was examined in endothelial cell nuclei in 2-D monolayers and in the cell nuclei of the 3-D micro-vasculature structures. Both protons at 0.22 keV/micrometer and Fe ions at 150 keV/micrometer showed similar kinetics of foci formation with peak yields at 1 hr and a 10 fold decline at 48hrs. However there were dramatic differences in the efficiency of focus formation. At the peak there was ~ one 53 BP-1 focus for each Fe ion traversal and ~ 1 focus for every 1,000 proton traversals. Human endothelial cells can form 3-D micro-vasculature like structures and show quantitative morphological and DNA damage responses after space-like radiations at moderate to high doses. At the fluences likely to be experienced in cells by man in space the question might reasonably be asked about the micro-vasculature; does this matter? Probably not.

Research Impact/Earth Benefits: Understanding the effects of ionizing radiation on the human endothelial cell and its consequences may aid in assessing the impact of diseases involving the circulatory system in general.

Task Progress & Bibliography Information FY2011 
Task Progress: [Editor's note 6/3/2013: No Task Book report received. Progress section and Bibliography compiled from PI's Final Technical Report.]

The most significant achievement from the body of work carried out under support from this grant was the development and introduction to space radiation biology of a human model tissue system. Normal human endothelial cells were encouraged to develop into the capillary-like structures of the human circulatory system. At various stages of development these structures were exposed to proscribed doses of energetic iron particles or protons as found in space, and responses assessed. Along with continued participation in national and international meetings where information was presented and encouragingly discussed, three peer reviewed publications resulted. The last of these was published in June 2012, after submission in December 2011, and acceptance in March 2012. Two highlights resulting from the publications are worth of note. The paper published in the International Journal of Radiation Biology in June 2012 was accorded the honor of having a representative figure of treated capillary structures from the manuscript on the front cover. The paper published in the journal, Radiation Research, in January 2011, was chosen by members of the Radiation Research Society as the most scientifically compelling of the issue. This led to an interview by Marjan Boerman, a student representative, with the PI and colleague Dr. Peter Grabham. The interview is available as a Podcast from the Radiation Research Society.

Bibliography Type: Description: (Last Updated: 06/03/2013) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Grabham P, Hu B, Sharma P, Geard C. "Effects of ionizing radiation on three-dimensional human vessel models: differential effects according to radiation quality and cellular development." Radiat Res. 2011 Jan;175(1):21-8. Epub 2010 Nov 4. PMID: 21175343 , Jan-2011
Articles in Peer-reviewed Journals Grabham P, Bigelow A, Geard C. "DNA damage foci formation and decline in two-dimensional monolayers and in three-dimensional human vessel models: Differential effects according to radiation quality." International Journal of Radiation Biology. 2012 Jun;88(6):493-500. Epub 2012 Apr 30. PMID: 22449005 , Jun-2012
Journal/Magazine covers Grabham P, Bigelow A, Geard C. "Cover in International Journal of Radiation Biology included image from the PI's paper, '"DNA damage foci formation and decline in two-dimensional monolayers and in three-dimensional human vessel models: Differential effects according to radiation quality.' " International Journal of Radiation Biology. 2012 Jun;88(6):493-500. PMID: 22449005 , Jun-2012
Project Title:  Human endothelial cells in 2-D and 3-D systems; non-cancer effects and space-related radiations Reduce
Fiscal Year: FY 2009 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2005  
End Date: 09/30/2011  
Task Last Updated: 10/12/2009 
Download report in PDF pdf
Principal Investigator/Affiliation:   Geard, Charles Ray Ph.D. / Columbia University 
Address:  Center for Radiological Research 
VC 11-206, 630 W 168TH ST 
New York , NY 10032-3702 
Email: crg4@columbia.edu  
Phone: 212-305-5662   
Congressional District: 15 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Columbia University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Grabham, Peter  Columbia University 
Hu, Burong  Columbia University 
Ponnaiya, Brian  Columbia University 
Project Information: Grant/Contract No. NNJ05HI37G 
Responsible Center: NASA JSC 
Grant Monitor: Cucinott1a, Francis  
Center Contact: 281-483-0968 
noaccess@nasa.gov 
Solicitation / Funding Source: 2004 Radiation Biology NNH04ZUU005N 
Grant/Contract No.: NNJ05HI37G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Degen01:How can tissue specific experimental models be developed for the major degenerative tissue risks, including cardiovascular, lens, digestive, endocrine, and other tissue systems in order to estimate space radiation risks for degenerative diseases? (IRP Rev F)
(2) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
Flight Assignment/Project Notes: NOTE: Received no-cost extension to 9/30/2011 per C. Guidry/JSC (10/2010)

NOTE: Received no-cost extension to 9/30/2010 per J. Dardano/JSC (8/09)

Task Description: Though not prone to carcinogenic change the endothelial cell is of critical importance to the normal functioning of all tissues and organs of the body. Endothelial cells constitute the linings of the blood circulatory system, and disruption of this function can lead to multiple changes, from minor to catastrophic. Cardio-vascular diseases are the leading cause of death in developed societies. Endothelial cells have been studied in monolayers [2-dimensional ] for many years, however it is clear that cell behavior in the third dimension [tissue-like structures] is not necessarily well represented by such studies. Recognizing the crucial role of the endothelial cell we studied the radiation sensitivity of the chromosomes of normal human umbilical vein endothelial cells [HUVEC] to low LET radiation. It was determined that chromatid-type aberrations in late G2 cells were exquisitely linearly sensitive to radiation doses in the range 0.0125 to 0.8 Gy. This response was ~ 3 times more sensitive than that of early-mid G2 cellls, and ~15 times more sensitive than for chromosome-type aberrations in non-cycling G1 cells [dose range, 0.5-8.0 Gy]. Recently we have obtained 3-dimensional capillary like tubular structures from the culture of HUVECs in collagen gel matrices. We propose to irradiate 2D [cell monolayers] and 3D [capillary-like cell structures] with Fe ions at 1GeV with doses where a bystander effect may apply [< 0.1 Gy] to doses where multiple traversals are expected [up to 1Gy]. We will compare responses to low LET X-rays and to alpha particles at the same LET as the Fe ions, where delta rays are less likely to be influential. Chromosomal changes using G2-PCC`s and state of the art m-FISH, micronuclei, apoptosis and cell-cell, cell-matrix interacting proteins will be quantified. We hypothesize that 2D versus 3D culture results in no difference in the responsiveness of human endothelial cells. We further hypothesize that space related radiations are not more effective than low LET radiations for these cells with their crucial role in the maintenance of normal bodily functions.

We have successfully developed 3-D human micro-vasculature models from normal human umbilical vein endothelial cells. These structures have been characterized by multi- photon microscopy and have been irradiated with high energy iron ions and protons. Irradiation of mature vessels led to a breakdown of the vessels after low doses of iron ions [<1 Gy] but no effect of protons out to 3.2 Gray. Monitoring vessel structures over time led to the observation that the 3-D mature vessel network is essentially restored by 12 days, even after 3.2 Gy of iron ions. By contrast the irradiation of developing vessels showed that both protons and iron ions at 1GeV similarly disrupt network vessel development, with ~50% loss of intact vessel length [relative to control] at 3 days after 0.8 Gy. The full pattern of vessel recovery remains to be determined. DNA damage foci [53BP-1] formation was examined in endothelial cell nuclei in 2-D monolayers and in the cell nuclei of the 3-D micro-vasculature structures. Both protons at 0.22 keV/micrometer and Fe ions at 150 keV/micrometer showed similar kinetics of foci formation with peak yields at 1 hr and a 10 fold decline at 48hrs. However there were dramatic differences in the efficiency of focus formation. At the peak there was ~ one 53 BP-1 focus for each Fe ion traversal and ~ 1 focus for every 1,000 proton traversals. Human endothelial cells can form 3-D micro-vasculature like structures and show quantitative morphological and DNA damage responses after space-like radiations at moderate to high doses. At the fluences likely to be experienced in cells by man in space the question might reasonably be asked about the micro-vasculature; does this matter? Probably not.

Research Impact/Earth Benefits: Understanding the effects of ionizing radiation on the human endothelial cell and its consequences may aid in assessing the impact of diseases involving the circulatory system in general.

Task Progress & Bibliography Information FY2009 
Task Progress: Discussions and Conclusions

Fe ions affect mature and developing vessel structures with the same dose response. The 3 dimensional micro-vascular structure is however reconstituted with time.

Mature vessels are unaffected by protons up to 3.2 Gy.

Developing vessel structure formation is sensitive to protons.

Compared to protons Fe ions are highly efficient at causing DNA damage. At the peak there is ~ one 53 BP-1 focus for each Fe ion traversal and ~ 1 focus for every 1,000 proton traversals.

Both particles produce DNA damage tracks and foci. Tracks are longer and broader after Fe ion exposure and persist longer.

Human endothelial cells can form 3 D micro-vasculature like structures and show quantitative morphological and DNA damage responses after space-like radiations at moderate to high doses.

At this time, it is uncertain whether these responses reflect damage that may be of consequence in the space environment.

Bibliography Type: Description: (Last Updated: 06/03/2013) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Bigelow AW, Geard CR, Randers-Pehrson G, Brenner DJ. "Microbeam-integrated multiphoton imaging system." Rev Sci Instrum. 2008 Dec;79(12):123707. PubMed PMID: 19123569 , Dec-2008
Project Title:  Human endothelial cells in 2-D and 3-D systems; non-cancer effects and space-related radiations Reduce
Fiscal Year: FY 2008 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2005  
End Date: 09/30/2010  
Task Last Updated: 08/28/2008 
Download report in PDF pdf
Principal Investigator/Affiliation:   Geard, Charles Ray Ph.D. / Columbia University 
Address:  Center for Radiological Research 
VC 11-206, 630 W 168TH ST 
New York , NY 10032-3702 
Email: crg4@columbia.edu  
Phone: 212-305-5662   
Congressional District: 15 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Columbia University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Grabham, Peter  Columbia University 
Hu, Burong  Columbia University 
Ponnaiya, Brian  Columbia University 
Project Information: Grant/Contract No. NNJ05HI37G 
Responsible Center: NASA JSC 
Grant Monitor: Cucinott1a, Francis  
Center Contact: 281-483-0968 
noaccess@nasa.gov 
Solicitation / Funding Source: 2004 Radiation Biology NNH04ZUU005N 
Grant/Contract No.: NNJ05HI37G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Degen01:How can tissue specific experimental models be developed for the major degenerative tissue risks, including cardiovascular, lens, digestive, endocrine, and other tissue systems in order to estimate space radiation risks for degenerative diseases? (IRP Rev F)
(2) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
Flight Assignment/Project Notes: NOTE: Received no-cost extension to 9/30/2010 per J. Dardano/JSC (8/09)

Task Description: Though not prone to carcinogenic change the endothelial cell is of critical importance to the normal functioning of all tissues and organs of the body. Endothelial cells constitute the linings of the blood circulatory system, and disruption of this function can lead to multiple changes, from minor to catastrophic. Cardio-vascular diseases are the leading cause of death in developed societies. Endothelial cells have been studied in monolayers [2-dimensional ] for many years, however it is clear that cell behavior in the third dimension [tissue-like structures] is not necessarily well represented by such studies. Recognizing the crucial role of the endothelial cell we studied the radiation sensitivity of the chromosomes of normal human umbilical vein endothelial cells [HUVEC] to low LET radiation. It was determined that chromatid-type aberrations in late G2 cells were exquisitely linearly sensitive to radiation doses in the range 0.0125 to 0.8 Gy. This response was ~ 3 times more sensitive than that of early-mid G2 cellls, and ~15 times more sensitive than for chromosome-type aberrations in non-cycling G1 cells [dose range, 0.5-8.0 Gy]. Recently we have obtained 3-dimensional capillary like tubular structures from the culture of HUVECs in collagen gel matrices. We propose to irradiate 2D [cell monolayers] and 3D [capillary-like cell structures] with Fe ions at 1GeV with doses where a bystander effect may apply [< 0.1 Gy] to doses where multiple traversals are expected [up to 1Gy]. We will compare responses to low LET X-rays and to alpha particles at the same LET as the Fe ions, where delta rays are less likely to be influential. Chromosomal changes using G2-PCC`s and state of the art m-FISH, micronuclei, apoptosis and cell-cell, cell-matrix interacting proteins will be quantified. We hypothesize that 2D versus 3D culture results in no difference in the responsiveness of human endothelial cells. We further hypothesize that space related radiations are not more effective than low LET radiations for these cells with their crucial role in the maintenance of normal bodily functions.

We have successfully developed 3-D human micro-vasculature models from normal human umbilical vein endothelial cells. These structures have been characterized by multi- photon microscopy and have been irradiated with high energy iron ions and protons. Irradiation of mature vessels led to a breakdown of the vessels after low doses of iron ions [<1 Gy] but no effect of protons out to 3.2 Gray. Monitoring vessel structures over time led to the observation that the 3-D mature vessel network is essentially restored by 12 days, even after 3.2 Gy of iron ions. By contrast the irradiation of developing vessels showed that both protons and iron ions at 1GeV similarly disrupt network vessel development, with ~50% loss of intact vessel length [relative to control] at 3 days after 0.8 Gy. The full pattern of vessel recovery remains to be determined. DNA damage foci [53BP-1] formation was examined in endothelial cell nuclei in 2-D monolayers and in the cell nuclei of the 3-D micro-vasculature structures. Both protons at 0.22 keV/micrometer and Fe ions at 150 keV/micrometer showed similar kinetics of foci formation with peak yields at 1 hr and a 10 fold decline at 48hrs. However there were dramatic differences in the efficiency of focus formation. At the peak there was ~ one 53 BP-1 focus for each Fe ion traversal and ~ 1 focus for every 1,000 proton traversals. Human endothelial cells can form 3-D micro-vasculature like structures and show quantitative morphological and DNA damage responses after space-like radiations at moderate to high doses. At the fluences likely to be experienced in cells by man in space the question might reasonably be asked about the micro-vasculature; does this matter? Probably not.

Research Impact/Earth Benefits: Understanding the effects of ionizing radiation on the human endothelial cell and its consequences may aid in assessing the impact of diseases involving the circulatory system in general.

Task Progress & Bibliography Information FY2008 
Task Progress: We have successfully developed 3-D human micro-vasculature models from normal human umbilical vein endothelial cells. These structures have been characterized by multi- photon microscopy and have been irradiated with high energy iron ions and protons. Irradiation of mature vessels led to a breakdown of the vessels after low doses of iron ions [<1 Gy] but no effect of protons out to 3.2 Gray. Monitoring vessel structures over time led to the observation that the 3-D mature vessel network is essentially restored by 12 days, even after 3.2 Gy of iron ions. By contrast the irradiation of developing vessels showed that both protons and iron ions at 1GeV similarly disrupt network vessel development, with ~50% loss of intact vessel length [relative to control] at 3 days after 0.8 Gy. The full pattern of vessel recovery remains to be determined.

DNA damage foci [53BP-1] formation was examined in endothelial cell nuclei in 2-D monolayers and in the cell nuclei of the 3-D micro-vasculature structures. Both protons at 0.22 keV/micrometer and Fe ions at 150 keV/micrometer showed similar kinetics of foci formation with peak yields at 1 hr and a 10 fold decline at 48hrs. However there were dramatic differences in the efficiency of focus formation. At the peak there was ~ one 53 BP-1 focus for each Fe ion traversal and ~ 1 focus for every 1,000 proton traversals. Human endothelial cells can form 3-D micro-vasculature like structures and show quantitative morphological and DNA damage responses after space-like radiations at moderate to high doses. At the fluences likely to be experienced in cells by man in space the question might reasonably be asked about the micro-vasculature; does this matter? Probably not.

Bibliography Type: Description: (Last Updated: 06/03/2013) 

Show Cumulative Bibliography Listing
 
 None in FY 2008
Project Title:  Human endothelial cells in 2-D and 3-D systems; non-cancer effects and space-related radiations Reduce
Fiscal Year: FY 2007 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2005  
End Date: 09/30/2009  
Task Last Updated: 08/06/2007 
Download report in PDF pdf
Principal Investigator/Affiliation:   Geard, Charles Ray Ph.D. / Columbia University 
Address:  Center for Radiological Research 
VC 11-206, 630 W 168TH ST 
New York , NY 10032-3702 
Email: crg4@columbia.edu  
Phone: 212-305-5662   
Congressional District: 15 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Columbia University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Grabham, Peter  Columbia University 
Hu, Burong  Columbia University 
Ponnaiya, Brian  Columbia University 
Project Information: Grant/Contract No. NNJ05HI37G 
Responsible Center: NASA JSC 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2004 Radiation Biology NNH04ZUU005N 
Grant/Contract No.: NNJ05HI37G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Degen01:How can tissue specific experimental models be developed for the major degenerative tissue risks, including cardiovascular, lens, digestive, endocrine, and other tissue systems in order to estimate space radiation risks for degenerative diseases? (IRP Rev F)
(2) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
Task Description: Though not prone to carcinogenic change the endothelial cell is of critical importance to the normal functioning of all tissues and organs of the body. Endothelial cells constitute the linings of the blood circulatory system, and disruption of this function can lead to multiple changes, from minor to catastrophic. Cardio-vascular diseases are the leading cause of death in developed societies. Endothelial cells have been studied in monolayers [2-dimensional ] for many years, however it is clear that cell behavior in the third dimension [tissue-like structures] is not necessarily well represented by such studies. Recognizing the crucial role of the endothelial cell we studied the radiation sensitivity of the chromosomes of normal human umbilical vein endothelial cells [HUVEC] to low LET radiation. It was determined that chromatid-type aberrations in late G2 cells were exquisitely linearly sensitive to radiation doses in the range 0.0125 to 0.8 Gy. This response was ~ 3 times more sensitive than that of early-mid G2 cellls, and ~15 times more sensitive than for chromosome-type aberrations in non-cycling G1 cells [dose range, 0.5-8.0 Gy]. Recently we have obtained 3-dimensional capillary like tubular structures from the culture of HUVECs in collagen gel matrices. We propose to irradiate 2D [cell monolayers] and 3D [capillary-like cell structures] with Fe ions at 1GeV with doses where a bystander effect may apply [< 0.1 Gy] to doses where multiple traversals are expected [up to 1Gy]. We will compare responses to low LET X-rays and to alpha particles at the same LET as the Fe ions, where delta rays are less likely to be influential. Chromosomal changes using G2-PCC`s and state of the art m-FISH, micronuclei, apoptosis and cell-cell, cell-matrix interacting proteins will be quantified. We hypothesize that 2D versus 3D culture results in no difference in the responsiveness of human endothelial cells. We further hypothesize that space related radiations are not more effective than low LET radiations for these cells with their crucial role in the maintenance of normal bodily functions.

Research Impact/Earth Benefits: Understanding the effects of ionizing radiation on the human endothelial cell and its consequences may aid in assessing the impact of diseases involving the circulatory system in general.

Task Progress & Bibliography Information FY2007 
Task Progress: The ionizing radiations to which humans are likely to be exposed in a space environment are rarely encountered in an earth environment. These consist largely of energetic low LET [linear energy transfer protons] and high LET fe ions. Little is known about the effects of space radiations on endothelial cells, the cells that provide the underpinning of the circulatory system. This study is aimed at understanding the effects of space radiations on endothelial cells using 2-dimensional [2D] and 3D culture systems of human umbilical vein endothelial cells [HUVEC]. Monolayers are being used to investigate the effect of these radiations on chromosome damage and would thus be of importance to cycling endothelial cells. Since atomic bomb survivors show non-cancer disease mortality including vascular diseases, a 3D tissue model is being used to determine the effects of space radiation on blood vessel formation and maintenance.

Both high LET Fe ions and low LET protons, in addition to gamma radiation cause chromosome damage in HUVECS growing in 2D cultures. mFISH is being used to identify chromosome specific aberrations. For example, in response to 0.8 Gy Fe ions, cells showed a large number of aberrations [94% of cells] involving primarily chromosomes 1, 2, 4, 5, 7, 7, 9, and X. These include stable aberrations such as reciprocal translocations.

Endothelial cells [HUVEC`s] have been successfully cultured in 3D matrices, and in the presence of appropriate growth factors found to differentiate and assemble into capillary tubes. Cells were fluorescently labelled with a long-live cyto-tracker, suspended in collagen gels and stimulated to differentiate and form vessels. Live 3D imaging of cells showed distinct stages of development starting with the formation of vacuoles, followe by cell elongation and cellular coalecence leading to the formation of capillary tube structures. Having established this scenario the effects of space-related radiations on vessel formation from individual cells, and the integrity of mature vessels was assessed. Irradiation of cells while dividing showed that a dose of 0.2 Gy of Fe ions can cause a significant decrease in vessel formation.

Irradiation of mature vessels revealed that they were much more sensitive to Fe ions than they were to low LET protons. Doses of 0.8 to 1.6 Gy causing significant loss of vessel integrity, while after the highest dose of protons [3.2 Gy], vessels were indistiguishable from controls. Formed vessels are also highly resitant to gamma radiation, with limited effects at doses up to 16 Gy.

A technique was developed to monitor cellular apoptosis in the 3D cultures , along with the 2D system and will be applied to radiation-type comparisons in the future. The appproach outlined has succeeded in providing the first information on the effects of space related radiations on human endothelial cells in a 3D tissue configuration. There are clear differences between the effectiveness of different radiations in these non-dividing differentiated cells. The meaning, and the mechanistic bases of these findings will be explored in future cycles, and will lead to assessments of potential consequences to the cardio-vascular system of the space traveller.

Bibliography Type: Description: (Last Updated: 06/03/2013) 

Show Cumulative Bibliography Listing
 
 None in FY 2007
Project Title:  Human endothelial cells in 2-D and 3-D systems; non-cancer effects and space-related radiations Reduce
Fiscal Year: FY 2006 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2005  
End Date: 09/30/2009  
Task Last Updated: 09/13/2006 
Download report in PDF pdf
Principal Investigator/Affiliation:   Geard, Charles Ray Ph.D. / Columbia University 
Address:  Center for Radiological Research 
VC 11-206, 630 W 168TH ST 
New York , NY 10032-3702 
Email: crg4@columbia.edu  
Phone: 212-305-5662   
Congressional District: 15 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Columbia University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Jenkins-Baker, Gloria  Columbia University 
Grabham, Peter  Columbia University 
Hu, Burong  Columbia University 
Ponnaiya, Brian  Columbia University 
Project Information: Grant/Contract No. NNJ05HI37G 
Responsible Center: NASA JSC 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2004 Radiation Biology NNH04ZUU005N 
Grant/Contract No.: NNJ05HI37G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Degen01:How can tissue specific experimental models be developed for the major degenerative tissue risks, including cardiovascular, lens, digestive, endocrine, and other tissue systems in order to estimate space radiation risks for degenerative diseases? (IRP Rev F)
(2) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
Task Description: Though not prone to carcinogenic change the endothelial cell is of critical importance to the normal functioning of all tissues and organs of the body. Endothelial cells constitute the linings of the blood circulatory system, and disruption of this function can lead to multiple changes, from minor to catastrophic. Cardio-vascular diseases are the leading cause of death in developed societies. Endothelial cells have been studied in monolayers [2-dimensional ] for many years, however it is clear that cell behavior in the third dimension [tissue-like structures] is not necessarily well represented by such studies. Recognizing the crucial role of the endothelial cell we studied the radiation sensitivity of the chromosomes of normal human umbilical vein endothelial cells [HUVEC] to low LET radiation. It was determined that chromatid-type aberrations in late G2 cells were exquisitely linearly sensitive to radiation doses in the range 0.0125 to 0.8 Gy. This response was ~ 3 times more sensitive than that of early-mid G2 cellls, and ~15 times more sensitive than for chromosome-type aberrations in non-cycling G1 cells [dose range, 0.5-8.0 Gy]. Recently we have obtained 3-dimensional capillary like tubular structures from the culture of HUVECs in collagen gel matrices. We propose to irradiate 2D [cell monolayers] and 3D [capillary-like cell structures] with Fe ions at 1GeV with doses where a bystander effect may apply [< 0.1 Gy] to doses where multiple traversals are expected [up to 1Gy]. We will compare responses to low LET X-rays and to alpha particles at the same LET as the Fe ions, where delta rays are less likely to be influential. Chromosomal changes using G2-PCC`s and state of the art m-FISH, micronuclei, apoptosis and cell-cell, cell-matrix interacting proteins will be quantified. We hypothesize that 2D versus 3D culture results in no difference in the responsiveness of human endothelial cells. We further hypothesize that space related radiations are not more effective than low LET radiations for these cells with their crucial role in the maintenance of normal bodily functions.

Research Impact/Earth Benefits: Understanding the effects of ionizing radiation on the human endothelial cell and its consequences may aid in assessing the impact of diseases involving the circulatory system in general.

Task Progress & Bibliography Information FY2006 
Task Progress: In this first year of this grant the first irradiations of normal human endothelial cells with 1Gev iron ions and 1 GeV protons was undertaken during the summer run at the NASA sponsored facility at the Brookhaven National Laboratory. Evaluations of radiation induced chromosomal cxhanges as a function of dose and time are in progress and no conclusion can be drawn at this time.

Bibliography Type: Description: (Last Updated: 06/03/2013) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Geard C, Jenkins-Baker G, Grabham P, Hu B, Ponnaiya B. "Human endothelial cells in 2-D and 3-D systems; non-cancer effects and space-related radiations." International Space Radiation Health Meeting and Space Radiation Health Investigators Workshop, Moscow and St. Petersburgh, Russia, June, 2006.

Space Radiation Health Investigators Workshop, Moscow and St. Petersburgh, Russia, June, 2006. , Jun-2006

Project Title:  Human endothelial cells in 2-D and 3-D systems; non-cancer effects and space-related radiations Reduce
Fiscal Year: FY 2005 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2005  
End Date: 09/30/2009  
Task Last Updated: 05/25/2006 
Download report in PDF pdf
Principal Investigator/Affiliation:   Geard, Charles Ray Ph.D. / Columbia University 
Address:  Center for Radiological Research 
VC 11-206, 630 W 168TH ST 
New York , NY 10032-3702 
Email: crg4@columbia.edu  
Phone: 212-305-5662   
Congressional District: 15 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Columbia University 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NNJ05HI37G 
Responsible Center: NASA JSC 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2004 Radiation Biology NNH04ZUU005N 
Grant/Contract No.: NNJ05HI37G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Degen01:How can tissue specific experimental models be developed for the major degenerative tissue risks, including cardiovascular, lens, digestive, endocrine, and other tissue systems in order to estimate space radiation risks for degenerative diseases? (IRP Rev F)
(2) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
Task Description: Though not prone to carcinogenic change the endothelial cell is of critical importance to the normal functioning of all tissues and organs of the body. Endothelial cells constitute the linings of the blood circulatory system, and disruption of this function can lead to multiple changes, from minor to catastrophic. Cardio-vascular diseases are the leading cause of death in developed societies. Endothelial cells have been studied in monolayers [2-dimensional ] for many years, however it is clear that cell behavior in the third dimension [tissue-like structures] is not necessarily well represented by such studies. Recognizing the crucial role of the endothelial cell we studied the radiation sensitivity of the chromosomes of normal human umbilical vein endothelial cells [HUVEC] to low LET radiation. It was determined that chromatid-type aberrations in late G2 cells were exquisitely linearly sensitive to radiation doses in the range 0.0125 to 0.8 Gy. This response was ~ 3 times more sensitive than that of early-mid G2 cellls, and ~15 times more sensitive than for chromosome-type aberrations in non-cycling G1 cells [dose range, 0.5-8.0 Gy]. Recently we have obtained 3-dimensional capillary like tubular structures from the culture of HUVECs in collagen gel matrices. We propose to irradiate 2D [cell monolayers] and 3D [capillary-like cell structures] with Fe ions at 1GeV with doses where a bystander effect may apply [< 0.1 Gy] to doses where multiple traversals are expected [up to 1Gy]. We will compare responses to low LET X-rays and to alpha particles at the same LET as the Fe ions, where delta rays are less likely to be influential. Chromosomal changes using G2-PCC`s and state of the art m-FISH, micronuclei, apoptosis and cell-cell, cell-matrix interacting proteins will be quantified. We hypothesize that 2D versus 3D culture results in no difference in the responsiveness of human endothelial cells. We further hypothesize that space related radiations are not more effective than low LET radiations for these cells with their crucial role in the maintenance of normal bodily functions.

Research Impact/Earth Benefits: 0

Task Progress & Bibliography Information FY2005 
Task Progress: Please note that this is a new grant for the FY 2005 year. The investigator will provide a task progress at the time of the one year anniversary of the grant. If you need more information, please contact the Task Book Help Desk at taskbook@nasaprs.com.

Bibliography Type: Description: (Last Updated: 06/03/2013) 

Show Cumulative Bibliography Listing
 
 None in FY 2005