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Project Title:  Development of a Flow-Perfused and Immunocompetent 3-D Vascular Model for Radiation Risk Assessment of Cardiovascular Disease and Countermeasure Screening Reduce
Fiscal Year: FY 2016 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
 Start Date: 03/01/2015  
End Date: 09/01/2016  
Task Last Updated: 02/01/2017 		 Download report in PDF pdf
Principal Investigator/Affiliation:   Patel, Zarana  Ph.D. / KBRwyle/NASA Johnson Space Center 
Address:  Science, Technology and Engineering Group 
2400 NASA Parkway 
Houston , TX 77058 		 Email: zarana.s.patel@nasa.gov 
Phone: 281-483-3723  
Congressional District: 22 
Web:  
 Organization Type: NASA CENTER 
Organization Name: KBRwyle/NASA Johnson Space Center 
Joint Agency:  
Comments: NOTE: PI moved to Wyle in 2014; previously at Universities Space Research Association. 
Co-Investigator(s)
Affiliation: 
Grande-Allen, K. Jane  Ph.D. Rice University 
Project Information: Grant/Contract No. Internal Project 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Unique ID: 10034  		Solicitation / Funding Source: 2013 HERO NNJ13ZSA002N-Crew Health OMNIBUS 
Grant/Contract No.: Internal Project 
Project Type: GROUND 
Flight Program:  
TechPort: No  		No. of Post Docs: 1 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Flight Assignment/Project Notes: NOTE: Extended to 9/1/2016 per S. Monk/SR HRP (Ed., 3/14/16)

NOTE: change in period of performance per PI (originally 10/1/2014-9/30/2015)--Ed., 7/11/15

Task Description: Radiation exposure is known to result in degenerative effects on the cardiovascular system, resulting in ischemic heart disease and strokes and includes the development of atherosclerosis. Data from low-LET (linear energy transfer) exposures, including from radiotherapy, occupational, and environmental exposures, show a dose-dependent effect. However, only a few studies have examined the effects of heavy ion radiation on atherosclerosis, and at lower, space-relevant doses, the association between exposure and cardiovascular pathology is more varied and unclear. To date, there has been very limited use of in vitro coculture systems that include multiple cell types for space radiation risk assessment of degenerative cardiovascular diseases. The objective of this work was to utilize an innovative, tissue engineering approach to address the Human Research Program (HRP) Space Radiation Degen-1 knowledge gap with the development of cocultures of human endothelial cells and smooth muscle cells using hydrogel scaffolds. These 3D models can be used to profile the effects of radiation on markers of endothelial dysfunction, an important and early indicator of heart disease.

Research Impact/Earth Benefits: Development and validation of this model will allow for the quantitative assessment of the degenerative risk of radiation exposure on heart disease and allow for countermeasure screening without the use of animals. This has direct relevance to radiation-related cardiotoxicities that are being observed in the clinic, either due to radiotherapy for cancer treatments, occupational exposures to cardiologists, or by environmental exposures from nuclear accidents.

Task Progress & Bibliography Information FY2016 
Task Progress: We have developed a pilot vascular co-culture model that incorporates human coronary artery smooth muscle cells (hCASMCs) into the body of a PEG hydrogel and human coronary artery endothelial cells (hCAECs) on to the surface of the hydrogel. The hydrogel is functionalized with two different peptides to facilitate degradation by the SMCs and adhesion of the ECs (endothelial cells). Optimized seeding densities for the two cell types was established. We tested the feasibility of using the co-culture hydrogels as a model to study radiation-induced atherosclerosis by irradiating the hydrogels with gamma irradiation and costaining with alpha-smooth muscle actin and markers of DNA damage (53BP1). Further experimentation revealed that staining for an endothelial marker such as CD31 allowed for easier differentiation between the cell types. The co-culture gels were stained to visualize cell nuceli, alpha-SMA, and 53BP1. Foci formation has been quantified over a time course of 24 hours. Markers of endothelial dysfunction will also be quantified.

Bibliography: Description: (Last Updated: 08/25/2020) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Patel ZS, Hada M, Kang MK, Grande-Allen KJ. "Irradiation Effects on Vascular Dysfunction in a 3D Human Cell Vascular Model." Presented at the 62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016.

62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016. , Oct-2016

Abstracts for Journals and Proceedings Kang MK, Patel ZS, Hada M, Grande-Allen KJ. "Irradiation Effects on Vascular Dysfunction in a 3D Human Cell Vascular Model." Presented at the Gulf Coast Vascular Research Consortium, Shreveport, LA, August 26-27, 2016.

Gulf Coast Vascular Research Consortium, Shreveport, LA, August 26-27, 2016. , Aug-2016

Abstracts for Journals and Proceedings Patel ZS, Hada M, Kang MK, Grande-Allen KJ. "Project Summary of 3D Vascular Model Development." 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. , Feb-2016

Abstracts for Journals and Proceedings Patel ZS, Hada M, Kang MK, Grande-Allen KJ. "Radiation Quality Effects on Markers of Endothelial Dysfunction in a Human Vascular Model." Presented at the 61st Annual Meeting of the Radiation Research Society, Weston, FL, September 19-22, 2015.

61st Annual Meeting of the Radiation Research Society, Weston, FL, September 19-22, 2015. , Sep-2015

Abstracts for Journals and Proceedings Patel ZS, Hada M, Grande-Allen KJ. "Effects of Low- and High-LET Radiation on Markers of Endothelial Dysfunction in a Human Vascular Model." Presented at the 15th International Congress of Radiation Research (ICRR), Kyoto, Japan, May 25-29, 2015.

15th International Congress of Radiation Research (ICRR), Kyoto, Japan, May 25-29, 2015. , May-2015

Articles in Peer-reviewed Journals Sylvester CB, Abe JI, Patel ZS, Grande-Allen KJ. "Radiation-induced cardiovascular disease: Mechanisms and importance of linear energy transfer." Front Cardiovasc Med. 2018 Jan 31;5:5. https://doi.org/10.3389/fcvm.2018.00005 ; PMID: 29445728; PMCID: PMC5797745 , Jan-2018
Articles in Peer-reviewed Journals Ko KA, Wang Y, Kotla S, Fujii Y, Vu HT, Venkatesulu BP, Thomas TN, Medina JL, Gi YJ, Hada M, Grande-Allen J, Patel ZS, Milgrom SA, Krishnan S, Fujiwara K, Abe JI. "Developing a reliable mouse model for cancer therapy-induced cardiovascular toxicity in cancer patients and survivors." Front Cardiovasc Med. 2018 Apr 5;5:26. https://doi.org/10.3389/fcvm.2018.00026 ; PMID: 29675417; PMCID: PMC5896304 , Apr-2018
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Project Title:  Development of a Flow-Perfused and Immunocompetent 3-D Vascular Model for Radiation Risk Assessment of Cardiovascular Disease and Countermeasure Screening Reduce
Fiscal Year: FY 2015 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
 Start Date: 03/01/2015  
End Date: 09/01/2016  
Task Last Updated: 11/21/2014 		 Download report in PDF pdf
Principal Investigator/Affiliation:   Patel, Zarana  Ph.D. / KBRwyle/NASA Johnson Space Center 
Address:  Science, Technology and Engineering Group 
2400 NASA Parkway 
Houston , TX 77058 		 Email: zarana.s.patel@nasa.gov 
Phone: 281-483-3723  
Congressional District: 22 
Web:  
 Organization Type: NASA CENTER 
Organization Name: KBRwyle/NASA Johnson Space Center 
Joint Agency:  
Comments: NOTE: PI moved to Wyle in 2014; previously at Universities Space Research Association. 
Co-Investigator(s)
Affiliation: 
Grande-Allen, Kathryn  Ph.D. Rice University 
Project Information: Grant/Contract No. Internal Project 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Unique ID: 10034  		Solicitation / Funding Source: 2013 HERO NNJ13ZSA002N-Crew Health OMNIBUS 
Grant/Contract No.: Internal Project 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Flight Assignment/Project Notes: NOTE: Extended to 9/1/2016 per S. Monk/SR HRP (Ed., 3/14/16)

NOTE: change in period of performance per PI (originally 10/1/2014-9/30/2015)--Ed., 7/11/15

Task Description: Exposure to the types of radiation encountered in space is known to result in degenerative effects on vascular tissue, including the development of atherosclerosis. In this pathology, monocytes and macrophages play a key role in initiating events and lesion formation in response to radiation injury; they are a prime source of reactive oxygen species and a milieu of pro-inflammatory mediators and growth factors that mediate disease progression. To date, there has been very limited use of in vitro coculture systems that include immune cells in cell culture experiments for space radiation risk assessment of degenerative cardiovascular diseases. We propose an innovative approach to address the Degen-1 knowledge gap with the development of cocultures of human endothelial cells, smooth muscle cells, and macrophages, providing an immunocompetent 3-D vascular model grown under shear flow conditions for ground-based research. This model will allow for the quantitative assessment of the degenerative risk of space radiation exposure on atherosclerosis, and allow for countermeasure screening without the use of animals. We will also adapt the system to a spheroid format that will make it readily available for use in rotating wall vessel bioreactors for microgravity studies and future flight definition investigations. Development of this model will partially close the Degen-1 gap by providing a realistic, 3-D cell culture model for mechanistic research on the development of vascular diseases caused by space radiation exposure.

Research Impact/Earth Benefits:

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

Bibliography: Description: (Last Updated: 08/25/2020) 

Show Cumulative Bibliography
 
 None in FY 2015
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