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Project Title:  A mechanistic investigation of space radiation-induced carcinogenesis--NNX12AB88G Reduce
Fiscal Year: FY 2014 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/01/2012  
End Date: 10/31/2013  
Task Last Updated: 02/12/2014 
Download report in PDF pdf
Principal Investigator/Affiliation:   Li, Chuan-Yuan  Ph.D. / Duke University 
Address:  Box 3135, DUMC C303A/LSRC 
 
Durham , NC 27710 
Email: chuan.li@duke.edu 
Phone: 919 613 8754  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Duke University 
Joint Agency:  
Comments: PI moved to Duke University in December 2011. Formerly at University of Colorado Denver (Ed., 2/8/2012) 
Co-Investigator(s)
Affiliation: 
Li, Fang  Duke University 
Project Information: Grant/Contract No. NNX12AB88G  
Responsible Center: NASA ARC 
Grant Monitor: Bhattacharya, Sharmila  
Center Contact:  
Sharmila.Bhattacharya@nasa.gov  
Solicitation / Funding Source: 2008 Space Radiobiology NNJ08ZSA001N 
Grant/Contract No.: NNX12AB88G  
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) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer03:How can experimental models of carcinogenesis be applied to reduce the uncertainties in radiation quality effects from SPEs and GCR, including effects on tumor spectrum, burden, latency and progression (e.g., tumor aggression and metastatic potential)? (IRP Rev F)
Flight Assignment/Project Notes: NOTE: Extended to 10/31/2013 per A. Chu/ARC and NSSC information (Ed., 11/1/2012)

Task Description: One of major concerns for manned space missions of NASA is exposure to galactic cosmic rays (GCRs) or highly charged energetic (HZE) particles, which carries distinct health risks. The major goal of the NASA Bioastroanautics Roadmap and NASA ground-based studies in radiation biology is to assess potential risks of human exposure to HZE particles and to generate knowledge that can be used to mitigate the health risks of HZE particle exposure eventually. In this project, our two original specific aims focused on the study of HZE particle-induced mutagenesis and carcinogenesis in mammalian cells. These are: 1. To determine the potential interactions of reactive oxygen/nitrogen species and apoptosis in regulating HZE radiation-induced mutagenesis in mammalian cells. 2) to determine the roles of program cell death in HZE radiation induced mutagenesis/carcinogenesis. Later, after approval from NASA program manager, we have re-focused our efforts to some extent to study the effect of apoptotic caspases on the space radiation induced mutagenesis and carcinogenesis.

Research Impact/Earth Benefits: Our research will have the following potential benefit for life on Earth: 1) we will develop state-of-art techniques to monitor radiation induced DNA damage, which will facility a better understanding radiation induced carcinogenesis in humans. 2) our study may lead to fundamental insights into how cells deal with DNA damage. 3) we hope to achieve novel, mechanistic insights into the carcinogenic risks of radiation, which is universally present on Earth.

Task Progress & Bibliography Information FY2014 
Task Progress: This grant was initially awarded when the PI was at the University of Colorado School of Medicine. Part of funds that were unspent were transferred to Duke University where the PI moved in 2011. Despite the move, the major focus of the project remained the same: to carry out mechanistic investigations of space radiation-induced mutagenesis and carcinogenesis. Towards these goals, we have made a substantial amount of progress in the funding period.

Major achievements include:

A). The development of a non-invasive bioluminescence-based imaging method to monitor gammaH2AX foci, a major indicator of DNA double strand breaks (DSBs) (Li et al., Cancer Research, 2011, 71:4130-7). Using this reporter, we showed that space radiation induced DSBs came in two waves. The first wave occurs within minutes and lasted for hours while the second wave occurs after 24 hrs and lasted for more than a week. The second wave of DNA damage has strong implications for space radiation induced DNA damage and carcinogenesis. This type of damage could be responsible for persistent genetic instability often observed after radiation exposure.

B). The discovery of the “Phoenix Rising” pathway for wound healing and tissue regeneration. We discovered that dying cells in damaged tissues play a key role in mediating wound healing and tissue regeneration (Li et al., Science Signaling, 2010, 3:110: ra3) Surprisingly, caspase 3 and caspase 7, which are usually recognized as executioners of damaged or unwanted cells, play key facilitative roles regulating growth-promoting signals from dying cells. The elucidation of the counter-intuitive roles of apoptotic cells and apoptotic caspases significantly advanced our understanding of tissue homeostasis mechanisms in metazoan organisms.

C). We also found that the same “Phoenix Rising” pathway was hijacked by tumors during radiotherapy. Dying cells in tumors exposed to radiation release potent caspase 3-controlled growth signals that promote the growth of surviving tumor cells, which fuels the repopulation of damaged tumor. Most importantly, consistent with these findings, higher levels of activated caspase 3 in tumor samples from human patients correlated with worse prognosis. These results are counter-intuitive and significantly changed the way we view cell death during tumor radiotherapy.

D). Another discovery that we made concerns with surprising roles of caspases 3&8 in epigenetic reprogramming. We show that during induction of induced pluripotent stem (iPS) cells from human and mouse fibroblasts, caspases 3 and 8 are clearly activated. However, contrary to conventional wisdom, we found that blocking caspase activation did not increase the efficiency of iPSC induction. Instead, it significantly attenuated or completely blocked iPSC induction (Li et al., Cell Stem Cell, 2010, 7:508-20). These findings suggest that capases played a facilitative role for epigenetic reprogramming, a role that has not been suggested before. Our paper was the cover story for Cell Stem Cell. This finding may have significant implications for space radiation and other forms of carcinogenesis.

E). Still another significant finding in the funding period of this project involves the successful reprogramming of primary human fibroblasts into dopaminergic neurons (Liu et al., Cell Research, 22:321-32). We showed that a combination of 5 transcription factors (Mash1, Ngn2, Sox2, Nurr1, and Pitx3) can directly reprogram human primary fibroblasts into dopaminergic neurons. These cells should stimulate research in providing a promising autologous source for cell replacement therapy for Parkinson’s disease.

F). We have also discovered a counter-intuitive role for caspase 3 in facilitating space radiation induced DNA damage and carcinogenesis. Instead of acting as a tumor suppressor, which is the prevalent current thinking, we found strong evidence indicating that caspase 3 is causing additional damage is cells that survived the radiation insult. We are currently working hard to publish our results. A manuscript on these findings is now being considered by the journal Cell.

Bibliography Type: Description: (Last Updated: 10/30/2019) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Ng WL, Huang Q, Liu X, Zimmerman M, Li F, Li CY. "Molecular mechanisms involved in tumor repopulation after radiotherapy." Translational Cancer Research. 2013 Oct;2(5):442-8. http://dx.doi.org/10.3978/j.issn.2218-676X.2013.10.03 , Oct-2013
Articles in Peer-reviewed Journals Zimmerman MA, Huang Q, Li F, Liu X, Li CY. "Cell death-stimulated cell proliferation: a tissue regeneration mechanism usurped by tumors during radiotherapy." Semin Radiat Oncol. 2013 Oct;23(4):288-95. http://dx.doi.org/10.1016/j.semradonc.2013.05.003 ; PubMed PMID: 24012343 , Oct-2013
Articles in Peer-reviewed Journals Liu X, He Y, Li F, Huang Q, Kato TA, Hall RP, Li CY. "Redefining the roles of apoptotic factors in carcinogenesis." Mol Cell Oncol. 2016 May;3(3): e1054550. https://doi.org/10.1080/23723556.2015.1054550 ; PubMed PMID: 27314073; PubMed Central PMCID: PMC4909400 , May-2016
Articles in Peer-reviewed Journals Liu X, He Y, Li F, Huang Q, Kato TA, Hall RP, Li CY. "Caspase-3 promotes genetic instability and carcinogenesis." Mol Cell. 2015 Apr 16;58(2):284-96. Epub 2015 Apr 9. https://doi.org/10.1016/j.molcel.2015.03.003 ; PubMed PMID: 25866249; PubMed Central PMCID: PMC4408780 , Apr-2015
Project Title:  A mechanistic investigation of space radiation-induced carcinogenesis--NNX12AB88G Reduce
Fiscal Year: FY 2013 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/01/2012  
End Date: 10/31/2013  
Task Last Updated: 10/31/2012 
Download report in PDF pdf
Principal Investigator/Affiliation:   Li, Chuan-Yuan  Ph.D. / Duke University 
Address:  Box 3135, DUMC C303A/LSRC 
 
Durham , NC 27710 
Email: chuan.li@duke.edu 
Phone: 919 613 8754  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Duke University 
Joint Agency:  
Comments: PI moved to Duke University in December 2011. Formerly at University of Colorado Denver (Ed., 2/8/2012) 
Co-Investigator(s)
Affiliation: 
Li, Fang  Duke University 
Project Information: Grant/Contract No. NNX12AB88G  
Responsible Center: NASA ARC 
Grant Monitor: Bhattacharya, Sharmila  
Center Contact:  
Sharmila.Bhattacharya@nasa.gov  
Solicitation / Funding Source: 2008 Space Radiobiology NNJ08ZSA001N 
Grant/Contract No.: NNX12AB88G  
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) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer03:How can experimental models of carcinogenesis be applied to reduce the uncertainties in radiation quality effects from SPEs and GCR, including effects on tumor spectrum, burden, latency and progression (e.g., tumor aggression and metastatic potential)? (IRP Rev F)
Flight Assignment/Project Notes: NOTE: to be extended to 10/31/2013 per A. Chu/ARC and NSSC information (Ed., 11/1/2012)

Task Description: One of major concerns for manned space missions of NASA is exposure to galactic cosmic rays (GCRs) or highly charged energetic (HZE) particles, which carries distinct health risks. The major goal of the NASA Bioastroanautics Roadmap and NASA ground-based studies in radiation biology is to assess potential risks of human exposure to HZE particles and to generate knowledge that can be used to mitigate the health risks of HZE particle exposure eventually. In this project, we will two specific aims to study HZE particle-induced mutagenesis and carcinogenesis in mammalian cells. These are: 1. To determine the potential interactions of reactive oxygen/nitrogen species and apoptosis in regulating HZE radiation-induced mutagenesis in mammalian cells. 2) to determine the roles of program cell death in HZE radiation induced mutagenesis/carcinogenesis.

Research Impact/Earth Benefits: Our research will have the following potential benefit for life on Earth: 1) we will develop state-of-art techniques to monitor radiation induced DNA damage, which will facility a better understanding radiation induced carcinogenesis in humans. 2) our study may lead to fundamental insights into how cells deal with DNA damage. 3) we hope to achieve novel, mechanistic insights into the carcinogenic risks of radiation, which is universally present on Earth.

Task Progress & Bibliography Information FY2013 
Task Progress: Our current grant, NNX12AB88G, is a transfer grant from University of Colorado Denver to Duke University. This is a result of the PI’s moving from the University of Colorado to Duke. The major goals of this project are to understand the roles of free radicals and programmed cell death in space radiation induced mutagenesis and carcinogenesis. Towards these goals, we have made major progress in the funding period. Major achievements include:

A). The development of a non-invasive bioluminescence-based imaging method to monitor gamma H2AX foci, a major indicator of DNA double strand breaks (DSBs) (Li et al., Cancer Research, 2011, 71:4130-7). Using this reporter, we showed that space radiation induced DSBs came in two waves. The first wave occurs within minutes and lasted for hours while the second wave occurs after 24 hrs and lasted for more than a week. The second wave of DNA damage has strong implications for space radiation induced DNA damage and carcinogenesis. This type of damage could be responsible for persistent genetic instability often observed after radiation exposure.

B). The discovery of the “Phoenix Rising” pathway for wound healing and tissue regeneration. We discovered that dying cells in damaged tissues play a key role in mediating wound healing and tissue regeneration (Li et al., Science Signaling, 2010, 3:110: ra3) Surprisingly, caspase 3 and caspase 7, which are usually recognized as executioners of damaged or unwanted cells, play key facilitative roles regulating growth-promoting signals from dying cells. The elucidation of the counter-intuitive roles of apoptotic cells and apoptotic caspases significantly advanced our understanding of tissue homeostasis mechanisms in metazoan organisms.

C). We also found that the same “Phoenix Rising” pathway was hijacked by tumors during radiotherapy. Dying cells in tumors exposed to radiation release potent caspase 3-controlled growth signals that promote the growth of surviving tumor cells, which fuels the repopulation of damaged tumor. Most importantly, consistent with these findings, higher levels of activated caspase 3 in tumor samples from human patients correlated with worse prognosis. These results are counter-intuitive and significantly changed the way we view cell death during tumor radiotherapy.

D). Another discovery that we made concerns with surprising roles of caspases 3&8 in epigenetic reprogramming. We show that during induction of induced pluripotent stem (iPS) cells from human and mouse fibroblasts, caspases 3 and 8 are clearly activated. However, contrary to conventional wisdom, we found that blocking caspase activation did not increase the efficiency of iPSC induction. Instead, it significantly attenuated or completely blocked iPSC induction (Li et al., Cell Stem Cell, 2010, 7:508-20). These findings suggest that capases played a facilitative role for epigenetic reprogramming, a role that has not been suggested before. Our paper was the cover story for Cell Stem Cell. This finding may have significant implications for space radiation and other forms of carcinogenesis.

E). Still another significant finding in the funding period of this project involves the successful reprogramming of primary human fibroblasts into dopaminergic neurons (Liu et al,, Cell Research, 22:321-332). We showed that a combination of 5 transcription factors (Mash1, Ngn2, Sox2, Nurr1, and Pitx3) can directly reprogram human primary fibroblasts into doparminergic neurons. These cells should stimulate research in providing a promising autologous source for cell replacement therapy for Parkinson’s disease.

In addition to the above accomplishments, we have now focused our attention on the roles of caspases on space radiation induced carcinogenesis and mutagenesis. We have obtained preliminary evidence that caspase 3 activation plays a key role in mediating space radiation induced carcinogenesis and mutagenesis. In the remaining time of our grant (under request for no-cost extension), we will focus our attention on obtaining sufficient data to publish this very important new finding.

Bibliography Type: Description: (Last Updated: 10/30/2019) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Brogan J, Li F, Li W, He Z, Huang Q, Li C-Y. "Imaging molecular pathways: reporter genes." Radiation Research. 2012 Apr;177(4):508-13. Epub 2012 Feb 21. Review. PubMed PMID: 22348248 , Apr-2012
Articles in Peer-reviewed Journals Kon T, Zhang X, Huang Q, Yang Z, Liu S, Yan B, Li F, Wang H, Li C-Y. "Oncolytic virus-mediated tumor radiosensitization in mice through DNA-PKcs-specific shRNA " Translational Cancer Research. 2012 Jun;1(1):6-14. PMID: 22924158 ; http://dx.doi.org/10.3978/j.issn.2218-676X.2012.05.02 , Jun-2012
Journal/Magazine covers Kon T, Zhang X, Huang Q, Yang Z, Liu S, Yan B, Li F, Wang H, Li CY. "Cover in first issue of the journal Translational Cancer Research for article, Oncolytic virus-mediated tumor radiosensitization in mice through DNA-PKcs-specific shRNA." Translational Cancer Research. 2012 Jun;1(1):6-14. http://dx.doi.org/10.3978/j.issn.2218-676X.2012.05.02 , Jun-2012
Project Title:  A mechanistic investigation of space radiation-induced carcinogenesis--NNX12AB88G Reduce
Fiscal Year: FY 2012 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/01/2012  
End Date: 12/31/2012  
Task Last Updated: 02/08/2012 
Download report in PDF pdf
Principal Investigator/Affiliation:   Li, Chuan-Yuan  Ph.D. / Duke University 
Address:  Box 3135, DUMC C303A/LSRC 
 
Durham , NC 27710 
Email: chuan.li@duke.edu 
Phone: 919 613 8754  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Duke University 
Joint Agency:  
Comments: PI moved to Duke University in December 2011. Formerly at University of Colorado Denver (Ed., 2/8/2012) 
Co-Investigator(s)
Affiliation: 
Li, Fang  Duke University 
Project Information: Grant/Contract No. NNX12AB88G  
Responsible Center: NASA ARC 
Grant Monitor: Bhattacharya, Sharmila  
Center Contact:  
Sharmila.Bhattacharya@nasa.gov  
Solicitation / Funding Source: 2008 Space Radiobiology NNJ08ZSA001N 
Grant/Contract No.: NNX12AB88G  
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) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer03:How can experimental models of carcinogenesis be applied to reduce the uncertainties in radiation quality effects from SPEs and GCR, including effects on tumor spectrum, burden, latency and progression (e.g., tumor aggression and metastatic potential)? (IRP Rev F)
Task Description: One of major concerns for manned space missions of NASA is exposure to galactic cosmic rays (GCRs) or highly charged energetic (HZE) particles, which carries distinct health risks. The major goal of the NASA Bioastroanautics Roadmap and NASA ground-based studies in radiation biology is to assess potential risks of human exposure to HZE particles and to generate knowledge that can be used to mitigate the health risks of HZE particle exposure eventually. In this project, we will two specific aims to study HZE particle-induced mutagenesis and carcinogenesis in mammalian cells. These are: 1. To determine the potential interactions of reactive oxygen/nitrogen species and apoptosis in regulating HZE radiation-induced mutagenesis in mammalian cells. 2) to determine the roles of program cell death in HZE radiation induced mutagenesis/carcinogenesis.

Research Impact/Earth Benefits: Our research will have the following potential benefit for life on earth: 1) we will develop a state-of-art techniques to monitor radiation induced DNA damage, which will facility a better understanding radiation induced carcinogenesis in humans. 2) Our study may lead to fundamental insights into how cells deal with DNA damage. 3) we hope to achieve novel, mechanistic insights into the carcinogenic risks of radiation, which is universally present on earth.

Task Progress & Bibliography Information FY2012 
Task Progress: New project for FY2012, established when PI moved from University of Colorado Denver back to Duke University in December 2011. See project with same title (A mechanistic investigation of space radiation-induced carcinogenesis) for previous reports.

Bibliography Type: Description: (Last Updated: 10/30/2019) 

Show Cumulative Bibliography Listing
 
 None in FY 2012