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Project Title:  Mechanistic Study of the Risk of Low Doses of HZE Particles on Human Cell Pre-Malignant Transformation Reduce
Fiscal Year: FY 2014 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2012  
End Date: 11/30/2014  
Task Last Updated: 08/02/2013 
Download report in PDF pdf
Principal Investigator/Affiliation:   Wang, Minli  M.D. / Universities Space Research Association 
Address:  3600 Bay Area Blvd 
 
Houston , TX 77058-1113 
Email: minli.wang@nasa.gov 
Phone: 281-483-4986  
Congressional District: 22 
Web:  
Organization Type: NON-PROFIT 
Organization Name: Universities Space Research Association 
Joint Agency:  
Comments: USRA corporate address: 10211 WINCOPIN CIR 500, Columbia, MD 21044-3405. 
Co-Investigator(s)
Affiliation: 
Wang, Ya  Emory University 
Key Personnel Changes / Previous PI: ED. NOTE (December 2015): Per Space Radiation Element Manager L. Simonsen, PI Dr. Minli Wang moved from Universities Space Research Association in 2014; the study is now inactive.
Project Information: Grant/Contract No. Internal Project 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2012 Space Radiobiology NNJ12ZSA001N 
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) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer01:How can experimental models of tumor development for the major tissues (lung, colon, stomach, breast, liver, and leukemias) be developed to represent the major processes in radiation carcinogenesis and extrapolated to human risk and clinical outcome projections? (IRP Rev J)
(2) 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)
(3) Cancer04:How can models of cancer risk be applied to reduce the uncertainties in dose-rate dependence of risks from SPEs and GCR?
(4) Cancer07:How can systems biology approaches be used to integrate research on the molecular, cellular, and tissue mechanisms of radiation damage to improve the prediction of the risk of cancer and to evaluate the effectiveness of CMs? How can epidemiology data and scaling factors support this approach?
Flight Assignment/Project Notes: NOTE: Extended to 11/30/14 per PI; original end date was 9/30/13 (Ed., 7/31/13)

Task Description: Establishing the scientific basis of radiation cancer risk is a primary goal for the NASA Space Radiation Program. There are large uncertainties in approaches to extrapolate experimental or human epidemiology data from high to low doses, and from high LET to low LET radiation. In this proposed study, we will use the cell transformation (pre-malignance) assay, which occurs much earlier than carcinogenesis after radiation exposure, to elucidate mechanisms and to provide important quantitative data on radiation quality effects related to cancer risks from low doses of HZE particles. We proposed two aims to test our hypothesis that p63 plays an important role in HZE particle-induced human cell pre-malignant transformation. Aim1: Investigate how p63 promotes HZE particle-induced human epithelial cell transformation through the JAG1/Wnt4#Myc pathway. Aim2: Investigate how p63 promotes HZE particle-induced human epithelial cell transformation through the CD95#JNK#Jun pathway. The results from this proposal are expected to reveal the importance of p63 in HZE particle-induced human epithelial cell transformation. Since majority of human tumors are derived from epithelial cells, the results from this proposal will make important contribution to the mechanism of HZE particle-induced carcinogenesis and therefore, providing valuable information for estimating the risk of space radiation-induced carcinogenesis and for further protection from such risk.

Research Impact/Earth Benefits: The results from this proposed work will reveal the important role of p63 in HZE particle-induced human epithelial cell transformation. Since the majority of human tumors (more than 90%) are derived from epithelial cells, the results from this proposal will make an important contribution to the understanding of how low doses of HZE particles can promote carcinogenesis and, therefore, provide valuable information for estimating the risk of space radiation-induced carcinogenesis and for further attempting to reduce such risk.

Task Progress & Bibliography Information FY2014 
Task Progress: During the first year of this grant, we have confirmed the important role of p63 in HZE particle radiation-induced human epithelial cell transformation. We have published two articles discovering the roles of TGFbeta/Smad pathway in HZE particle radiation induced tissue/cell damage. To investigate the two pathways, p63-JAG1/Wnt4-Myc and p63-CD95-JNK-Jun, proposed in our hypothesis, we have irradiated the p63 down-regulated human epithelial cells or up-regulated fibroblasts with low doses of HZE particles. Materials for the detection of the components in these two pathways have been prepared. We are expecting to obtain our preliminary data in a short period of time. In the fall we will investigate the possible crosstalk of p63 and p53 in TGFbeta/Smad signaling pathway.

ED. NOTE (December 2015): Per Space Radiation Element Manager L. Simonsen, PI Dr. Minli Wang moved from Universities Space Research Association in 2014; the study is now inactive.

Bibliography Type: Description: (Last Updated: 12/09/2015) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Wang M, Saha J, Cucinotta FA. "Smad7 foci are present in micronuclei induced by heavy particle radiation." Mutation Research. 2013 Aug 30;756(1-2):108-14. Epub 2013 Apr 30. http://dx.doi.org/10.1016/j.mrgentox.2013.04.011 ; PubMed PMID: 23643526 , Aug-2013
Articles in Peer-reviewed Journals Wang M, Saha J, Hada M, Anderson JA, Pluth JM, O'Neill P, Cucinotta FA. "Novel Smad proteins localize to IR-induced double-strand breaks: interplay between TGFß and ATM pathways." Nucleic Acids Res. 2013 Jan;41(2):933-42. http://dx.doi.org/10.1093/nar/gks1038 ; PubMed PMID: 23221633 , Jan-2013
Articles in Peer-reviewed Journals Saha J, Wang M, Cucinotta FA. "Investigation of switch from ATM to ATR signaling at the sites of DNA damage induced by low and high LET radiation." DNA Repair. 2013 Dec;12(12):1143-51. http://dx.doi.org/10.1016/j.dnarep.2013.10.004 (Originally reported in August 2013 as "in press" as of August 2013.) , Dec-2013
Project Title:  Mechanistic Study of the Risk of Low Doses of HZE Particles on Human Cell Pre-Malignant Transformation Reduce
Fiscal Year: FY 2013 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2012  
End Date: 11/30/2014  
Task Last Updated: 11/13/2012 
Download report in PDF pdf
Principal Investigator/Affiliation:   Wang, Minli  M.D. / Universities Space Research Association 
Address:  3600 Bay Area Blvd 
 
Houston , TX 77058-1113 
Email: minli.wang@nasa.gov 
Phone: 281-483-4986  
Congressional District: 22 
Web:  
Organization Type: NON-PROFIT 
Organization Name: Universities Space Research Association 
Joint Agency:  
Comments: USRA corporate address: 10211 WINCOPIN CIR 500, Columbia, MD 21044-3405. 
Co-Investigator(s)
Affiliation: 
Wang, Ya  Emory University 
Project Information: Grant/Contract No. Internal Project 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2012 Space Radiobiology NNJ12ZSA001N 
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) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer01:How can experimental models of tumor development for the major tissues (lung, colon, stomach, breast, liver, and leukemias) be developed to represent the major processes in radiation carcinogenesis and extrapolated to human risk and clinical outcome projections? (IRP Rev J)
(2) 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)
(3) Cancer04:How can models of cancer risk be applied to reduce the uncertainties in dose-rate dependence of risks from SPEs and GCR?
(4) Cancer07:How can systems biology approaches be used to integrate research on the molecular, cellular, and tissue mechanisms of radiation damage to improve the prediction of the risk of cancer and to evaluate the effectiveness of CMs? How can epidemiology data and scaling factors support this approach?
Flight Assignment/Project Notes: NOTE: Extended to 11/30/14 per PI; original end date was 9/30/13 (Ed., 7/31/13)

Task Description: Establishing the scientific basis of radiation cancer risk is a primary goal for the NASA Space Radiation Program. There are large uncertainties in approaches to extrapolate experimental or human epidemiology data from high to low doses, and from high LET to low LET radiation. In this proposed study, we will use the cell transformation (pre-malignance) assay, which occurs much earlier than carcinogenesis after radiation exposure, to elucidate mechanisms and to provide important quantitative data on radiation quality effects related to cancer risks from low doses of HZE particles. We proposed two aims to test our hypothesis that p63 plays an important role in HZE particle-induced human cell pre-malignant transformation. Aim1: Investigate how p63 promotes HZE particle-induced human epithelial cell transformation through the JAG1/Wnt4#Myc pathway. Aim2: Investigate how p63 promotes HZE particle-induced human epithelial cell transformation through the CD95#JNK#Jun pathway. The results from this proposal are expected to reveal the importance of p63 in HZE particle-induced human epithelial cell transformation. Since majority of human tumors are derived from epithelial cells, the results from this proposal will make important contribution to the mechanism of HZE particle-induced carcinogenesis and therefore, providing valuable information for estimating the risk of space radiation-induced carcinogenesis and for further protection from such risk.

Research Impact/Earth Benefits: 0

Task Progress & Bibliography Information FY2013 
Task Progress: New project for FY2013.

Bibliography Type: Description: (Last Updated: 12/09/2015) 

Show Cumulative Bibliography Listing
 
 None in FY 2013