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Project Title:  Molecular Basis of DNA Repair and Protection from Apoptosis in Neuronal Progenitors Exposed to Space Radiation Reduce
Fiscal Year: FY 2015 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2008  
End Date: 10/01/2014  
Task Last Updated: 08/02/2014 
Download report in PDF pdf
Principal Investigator/Affiliation:   Wang, Huichen   / Prairie View A & M University 
Address:  P.O. Box 519 MS2230 
New Science Bldg 322 
Prairie View , TX 77446 
Email: huwang@pvamu.edu 
Phone: 936-261-3156  
Congressional District: 10 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Prairie View A & M University 
Joint Agency:  
Comments: Formerly at Emory University, relocated in September 2014 (Ed., 7/7/15)  
Co-Investigator(s)
Affiliation: 
Krzysztof, Reiss  Neurological Cancer Research, Stanley S. Scott Cancer Center, Louisiana State University Health. Sciences Center, New Orleans, LA 
Project Information: Grant/Contract No. NNX08BA08G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2008 Space Radiobiology NNJ08ZSA001N 
Grant/Contract No.: NNX08BA08G 
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) CNS:Risk of Acute (In-flight) and Late Central Nervous System Effects from Radiation Exposure (IRP Rev G)
Human Research Program Gaps: (1) CNS02:Does space radiation exposure elicit key events in adverse outcome pathways associated with neurological diseases? What are the key events or hallmarks, their time sequence and their associated biomarkers? (IRP Rev F)
(2) CNS06:How can new knowledge and data from molecular, cellular, tissue and animal models of late CNS risks or clinical human data be used to estimate late CNS risks to astronauts from GCR and SPE?
Flight Assignment/Project Notes: NOTE: End date is 9/19/2014 (changed from 9/30/2015) per PI move; setting end date to 10/1/14 for reporting purposes (Ed., 7/7/15)

NOTE: End date is now 9/30/2015 per NSSC information (Ed., 7/11/14)

NOTE: End date is now 9/30/2014 per PI and NSSC information (Ed., 8/3/2013)

NOTE: End date is now 9/30/2013 per NSSC information (Ed., 3/12/2013)

NOTE: Extended to 3/31/2013 per NSSC information (Ed., 12/18/12)

Task Description: The health risks to astronauts exposed to space radiation include cognitive deficits and possibly accelerated aging. While the pathogenesis of radiation-induced cognitive dysfunction remains largely uncharacterized, it is thought to include loss of neural progenitors from the brain. Understanding of the molecular and cellular bases underlying neuronal loss and/or dysfunction is absolutely required for the development of countermeasures before, during and possibly after space missions. Since experiments in humans are not possible, studies in this direction will benefit from appropriate biological model systems. The neurodegenerative effects of space radiation are likely to derive from DNA damage in the central nervous system (CNS). Therefore, research involving repair of this type of DNA lesions is critical for the development of new neuroprotective countermeasures. In the present proposal, we introduce an in vitro model of neural progenitors (neurospheres), which is derive from the brain of mouse embryo from neurodegenerative transgenic mice to study the detrimental effects of space radiation at the mechanistic level. Using this biological model, we will study DNA damage repair and apoptosis of proliferating and differentiated neural progenitor exposed to low dose of high charge and energy nuclei and protons. The proposed studies will provide novel insights into the molecular and cellular mechanisms underlying CNS risks from space radiation and will help to predict and countermeasure health risks from space radiation particularly with regard to effects on the CNS.

Research Impact/Earth Benefits: This proposal will study the mechanism of DNA damage and oxidative stress in neuronal cells induced by high energy particle, iron, and protons, compared to X-ray. This study will provide possible ways to develop accurate quantitative estimates to the risk of the central nervous system (CNS) from galactic cosmic ray (GCR) and solar particles events following long-term space travel.

Task Progress & Bibliography Information FY2015 
Task Progress: High linear energy transfer (LET) radiation induces clustered DNA damage and delayed oxidative stress which prolongs their response signaling to the progeny of irradiated cells, leading to alteration of homeostasis, including cell death program (apoptosis, autophagy, and senescence) and cell growth. Here we investigated the molecular and cellular mechanism of persistent DNA damage response, cell survival, and cell death of hippocampal neuronal cells following exposure to heavy ion particles and proton. We found that DNA damage response signaling persists longer in hippocampal neuronal cells exposed to high LET radiation (56Fe (1Gev/n)) than to low LET radiation ( proton (1Gev/n)). High LET radiation induced higher phosphorylation of Tip60, expression of p53, p21, and PUMA than low LET radiation. GSK3 inhibitors reduced Tip60 phosphoryaltion, p53, and PUMA expression. Inhibition of GSK3 activity reduced the cell killing of hippocampal neuronal cells following exposure to high LET radiation. High LET radiation induced more apoptosis, senescence, and autophagy than low LET radiation. This suggests that high LET radiation may sustain DNA damage signaling and change cellular homeostasis of energy and growth, implying the risk to the central nervous system (CNS).

ED. NOTE (7/7/15): Project continues as "Molecular Basis of DNA Repair and Protection from Apoptosis in Neuronal Progenitors Exposed to Space Radiation" grant NNX14AT39G, due to PI move to Prairie View A&M University in September 2014.

Bibliography Type: Description: (Last Updated: 11/13/2019) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Kandimalla R, Tang X, Wang T, Wang H. "High LET radiation produces sustained DNA damaging signaling and change cellular homestasis in hippocampal neuronal cells." Presented at 2014 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 12-13, 2014.

2014 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 12-13, 2014. http://www.hou.usra.edu/meetings/hrp2014/pdf/3306.pdf , Feb-2014

Abstracts for Journals and Proceedings Werner E, Tang X, Wang H, Doetsch P. "The role of persistent phenotype in radiation-induced genomic instability." 2014 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 12-13, 2014.

2014 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 12-13, 2014. http://www.hou.usra.edu/meetings/hrp2014/pdf/3187.pdf , Feb-2014

Abstracts for Journals and Proceedings Werner E, Kandimalla R, Wang H, Doetsch P. "A role for reactive oxygen species in the resolution of persistent genomic instability after exposure to radiation." 6th International Workshop on Space Radiation Research, Chiba, Japan, 15-18 May 2013.

Journal of Radiation Research (Impact Factor: 1.45). 2014 Mar;55(Suppl 1):i14. http://dx.doi.org/10.1093/jrr/rrt183 , Mar-2014

Project Title:  Molecular Basis of DNA Repair and Protection from Apoptosis in Neuronal Progenitors Exposed to Space Radiation Reduce
Fiscal Year: FY 2014 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2008  
End Date: 09/30/2015  
Task Last Updated: 08/02/2013 
Download report in PDF pdf
Principal Investigator/Affiliation:   Wang, Huichen   / Prairie View A & M University 
Address:  P.O. Box 519 MS2230 
New Science Bldg 322 
Prairie View , TX 77446 
Email: huwang@pvamu.edu 
Phone: 936-261-3156  
Congressional District: 10 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Prairie View A & M University 
Joint Agency:  
Comments: Formerly at Emory University, relocated in September 2014 (Ed., 7/7/15)  
Co-Investigator(s)
Affiliation: 
Krzysztof, Reiss  Neurological Cancer Research, Stanley S. Scott Cancer Center, Louisiana State University Health. Sciences Center, New Orleans, LA 
Project Information: Grant/Contract No. NNX08BA08G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2008 Space Radiobiology NNJ08ZSA001N 
Grant/Contract No.: NNX08BA08G 
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) CNS:Risk of Acute (In-flight) and Late Central Nervous System Effects from Radiation Exposure (IRP Rev G)
Human Research Program Gaps: (1) CNS02:Does space radiation exposure elicit key events in adverse outcome pathways associated with neurological diseases? What are the key events or hallmarks, their time sequence and their associated biomarkers? (IRP Rev F)
(2) CNS06:How can new knowledge and data from molecular, cellular, tissue and animal models of late CNS risks or clinical human data be used to estimate late CNS risks to astronauts from GCR and SPE?
Flight Assignment/Project Notes: NOTE: End date is now 9/30/2015 per NSSC information (Ed., 7/11/14)

NOTE: End date is now 9/30/2014 per PI and NSSC information (Ed., 8/3/2013)

NOTE: End date is now 9/30/2013 per NSSC information (Ed., 3/12/2013)

NOTE: Extended to 3/31/2013 per NSSC information (Ed., 12/18/12)

Task Description: The health risks to astronauts exposed to space radiation include cognitive deficits and possibly accelerated aging. While the pathogenesis of radiation-induced cognitive dysfunction remains largely uncharacterized, it is thought to include loss of neural progenitors from the brain. Understanding of the molecular and cellular bases underlying neuronal loss and/or dysfunction is absolutely required for the development of counter measures before, during and possibly after space missions. Since experiments in humans are not possible, studies in this direction will benefit from appropriate biological model systems. The neurodegenerative effects of space radiation are likely to derive from DNA damage in the central nervous system (CNS). Therefore, research involving repair of this type of DNA lesions is critical for the development of new neuroprotective countermeasures. In the present proposal, we introduce an in vitro model of neural progenitors (neurospheres), which is derive from the brain of mouse embryo from neurodegenerative transgenic mice to study the detrimental effects of space radiation at the mechanistic level. Using this biological model, we will study DNA damage repair and apoptosis of proliferating and differentiated neural progenitor exposed to low dose of high charge and energy nuclei and protons. The proposed studies will provide novel insights into the molecular and cellular mechanisms underlying CNS risks from space radiation and will help to predict and countermeasure health risks from space radiation particularly with regard to effects on the CNS.

Research Impact/Earth Benefits: This proposal will study the mechanism of DNA damage and oxidative stress in neuronal cells induced by high energy particle, iron, and protons, compared to X-ray. This study will provide possible ways to develop accurate quantitative estimates to the risk of the central nervous system (CNS) from galactic cosmic ray (GCR) and solar particles events following long-term space travel.

Task Progress & Bibliography Information FY2014 
Task Progress: Galactic cosmic rays (GCR) and solar particle events (SPE) include high energy and high charge (HZE) nuclei and a large amount of high energy protons. Evidence from radiobiological studies points out that HZE and protons-induced behavior change resembles the aging process, and neurogenesis causes from oxidative stress. However, the inter-relationship between oxidative stress and neurogenesis in neuronal cells remain unclear. The long term objective of this project is to investigate mechanisms of DNA damage processing in the CNS and to provide new molecular targets for countermeasure of the CNS risks from space radiation. We hypothesize that DNA repair and transcriptional regulation via the PARP-1—ATM—CREB pathway play a pivotal role in neuronal defense responses to neurodegenerative effect of HZE and protons.

Task progress: In this year, we performed the following studies:

1. Live imaging DNA damage process in neuronal cells following exposure to 0.1- 1Gy of 56Fe(1 GeV) and proton (1 GeV). We found that HZE particle induced persistent DNA damage in neuronal cells. This DNA damage signaling may transit to progeny cells.

2. Detection of effect of poly(ADP-ribose) polymerase 1 in DNA damage response in neuronal cells. We found that PARP-1 dependent DNA repair pathway is involved in clustered DNA damage repair in neuronal cells following exposure HZE particles.

3. Detection of the effect of glycogen synthase kinase 3 on radiation response in neuronal cells. We found that inhibition of GSK3 protect neuronal cells from space radiation.

4. Study on the effect of HZE on the processing of Amyloid precusor proteins in neuronal cells. 56Fe(1GeV) induces cleavage of APP c-terminal and translocation to nuclear in neuronal cells.

5. Study on High LET radiation produces sustained DNA damage signaling and changes cellular homeostasis in hippocampal neuronal cells. 1 Gy 56Fe(1GeV) induced persistent increased p53 expression and camp response element binding protein phosphorylation.

The results are described in published papers, and presented as abstracts in the following list and in several manuscripts.

Manuscripts supported by NNX08BA08G

1. Wang, T., Wang, M., Tian, L., Wang, H. PARP-1 is involved in clustered DNA damage in neuronal cells. Pols one revised

2. Ramachandiran, S. and Wang, H., Bernal-Mizrachi L. The noncanonical NF-kB pathway suppresses DNA damage, centrosome amplification and chromosomal aberrations in diffuse large cell lymphomas, Leukemia, Clinical Cancer Research, revising.

3. Wang, M., Tian L., Wang, T., Tang X. and Wang H. Function of GSK3 in radiation induced apopotosis in neural cells, in preparation.

4. Li Z, Hudson FZ, Wang H, Wang Y, Bian Z, Murnane JP, Dynan WS "Increased mutagenic joining of enzymatically-induced DNA double-strand breaks in high-charge and energy particle irradiated human cells" Radiat Res. 2013 Jul;180(1):17-24 PMID: 23692479 , May-2013

Abstracts in professional meeting

1. Wang T Kandimalla R, , Tang X, Wang H APP intracellular domain increases DNA damage response in hippocampal neuronal cells following exposure to high LET radiation Heavy ion in therapy and space radiation symposium , 24th Annual NASA Space Radiation Investigators' Workshop, Chiba, Japan, May 15-18 2013

2. Wang T, Kandimalla R, Tang X, Wang H High LET radiation produces sustained DNA damage signaling and changes cellular homeostasis in hippocampal neuronal cells Heavy ion in therapy and space radiation symposium , 24th Annual NASA Space Radiation Investigators' Workshop, Chiba, Japan, May 15-18 2013

3. Werner E, Kandimalla R, Wang H, and Doetsch PW, A role for reactive oxgen species in the resolution of persistent genomic instability after exposure to radiation Heavy ion in therapy and space radiation symposium , 24th Annual NASA Space Radiation Investigators' Workshop, Chiba, Japan, May 15-18 2013

4. Werner E, Kandimalla R, Wang H, and Doetsch PW. Early and persistent effect of PARP inhibition after exposure to radiation Heavy ion in therapy and space radiation symposium, 24th Annual NASA Space Radiation Investigators' Workshop, Chiba, Japan, May 15-18 2013

5. Li Z, Hudson FZ, Wang H, Murane JP, Dynan Ws. Secretoty protein phenotypes accompanied by mutagenic joining of enzymatically-induced DNA double-strand breaks in a population of HZE-exposed human cells. Heavy ion in therapy and space radiation symposium, 24th Annual NASA Space Radiation Investigators' Workshop, Chiba, Japan, May 15-18 2013

Bibliography Type: Description: (Last Updated: 11/13/2019) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Wang T, Kandimalla R, Tang X, Wang H. "APP intracellular domain increases DNA damage response in hippocampal neuronal cells following exposure to high LET radiation." CNS risk. 24th Annual NASA Space Radiation Investigators' Workshop. HITSRS2013--Heavy Ion in Therapy and Space Radiation Symposium 2013, Chiba, Japan, May 15-18, 2013.

24th Annual NASA Space Radiation Investigators' Workshop. HITSRS2013--Heavy Ion in Therapy and Space Radiation Symposium 2013, Chiba, Japan, May 15-18, 2013. , May-2013

Abstracts for Journals and Proceedings Wang T, Kandimalla R, Tang X, Wang H. "High LET radiation produces sustained DNA damage signaling and changes cellular homeostasis in hippocampal neuronal cells." CNS risk. 24th Annual NASA Space Radiation Investigators' Workshop. HITSRS2013--Heavy Ion in Therapy and Space Radiation Symposium 2013, Chiba, Japan, May 15-18, 2013.

24th Annual NASA Space Radiation Investigators' Workshop. HITSRS2013--Heavy Ion in Therapy and Space Radiation Symposium 2013, Chiba, Japan, May 15-18, 2013. , May-2013

Abstracts for Journals and Proceedings Werner E, Kandimalla R, Wang H, Doetsch PW. "A role for reactive oxgen species in the resolution of persistent genomic instability after exposure to radiation." Carcinogenesis risk. 24th Annual NASA Space Radiation Investigators' Workshop. HITSRS2013--Heavy Ion in Therapy and Space Radiation Symposium 2013, Chiba, Japan, May 15-18, 2013.

24th Annual NASA Space Radiation Investigators' Workshop. HITSRS2013--Heavy Ion in Therapy and Space Radiation Symposium 2013, Chiba, Japan, May 15-18, 2013. , May-2013

Abstracts for Journals and Proceedings Werner E, Kandimalla R, Wang H, Doetsch PW. "Early and persistent effect of PARP inhibition after exposure to radiation." 24th Annual NASA Space Radiation Investigators' Workshop. HITSRS2013--Heavy Ion in Therapy and Space Radiation Symposium 2013, Chiba, Japan, May 15-18, 2013.

24th Annual NASA Space Radiation Investigators' Workshop. HITSRS2013--Heavy Ion in Therapy and Space Radiation Symposium 2013, Chiba, Japan, May 15-18, 2013. , May-2013

Abstracts for Journals and Proceedings Li Z, Hudson FZ, Wang H, Murane JP, Dynan WS. "Secretoty protein phenotypes accompanied by mutagenic joining of enzymatically-induced DNA double-strand breaks in a population of HZE-exposed human cells." 24th Annual NASA Space Radiation Investigators' Workshop. HITSRS2013--Heavy Ion in Therapy and Space Radiation Symposium 2013, Chiba, Japan, May 15-18, 2013.

24th Annual NASA Space Radiation Investigators' Workshop, Chiba, Japan, May15-18 2013. HITSRS2013--Heavy Ion in Therapy and Space Radiation Symposium 2013, Chiba, Japan, May 15-18, 2013. , May-2013

Articles in Peer-reviewed Journals Li Z, Hudson FZ, Wang H, Wang Y, Bian Z, Murnane JP, Dynan WS. "Increased mutagenic joining of enzymatically-induced DNA double-strand breaks in high-charge and energy particle irradiated human cells." Radiat Res. 2013 Jul;180(1):17-24. http://dx.doi.org/10.1667/RR3332.1 ; PubMed PMID: 23692479 , Jul-2013
Project Title:  Molecular Basis of DNA Repair and Protection from Apoptosis in Neuronal Progenitors Exposed to Space Radiation Reduce
Fiscal Year: FY 2013 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2008  
End Date: 09/30/2013  
Task Last Updated: 08/05/2012 
Download report in PDF pdf
Principal Investigator/Affiliation:   Wang, Huichen   / Prairie View A & M University 
Address:  P.O. Box 519 MS2230 
New Science Bldg 322 
Prairie View , TX 77446 
Email: huwang@pvamu.edu 
Phone: 936-261-3156  
Congressional District: 10 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Prairie View A & M University 
Joint Agency:  
Comments: Formerly at Emory University, relocated in September 2014 (Ed., 7/7/15)  
Co-Investigator(s)
Affiliation: 
Krzysztof, Reiss  Neurological Cancer Research, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 
Project Information: Grant/Contract No. NNX08BA08G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2008 Space Radiobiology NNJ08ZSA001N 
Grant/Contract No.: NNX08BA08G 
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) CNS:Risk of Acute (In-flight) and Late Central Nervous System Effects from Radiation Exposure (IRP Rev G)
Human Research Program Gaps: (1) CNS02:Does space radiation exposure elicit key events in adverse outcome pathways associated with neurological diseases? What are the key events or hallmarks, their time sequence and their associated biomarkers? (IRP Rev F)
(2) CNS06:How can new knowledge and data from molecular, cellular, tissue and animal models of late CNS risks or clinical human data be used to estimate late CNS risks to astronauts from GCR and SPE?
Flight Assignment/Project Notes: NOTE: End date is now 9/30/2013 per NSSC information (Ed., 3/12/2013)

NOTE: Extended to 3/31/2013 per NSSC information (Ed., 12/18/12)

Task Description: The health risks to astronauts exposed to space radiation include cognitive deficits and possibly accelerated aging. While the pathogenesis of radiation-induced cognitive dysfunction remains largely uncharacterized, it is thought to include loss of neural progenitors from the brain. Understanding of the molecular and cellular bases underlying neuronal loss and/or dysfunction is absolutely required for the development of counter measures before, during and possibly after space missions. Since experiments in humans are not possible, studies in this direction will benefit from appropriate biological model systems. The neurodegenerative effects of space radiation are likely to derive from DNA damage in the central nervous system (CNS). Therefore, research involving repair of this type of DNA lesions is critical for the development of new neuroprotective countermeasures. In the present proposal, we introduce an in vitro model of neural progenitors (neurospheres), which is derive from the brain of mouse embryo from neurodegenerative transgenic mice to study the detrimental effects of space radiation at the mechanistic level. Using this biological model, we will study DNA damage repair and apoptosis of proliferating and differentiated neural progenitor exposed to low dose of high charge and energy nuclei and protons. The proposed studies will provide novel insights into the molecular and cellular mechanisms underlying CNS risks from space radiation and will help to predict and countermeasure health risks from space radiation particularly with regard to effects on the CNS.

Research Impact/Earth Benefits: This proposal will study the mechanism of DNA damage and oxidative stress in neuronal cells induced by high energy particle, iron, and protons, compared to X-ray. This study will provide possible ways to develop accurate quantitative estimates to the risk of the central nervous system (CNS) from galactic cosmic ray (GCR) and solar particles events following long-term space travel.

Task Progress & Bibliography Information FY2013 
Task Progress: 3. Productivity of Funded NASA Research

Current NASA Grant: NNX08BA08G PI: Dr. Huichen Wang Project Title: Funding period: 10/1/09 to 9/30/12

The health and performance risks to astronauts exposed to space radiation from galactic cosmic rays (GCR) and solar particle events (SPEs) during space missions are still uncertain. Acute and late radiation damage to the central nervous system (CNS) may lead to changes in motor function and behavior, or neurological disorders. Evidence of space radiation risk to the CNS has been accumulated and reported. However, the pathogenesis of space radiation-induced cognitive dysfunction remains largely uncharacterized. The neurodegenerative effects of space radiation are likely to be derived from DNA damage in the central nervous system (CNS). In this project we used an in vitro system based on cultures of mouse embryo neuronal progenitor cells (neurospheres) to study the function of PARP-1 in the induction of clustered DNA damage after low LET an high LET radiation as well as molecular basis of DNA repair. Space radiation induced clustered DNA damage including oxidized base damage, DNA single-strand breaks and double-strand breaks were detected by a modified single cell electrophoresis, and immunodetection of 8-oxo-dG, in neurospheres and PARP-1 proficient and deficient cells. We found that Poly(ADP-ribose) Polymerase 1 (PARP-1) inhibitor induce more DNA damage in neuronal progenitor cells following 56Fe particle and proton irradiation. PARP-1 inhibition also delayed the decay of gamma H2AX foci and the residual foci associated with new replicated DNA. The level of ATM (Ataxia Telangiectasia Mutated) phosphorylations was increased in neurospheres after treatment with PARP-1 inhibitor and following irradiation. Mutation of PARP-1 in MEF cells dramatically decrease DNA damage repair. We observed that PARP-1 and PAR formed a foci track and colocalized with phosphorylated ATM and MRE11. Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine cyclin-dependent kinase in post-mitotic neurons and plays a critical role in neurogenesis. We found that the interaction of PARP-1 and CDK5 in radiation-induced DNA damage response in an in vitro system based on cultures of mouse embryo neuronal progenitor cells (neurospheres) from PARP-1 knockout mice and mouse hippocampal neuronal cells. CDK5 inhibitor (roscovitine) reversed the radiosensitivity of the PARP inhibitor in neural cells exposed to X-ray, proton and heavy ion radiation using a clonogenic survival assay. The PARP inhibitor increased radiation-induced DNA damage and apoptosis in neural cells. These effects were abrogated when the PARP inhibitor was combined with the CDK5 inhibitor. CDK5 PARP inhibitors increased radiation induced ATM expression and ATM phosphorylation in both cytoplasm and nucleus of neural cells. The GSK3 beta inhibitor also reversed radiosentitivity of neural cells. These suggest that the DNA repair pathway and the neuronal survival factors play a critical role in protecting neuronal cells following space radiation. The details of this mechanism and biological effectiveness will be discussed.

Conclusion

1. We described DNA repair pathways (PARP-1 and ATM) in neural cell survival following exposure to high LET radiation. High energy particles induced larger RBE in cell survival and DNA damage of hippocampal neurons compared to X-ray radiation. PARP and ATM deficiency increased the RBE of cell survival and DNA damage induced by high charge and energy particles.

Related publications:

Publications/submitted manuscripts supported by NNX08BA08G

1. Wang H., Liu S., et al. (2009). "S-phase cells are more sensitive to high-linear energy transfer radiation." Int J Radiat Oncol Biol Phys 74(4): 1236-1241.

2. Cucinotta F, Wang H, Huff JL. "Risk of Acute or Late Central Nervous System Effects from Radiation Exposure." Human Health and Performance Risks of Space Exploration Missions. ed. by J.C. McPhee and J.B. Charles. Houston, Texas. NASA, 2010. p. 191-212, NASA SP 2009

3. Shi Y. Zhang X., Tang X., Wang P., Wang H., and Wang Y.MiR-21 is Continually Elevated Long-Term in the Brain after Exposure to Ionizing Radiation, Radiation Research, 177(1):124-8, 2012

4. Zhang X., Wooi-Loon N., Wang P. Tian L., Werner E., Wang H. Doetsch PW., and Wang Y. MicroRNA-21 modulates reactive oxygen species levels via targeting SOD3 and TNFa, Cancer Research,

5. Ramachandiran, S. and Wang, H., Bernal-Mizrachi L. The noncanonical NF-gammaB pathway suppresses DNA damage, centrosome amplification and chromosomal aberrations in diffuse large cell lymphomas, Leukemia, Clinical Cancer Research, revising.

Manuscripts in preparation and in progression supported by NNX08BA08G

1. Wang, M., Tian, L., Wang, H. PARP-1 is involved in clustered DNA damage in neuronal cells. In preparation.

2. Wang, M., Tian L., Wang, T., Tang X. and Wang H. Function of GSK3 in radiation induced apopotosis in neural cells, in preparation.

3. Wang Y., Tang X. Wang M. and Wang H. Amentoflavone-mediated radioprotection of hippocampal neuronal cells through reduction of ROS and DNA damage, in preparation.

4. Homologous recombination mediates persistent clustered DNA damage induced by high LET radiation, in preparation.

Bibliography Type: Description: (Last Updated: 11/13/2019) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Kandimalla R, Wang T, Tang X, Wang H. "Interaction of APP(swe) mutant and GSK3 modulates radiation response in hippocampal neuronal cells." 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. Abstract 8091. , Jul-2012

Abstracts for Journals and Proceedings Wang T, Tang X, Wang Y, Wang C, Wang H. "Homologous recombination mediates persistent clustered DNA damage processing." 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. Abstract 8090. , Jul-2012

Abstracts for Journals and Proceedings Werner E, Tang X, Wang H, Doetsch PW. "Concurrent Delayed ROS Stress and Genomic Instability in Response to a Single Exposure to Ionizing Radiation." 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. Abstract 8048. , Jul-2012

Articles in Peer-reviewed Journals Zhang X, Ng WL, Wang P, Tian L, Werner E, Wang H, Doetsch P, Wang Y. "MicroRNA-21 modulates the levels of reactive oxygen species levels by targeting SOD3 and TNF." Cancer Research. 2012 Sep 15;72(18):4707-13. Epub 2012 Jul 25. PubMed PMID: 22836756 , Sep-2012
Articles in Peer-reviewed Journals Shi Y, Zhang X, Tang X, Wang P, Wang H, Wang Y. "MiR-21 is continually elevated long-term in the brain after exposure to ionizing radiation." Radiat Res. 2012 Jan;177(1):124-8. Epub 2011 Oct 28. PMID: 22034847 , Jan-2012
Project Title:  Molecular Basis of DNA Repair and Protection from Apoptosis in Neuronal Progenitors Exposed to Space Radiation Reduce
Fiscal Year: FY 2012 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2008  
End Date: 09/30/2012  
Task Last Updated: 07/31/2011 
Download report in PDF pdf
Principal Investigator/Affiliation:   Wang, Huichen   / Prairie View A & M University 
Address:  P.O. Box 519 MS2230 
New Science Bldg 322 
Prairie View , TX 77446 
Email: huwang@pvamu.edu 
Phone: 936-261-3156  
Congressional District: 10 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Prairie View A & M University 
Joint Agency:  
Comments: Formerly at Emory University, relocated in September 2014 (Ed., 7/7/15)  
Co-Investigator(s)
Affiliation: 
Krzysztof, Reiss  Neurological Cancer Research, Stanley S. Scott Cancer Center, Louisiana State University Health. Sciences Center, New Orleans, LA 
Project Information: Grant/Contract No. NNX08BA08G 
Responsible Center: NASA JSC 
Grant Monitor: Cucinott1a, Francis  
Center Contact: 281-483-0968 
noaccess@nasa.gov 
Solicitation / Funding Source: 2008 Space Radiobiology NNJ08ZSA001N 
Grant/Contract No.: NNX08BA08G 
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) CNS:Risk of Acute (In-flight) and Late Central Nervous System Effects from Radiation Exposure (IRP Rev G)
Human Research Program Gaps: (1) CNS02:Does space radiation exposure elicit key events in adverse outcome pathways associated with neurological diseases? What are the key events or hallmarks, their time sequence and their associated biomarkers? (IRP Rev F)
(2) CNS06:How can new knowledge and data from molecular, cellular, tissue and animal models of late CNS risks or clinical human data be used to estimate late CNS risks to astronauts from GCR and SPE?
Task Description: The health risks to astronauts exposed to space radiation include cognitive deficits and possibly accelerated aging. While the pathogenesis of radiation-induced cognitive dysfunction remains largely uncharacterized, it is thought to include loss of neural progenitors from the brain. Understanding of the molecular and cellular bases underlying neuronal loss and/or dysfunction is absolutely required for the development of counter measures before, during and possibly after space missions. Since experiments in humans are not possible, studies in this direction will benefit from appropriate biological model systems. The neurodegenerative effects of space radiation are likely to derive from DNA damage in the central nervous system (CNS). Therefore, research involving repair of this type of DNA lesions is critical for the development of new neuroprotective countermeasures. In the present proposal, we introduce an in vitro model of neural progenitors (neurospheres), which is derive from the brain of mouse embryo from neurodegenerative transgenic mice to study the detrimental effects of space radiation at the mechanistic level. Using this biological model, we will study DNA damage repair and apoptosis of proliferating and differentiated neural progenitor exposed to low dose of high charge and energy nuclei and protons. The proposed studies will provide novel insights into the molecular and cellular mechanisms underlying CNS risks from space radiation and will help to predict and countermeasure health risks from space radiation particularly with regard to effects on the CNS.

Research Impact/Earth Benefits: This proposal will study the mechanism of DNA damage and oxidative stress in neuronal cells induced by high energy particle, iron, and protons, compared to X-ray. This study will provide possible ways to develop accurate quantitative estimates to the risk of the central nervous system (CNS) from galactic cosmic ray (GCR) and solar particles events following long-term space travel.

Task Progress & Bibliography Information FY2012 
Task Progress: The health and performance risks to astronauts exposed to space radiation from galactic cosmic rays (GCR) and solar particle events (SPEs) during space missions are still uncertain. Acute and late radiation damage to the central nervous system (CNS) may lead to changes in motor function and behavior, or neurological disorders. Evidence of space radiation risk to the CNS has been accumulated and reported. However, the pathogenesis of space radiation-induced cognitive dysfunction remains largely uncharacterized. The neurodegenerative effects of space radiation are likely to be derived from DNA damage in the central nervous system (CNS). In this project we used an in vitro system based on cultures of mouse embryo neuronal progenitor cells (neurospheres) to study the function of PARP-1 in the induction of clustered DNA damage after low LET an high LET radiation as well as molecular basis of DNA repair. Space radiation induced clustered DNA damage including oxidized base damage, DNA single-strand breaks and double-strand breaks were detected by a modified single cell electrophoresis, and immunodetection of 8-oxo-dG, in neurospheres and PARP-1 proficient and deficient cells. We found that Poly(ADP-ribose) Polymerase 1 (PARP-1) inhibitor induce more DNA damage in neuronal progenitor cells following 56Fe particle and proton irradiation. PARP-1 inhibition also delayed the decay of gamma H2AX foci and the residual foci associated with new replicated DNA. The level of ATM (Ataxia Telangiectasia Mutated) phosphorylations was increased in neurospheres after treatment with PARP-1 inhibitor and following irradiation. Mutation of PARP-1 in MEF cells dramatically decrease DNA damage repair. We observed that PARP-1 and PAR formed a foci track and colocalized with phosphorylated ATM and MRE11. Inhibition of Cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 (GSK3) protect neuronal cells from high LET radiation. Here, we investigated the DNA damage complex formation and apoptosis in hippocampal neuronal cells exposed to iron particles using a novel approach to live imaging DNA damage track with fluorescent tagged DNA repair proteins (GFP-PARP-1, mCherry-53BP1 and YFP-MRE11) and live imaging caspase activity in single cell. We found that Mre11, PARP-1 and 53BP1 protein colocalized in DNA damage tracks. Less than one track was formed in each cell exposed 0.1 Gy of 56Fe (1 GeV/u) particle. Inhibition of PARP-1 reduced MRE11 track formation. This suggests that PARP-1 mediates Mre11 complex to DNA damage tracks in hippocampal neurons exposed to high LET radiation. In another study, we investigated the role of a purified component (amentoflavone) from plant extracts in radiation response in hippocampal neurons (HT22) and glioblastoma cells (U87 MG) following exposure to high linear transfer (LET) radiation and low LET radiation. We found that amentoflavone protects hippocampal neurons from radiation and enhances radiosensitivity of glioblastoma cells. Treatment of amentoflavone increased survival fractions in hippocampal neuronal cells following exposure to X-Ray radiation and 56Fe particles, though amentoflavone enhanced radiosensitivity of glioblastoma cells. Amentoflavone attenuated reactive oxygen species (ROS) and DNA damage in irradiated hippocampal neurons, and increased DNA repair activity and superoxide dismutase 1 (SOD1) expression. Pretreament of amentoflavone also increased the survival rate of mice from whole body gamma irradiation. This suggests that amentoflavone may have a potential function on cancer chemo- radiotherapy and radiation protection.

Bibliography Type: Description: (Last Updated: 11/13/2019) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Tang X, Renegar J, Wang Y, Wang M, Wang C, Wang H. "PARP-1 mediate Mre11 complex to DNA damage tracks in hippocampal neurons exposed to high LET radiation." Presented at International Symposium for Radiation Research and Medical Physics, Shanghai, China, May 30-June 2, 2011.

International Symposium for Radiation Research and Medical Physics, Shanghai, China, May 30-June 2, 2011, P52. , Jun-2011

Abstracts for Journals and Proceedings Wang H, Kong X, Tang X, Zheng X, Zhu Y, Wang S, Wang H. "Effect of amentoflavone on radiation response in neuronal cells." The American Association for Cancer Research 102nd Annual Meeting, Orlando, FL, April 2-6, 2011.

The American Association for Cancer Research 102nd Annual Meeting, Orlando, FL, April 2-6, 2011. Abstract #2678. http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=f9b6a23d-fa6c-4796-aba8-6fc62c56eb47&cKey=310e19c5-61b7-4d58-a41c-edaadac0154e&mKey={507D311A-B6EC-436A-BD67-6D14ED39622C} , Apr-2011

Abstracts for Journals and Proceedings Wang H, Wang Y, Kaluzova M, Tang X, Q Yin, Flemington EK, Hadjipanay C. "Effect of microRNA-155 on EGFRvIII mediated radiation response in glioblastoma tumors." The American Society for Radiation Oncology, 2011 Annual Meeting/53rd ASTRO Annual Meeting, Miami, Florida, October 2011.

International Journal of Radiation Oncology * Biology * Physics. 2011 Oct;81(2 Suppl):S713. Proceedings of the 53rd Annual ASTRO Meeting. The American Society for Radiation Oncology, 2011 Annual Meeting/53rd ASTRO Annual Meeting, Miami, Florida, October 2011. http://dx.doi.org/10.1016/j.ijrobp.2011.06.1265 and click on Full Text. , Oct-2011

Awards Wang H, Wang Y, Kaluzova M, Tang X, Q Yin, Flemington EK, Hadjipanay C. "The American Society for Radiation Oncology, 2011 Annual Meeting Scientific Abstract Award for 'Effect of microRNA-155 on EGFRvIII mediated radiation response in glioblastoma tumors.' 53rd ASTRO Annual Meeting, Miami, Florida, 2011." Oct-2011
Project Title:  Molecular Basis of DNA Repair and Protection from Apoptosis in Neuronal Progenitors Exposed to Space Radiation Reduce
Fiscal Year: FY 2011 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2008  
End Date: 09/30/2012  
Task Last Updated: 08/06/2010 
Download report in PDF pdf
Principal Investigator/Affiliation:   Wang, Huichen   / Prairie View A & M University 
Address:  P.O. Box 519 MS2230 
New Science Bldg 322 
Prairie View , TX 77446 
Email: huwang@pvamu.edu 
Phone: 936-261-3156  
Congressional District: 10 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Prairie View A & M University 
Joint Agency:  
Comments: Formerly at Emory University, relocated in September 2014 (Ed., 7/7/15)  
Co-Investigator(s)
Affiliation: 
Krzysztof, Reiss  Neurological Cancer Research, Stanley S. Scott Cancer Center, Louisiana State University Health. Sciences Center, New Orleans, LA 
Project Information: Grant/Contract No. NNX08BA08G 
Responsible Center: NASA JSC 
Grant Monitor: Cucinott1a, Francis  
Center Contact: 281-483-0968 
noaccess@nasa.gov 
Solicitation / Funding Source: 2008 Space Radiobiology NNJ08ZSA001N 
Grant/Contract No.: NNX08BA08G 
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) CNS:Risk of Acute (In-flight) and Late Central Nervous System Effects from Radiation Exposure (IRP Rev G)
Human Research Program Gaps: (1) CNS02:Does space radiation exposure elicit key events in adverse outcome pathways associated with neurological diseases? What are the key events or hallmarks, their time sequence and their associated biomarkers? (IRP Rev F)
(2) CNS06:How can new knowledge and data from molecular, cellular, tissue and animal models of late CNS risks or clinical human data be used to estimate late CNS risks to astronauts from GCR and SPE?
Task Description: The health risks to astronauts exposed to space radiation include cognitive deficits and possibly accelerated aging. While the pathogenesis of radiation-induced cognitive dysfunction remains largely uncharacterized, it is thought to include loss of neural progenitors from the brain. Understanding of the molecular and cellular bases underlying neuronal loss and/or dysfunction is absolutely required for the development of counter measures before, during and possibly after space missions. Since experiments in humans are not possible, studies in this direction will benefit from appropriate biological model systems. The neurodegenerative effects of space radiation are likely to derive from DNA damage in the central nervous system (CNS). Therefore, research involving repair of this type of DNA lesions is critical for the development of new neuroprotective countermeasures. In the present proposal, we introduce an in vitro model of neural progenitors (neurospheres), which is derive from the brain of mouse embryo from neurodegenerative transgenic mice to study the detrimental effects of space radiation at the mechanistic level. Using this biological model, we will study DNA damage repair and apoptosis of proliferating and differentiated neural progenitor exposed to low dose of high charge and energy nuclei and protons. The proposed studies will provide novel insights into the molecular and cellular mechanisms underlying CNS risks from space radiation and will help to predict and countermeasure health risks from space radiation particularly with regard to effects on the CNS.

Research Impact/Earth Benefits: This proposal will study the mechanism of DNA damage and oxidative stress in neuronal cells induced by high energy particle, iron, and protons, compared to X-ray. This study will provide possible ways to develop accurate quantitative estimates to the risk of the central nervous system (CNS) from galactic cosmic ray (GCR) and solar particles events following long-term space travel.

Task Progress & Bibliography Information FY2011 
Task Progress: We described DNA repair pathways (PARP-1 and ATM) in neural cell survival following exposure to high LET radiation. High energy particles induced larger RBE in cell survival and DNA damage of hippocampal neurons compared to X-ray radiation.

PARP and ATM deficiency increased the RBE of cell survival and DNA damage induced by high charge and energy particles.

We found that Inhibition of cyclin dependent kinase 5 and glycogen synthase kinase 3 beta could reverse radiation sensitivity in neuronal cells and neurospheres, but enhance radiation sensitivity in glioblastoma cells.

Bibliography Type: Description: (Last Updated: 11/13/2019) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Wang M, Tian L, Tang X. Wang H. "Interaction of PARP-1 and CDK5 in DNA damage response in neural cells exposed to space radiation." 21st Annual NASA Space Radiation Investigators' Workshop, Port Jefferson, New York, May 2010.

21st Annual NASA Space Radiation Investigators' Workshop, Port Jefferson, New York, May 2010. , May-2010

Articles in Peer-reviewed Journals Wang H, Liu S Zhang P, Zhang S, Naidu M, Wang H, Wang Y. "S-phase cells are more sensitive to high-linear energy transfer radiation." Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):1236-41. PubMed PMID: 19545789 , Jul-2009
NASA Technical Documents Cucinotta F, Wang H, Huff JL. "Risk of Acute or Late Central Nervous System Effects from Radiation Exposure." Human Health and Performance Risks of Space Exploration Missions. ed. by J.C. McPhee and J.B. Charles. Houston, Tex. : NASA, 2010. p. 191-212, NASA SP 2009. , May-2009
Project Title:  Molecular Basis of DNA Repair and Protection from Apoptosis in Neuronal Progenitors Exposed to Space Radiation Reduce
Fiscal Year: FY 2010 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2008  
End Date: 09/30/2012  
Task Last Updated: 07/29/2009 
Download report in PDF pdf
Principal Investigator/Affiliation:   Wang, Huichen   / Prairie View A & M University 
Address:  P.O. Box 519 MS2230 
New Science Bldg 322 
Prairie View , TX 77446 
Email: huwang@pvamu.edu 
Phone: 936-261-3156  
Congressional District: 10 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Prairie View A & M University 
Joint Agency:  
Comments: Formerly at Emory University, relocated in September 2014 (Ed., 7/7/15)  
Co-Investigator(s)
Affiliation: 
Reiss, Krzysztof  Temple University 
Project Information: Grant/Contract No. NNX08BA08G 
Responsible Center: NASA JSC 
Grant Monitor: Cucinott1a, Francis  
Center Contact: 281-483-0968 
noaccess@nasa.gov 
Solicitation / Funding Source: 2008 Space Radiobiology NNJ08ZSA001N 
Grant/Contract No.: NNX08BA08G 
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) CNS:Risk of Acute (In-flight) and Late Central Nervous System Effects from Radiation Exposure (IRP Rev G)
Human Research Program Gaps: (1) CNS02:Does space radiation exposure elicit key events in adverse outcome pathways associated with neurological diseases? What are the key events or hallmarks, their time sequence and their associated biomarkers? (IRP Rev F)
(2) CNS06:How can new knowledge and data from molecular, cellular, tissue and animal models of late CNS risks or clinical human data be used to estimate late CNS risks to astronauts from GCR and SPE?
Task Description: The health risks to astronauts exposed to space radiation include cognitive deficits and possibly accelerated aging. While the pathogenesis of radiation-induced cognitive dysfunction remains largely uncharacterized, it is thought to include loss of neural progenitors from the brain. Understanding of the molecular and cellular bases underlying neuronal loss and/or dysfunction is absolutely required for the development of counter measures before, during and possibly after space missions. Since experiments in humans are not possible, studies in this direction will benefit from appropriate biological model systems. The neurodegenerative effects of space radiation are likely to derive from DNA damage in the central nervous system (CNS). Therefore, research involving repair of this type of DNA lesions is critical for the development of new neuroprotective countermeasures. In the present proposal, we introduce an in vitro model of neural progenitors (neurospheres), which is derive from the brain of mouse embryo from neurodegenerative transgenic mice to study the detrimental effects of space radiation at the mechanistic level. Using this biological model, we will study DNA damage repair and apoptosis of proliferating and differentiated neural progenitor exposed to low dose of high charge and energy nuclei and protons. The proposed studies will provide novel insights into the molecular and cellular mechanisms underlying CNS risks from space radiation and will help to predict and countermeasure health risks from space radiation particularly with regard to effects on the CNS.

Research Impact/Earth Benefits: This proposal will study the mechanism of DNA damage and oxidative stress in neuronal cells induced by high energy particle, iron, and protons, compared to X-ray. This study will provide possible ways to develop accurate quantitative estimates to the risk of the central nervous system (CNS) from galactic cosmic ray (GCR) and solar particles events following long-term space travel.

Task Progress & Bibliography Information FY2010 
Task Progress: This is the first year term of NASA funded grant NNX08BA08G. During this period, we run one beam time (1.2 hour of 56Fe 1000 MeV and 2 hours od Proton 1000 MeV) in NASA Space Radiation Laboratory. The PI and two postdoctoral fellow presented the results at the 20th Annual NASA Space Radiation Health Investigators’ Workshop, 2009, and Radiation Research Society's 55th Annual Meeting, 2009. One paper had been published in peer reviewed journal. The PI, two postdoctoral fellows, and one master student candidate worked on this project.

A Summary of the results:

The health risks to astronauts exposed to space radiation include cognitive deficits and possibly accelerated aging. However, the pathogenesis of radiation-induced cognitive dysfunction remains largely uncharacterized. The neurodegenerative effects of space radiation are likely to derive from DNA damage in the central nervous system (CNS). PARP-1 catalyzes poly(ADP-ribosyl)ation on DNA and proteins as immediate response to DNA damage induced by ionizing radiation or following oxidative stress. . In this study, we used an in vitro system based on cultures of mouse embryo neuronal progenitor cells (neurospheres) to study the function of PARP-1 in the induction of clustered DNA damage after low LET an high LET radiation as well as molecular basis of DNA repair. Space radiation induced clustered DNA damage including oxidized base damage, DNA single-strand breaks and double-strand breaks were detected by a modified single cell electrophoresis, and immunodetection of 8-oxo-dG, in neurospheres and PARP-1 proficient and deficient cells. We found that Poly(ADP-ribose) Polymerase 1 (PARP-1) inhibitor induce more DNA damage in neuronal progenitor cells following 56Fe particle and proton irradiation. PARP-1 inhibition also delayed the decay of gamma-H2AX foci and the residual foci associated with new replicated DNA. The level of ATM (Ataxia Telangiectasia Mutated) phosphorylations was increased in neurospheres after treatment with PARP-1 inhibitor and following irradiation. Mutation of PARP-1 in MEF cells dramatically decrease DNA damage repair. These suggest that PARP-1 may play a role in protecting neuronal cells following space radiation. The detail of mechanism and biological effectiveness are under study.

Bibliography Type: Description: (Last Updated: 11/13/2019) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Wang H, Liu S, Zhang P, Zhang S, Naidu M, Wang H, Wang Y. "S-phase cells are more sensitive to high-linear energy transfer radiation." Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):1236-41. PubMed PMID: 19545789 , Jul-2009
Project Title:  Molecular Basis of DNA Repair and Protection from Apoptosis in Neuronal Progenitors Exposed to Space Radiation Reduce
Fiscal Year: FY 2009 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/01/2008  
End Date: 09/30/2012  
Task Last Updated: 10/28/2008 
Download report in PDF pdf
Principal Investigator/Affiliation:   Wang, Huichen   / Prairie View A & M University 
Address:  P.O. Box 519 MS2230 
New Science Bldg 322 
Prairie View , TX 77446 
Email: huwang@pvamu.edu 
Phone: 936-261-3156  
Congressional District: 10 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Prairie View A & M University 
Joint Agency:  
Comments: Formerly at Emory University, relocated in September 2014 (Ed., 7/7/15)  
Co-Investigator(s)
Affiliation: 
Reiss, Krzysztof  Temple University 
Project Information: Grant/Contract No. NNX08BA08G 
Responsible Center: NASA JSC 
Grant Monitor: Cucinott1a, Francis  
Center Contact: 281-483-0968 
noaccess@nasa.gov 
Solicitation / Funding Source: 2008 Space Radiobiology NNJ08ZSA001N 
Grant/Contract No.: NNX08BA08G 
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) CNS:Risk of Acute (In-flight) and Late Central Nervous System Effects from Radiation Exposure (IRP Rev G)
Human Research Program Gaps: (1) CNS02:Does space radiation exposure elicit key events in adverse outcome pathways associated with neurological diseases? What are the key events or hallmarks, their time sequence and their associated biomarkers? (IRP Rev F)
(2) CNS06:How can new knowledge and data from molecular, cellular, tissue and animal models of late CNS risks or clinical human data be used to estimate late CNS risks to astronauts from GCR and SPE?
Task Description: The health risks to astronauts exposed to space radiation include cognitive deficits and possibly accelerated aging. While the pathogenesis of radiation-induced cognitive dysfunction remains largely uncharacterized, it is thought to include loss of neural progenitors from the brain. Understanding of the molecular and cellular bases underlying neuronal loss and/or dysfunction is absolutely required for the development of counter measures before, during and possibly after space missions. Since experiments in humans are not possible, studies in this direction will benefit from appropriate biological model systems. The neurodegenerative effects of space radiation are likely to derive from DNA damage in the central nervous system (CNS). Therefore, research involving repair of this type of DNA lesions is critical for the development of new neuroprotective countermeasures. In the present proposal, we introduce an in vitro model of neural progenitors (neurospheres), which is derive from the brain of mouse embryo from neurodegenerative transgenic mice to study the detrimental effects of space radiation at the mechanistic level. Using this biological model, we will study DNA damage repair and apoptosis of proliferating and differentiated neural progenitor exposed to low dose of high charge and energy nuclei and protons. The proposed studies will provide novel insights into the molecular and cellular mechanisms underlying CNS risks from space radiation and will help to predict and countermeasure health risks from space radiation particularly with regard to effects on the CNS.

Research Impact/Earth Benefits: 0

Task Progress & Bibliography Information FY2009 
Task Progress: New project for FY2009.

Bibliography Type: Description: (Last Updated: 11/13/2019) 

Show Cumulative Bibliography Listing
 
 None in FY 2009