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Project Title:  Mechanisms of Ocular Cataracts Reduce
Fiscal Year: FY 2011 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/04/2005  
End Date: 09/30/2011  
Task Last Updated: 12/30/2011 
Download report in PDF pdf
Principal Investigator/Affiliation:   Hall, Eric J Ph.D., D.Sc. / Columbia University 
Address:  630 West 168th Street 
Center for Radiological Research 
New York , NY 10032 
Email: ejh1@columbia.edu 
Phone: 212-305-5660  
Congressional District: 15 
Web: http://cpmcnet.columbia.edu/dept/radoncology/crr  
Organization Type: UNIVERSITY 
Organization Name: Columbia University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Brenner, David  Ph.D. Columbia University 
Smilenov, Lubomir  Columbia University 
Kleiman, Norman  Columbia University 
Key Personnel Changes / Previous PI: Personnel unchanged
Project Information: Grant/Contract No. NNJ05HI38G 
Responsible Center: NASA JSC 
Grant Monitor: Cucinott1a, Francis  
Center Contact: 281-483-0968 
noaccess@nasa.gov 
Solicitation / Funding Source: 2004 Radiation Biology NNH04ZUU005N 
Grant/Contract No.: NNJ05HI38G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
Flight Assignment/Project Notes: NOTE: Received no-cost extension to 9/30/2011 per C. Guidry/JSC (8/10)

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

Task Description: Radiation exposure guidelines for space are different from those on earth. Exposures in space are potentially much higher than terrestrial irradiation due to galactic cosmic radiation, trapped radiation belts near the earth and solar particle events. Radiation exposures in space are relatively difficult to reduce and impossible to eliminate entirely. Other human health risks in this inherently hostile space environment may be more acute or drastic than those of radiation exposure. For these reasons, larger annual occupational dose limits have been permitted for astronauts than are recommended for earth-bound radiation workers (though career limits of risk have been roughly equalized). Nevertheless, earlier onset of cataract has been noted in the astronaut core and exposure to space radiation appears to be an important risk factor in its development.

It is clear that there is considerable heterogeneity in the human response to radiation, which is thought to be, in part, mediated by genetic differences in susceptibility. Nevertheless, a precise understanding of the relative role of individual genes thought to be important in mediating the cellular response to radiation exposure is lacking. This proposal hypothesizes that individuals who have defects in one or more genes governing recognition or repair of DNA damage or passage through the cell cycle may be at greater risk for radiation cataract development than normal individuals.

The hypothesis upon which this proposal is based is that heavy ions mediate their cataractogenic effect through errors in division and/or differentiation arising from radiation damage and subsequent misrepair of lens epithelial cells.

We investigated the mechanisms of cataractogenesis by looking at radiation cataract formation in animals haploinsufficient for one or more genes involved in DNA damage recognition and repair or cell cycle checkpoint control.

In particular, this project examined the influence of multiple haplo-insufficiencies in the development of high-LET radiation induced opacities in mice heterozygous for Atm, Mrad9 or Brca1. Cataract incidence and progression was quantified longitudinally and compared to that from similarly irradiated wild type animals. The findings from this work support the hypothesis of a genotoxic basis for radiation cataract and establish that combined haploinsufficiency for genes regulating the DNA damage/repair response can result in more profound severe radiation cataract effects than those observed in irradiated wild-type or singly heterozygous animals.

These studies provided an opportunity to study the influence and effects of genetic heterogeneity in an organized tissue, the lens, in a genetically defined mouse model that has great relevance and similarity to human response to radiation exposure and determination of appropriate human exposure guidelines. These findings have helped shed light on the genetic control and cellular mechanisms of heavy ion induced cataractogenesis and are likely to be important in determining future exposure guidelines for radiosensitive subsets of the human population, including the astronaut core.

Research Impact/Earth Benefits: Radiation exposures in Space are relatively difficult to reduce, and impossible to eliminate entirely. At the same time, other risks to humans in the hostile environment in space may be more acute than those of radiation. For this reason, larger annual dose limits have been tolerated for astronauts than recommended by NCRP for radiation workers on the ground, though career limits of risk have been roughly equalized. The purpose of radiation protection is to prevent deterministic effects of clinical significance and to limit stochastic effects to levels that are acceptable modulated by societal concerns. The deterministic effect already observed in a proportion of astronauts is early onset of ocular cataracts. Previous NASA funded studies from our laboratory demonstrated that mice haplo- insufficient for ATM (that contain one good copy and one bad copy of the Atm gene and a correspondingly reduced amount of ATM protein) develop high-LET (heavy-ion) radiation induced cataracts earlier and with more severity than wild type animals. This leads to speculation that the unexpected observation of cataractogenesis in the astronaut core might be explained, in part, by individual genetic differences in radiosensitivity.

The research reported here seeks to expand the library of genes involved in DNA damage recognition and repair and/or cell cycle checkpoint control and also to investigate the possible relationship(s) between heterozygosity for one or more such genes and cataractogenesis.

Findings from these studies are likely to shed light on the genetic control and cellular mechanisms of both heavy ion and proton induced cataractogenesis. More importantly, using the lens and radiation cataract induction as a model system, these findings may have important implications for radiosensitive subsets of the human population, including the astronaut core, and aid in determining future national space radiation risk policies and in determination of appropriate radiation human exposure guidelines.

We further hypothesize that that as radiation cataract is thought to arise from damaged or misrepaired DNA and subsequent errors in cell cycle control, division and differentiation, the cellular and molecular pathways of the biological response to space radiation exposure in the lens has fundamental relevance and parallels to DNA damaging processes and pathologies in other cells and tissues, including carcinogenesis.

Task Progress & Bibliography Information FY2011 
Task Progress: Introduction.

Radiation exposures in Space are relatively difficult to reduce, and impossible to eliminate entirely. At the same time, other risks to humans in the hostile environment in space may be more acute than those of radiation. For this reason, larger annual dose limits have been tolerated for astronauts than recommended by NCRP for radiation workers on the ground, though career limits of risk have been roughly equalized. The purpose of radiation protection is to prevent deterministic effects of clinical significance and to limit stochastic effects to levels that are acceptable modulated by societal concerns. The deterministic effect already observed in a proportion of astronauts is an early onset of ocular cataracts. Previous NASA funded studies from our laboratory demonstrated that mice haplo- insufficient for Atm (that contain one good copy and one bad copy of the Atm gene and a correspondingly reduced amount of ATM protein) develop high-LET (heavy-ion) radiation induced cataracts earlier and with more severity than wild type animals. This leads to speculation that the unexpected observation of cataractogenesis in the astronaut core might be explained, in part, by individual genetic differences in radiosensitivity.

The research reported here seeks to expand the library of genes involved in DNA damage recognition and repair and/or cell cycle checkpoint control and also to investigate the possible relationship(s) between heterozygosity for one or more such genes and cataractogenesis.

Project Aims.

This proposal was based on the hypothesis that, following exposure to heavy ions, aberrantly dividing and/or differentiating cells in the pre-equatorial region of the lens epithelium migrate to the posterior pole of the lens where they become opaque lens fiber cells. The plan was to investigate mechanisms of cataractogenesis by observing opacities produced by x-rays or heavy ions in mice that were haplo-insufficient for one or more genes involved in DNA damage recognition and repair and/or cell cycle checkpoint functions. The genes chosen were Atm, Brca1 and Rad9, based on experiments with cells in-vitro which indicated that heterozygosity for these genes confers radiosensitivity. There are corresponding human homologues for these genes and mutations and/or polymorphisms have been identified in a few percent of the human population. Thus, heterozygosity for these or similar genes could account for the unexpected observation of earlier onset or faster progression of cataracts in some individuals in the astronaut core.

Results.

1. RBE Studies with wild type mice and animals haploinsufficient for ATM.

Early studies demonstrated that heavy ions are significantly more effective than X-rays in producing cataracts in ATM haploinsufficient mice (Hall, 2006). ATM haploinsufficiency results in an enhanced sensitivity to X-rays compared to wild type, and this enhancement appears even larger after exposure to high-LET heavy ions. The studies demonstrated that high LET particles are much more effective than low LET X-rays in induced cataractogenesis and that this likely accounts for the reported earlier onset and faster progression of cataracts in the astronaut core.

2. Cataractogenesis in animals singly or doubly heterozygous for Atm or Brca1 exposed to x-rays or heavy ions at the NSRL in Brookhaven National Laboratory.

Mice irradiated with x-rays were utilized to examine the effect of single or dual heterozygosity for Atm and Brca1 on radiation cataract development. When average cataract stage was compared in each of the four genotypes in both irradiated and unirradiated animals, cataracts developed earlier in Atm+/- and Brca1+/- single heterozygotes than wild-type controls. However, Atm/Brca1 double heterozygotes did not exhibit faster onset of or more rapid progression of cataractogenesis as compared to the singly heterozygous animals. As compared to wildtype animals, all haploinsufficient genotypes exhibited faster onset of radiation-induced lens changes, even in unirradiated eyes. As Brca1 is known to exhibit some gender specificity, we also examined the the effect of gender on radiation cataract onset or progression. Single or doubly haploinsufficient female Brca1 mice were not any more radiosensitive to irradiation than their corresponding male counterparts. These results indicate heterozygosity for either Brca1 or Atm confers cataract radiosensitivity but that the effect of dual haploinsufficiency is not greater than that of each gene alone and for the radiation cataract endpoint, the effect of gender, and presumably sex hormonal influence, is minimal.

In a similar fashion, single and double heterozygous Atm and Brca1 mice were exposed to 50 mGy 56Fe at the Brookhaven National Laboratory NRSL facility and observed for cataract development. In contrast to the findings after low-LET x-ray exposure, double heterozygous Atm/Brca1 animals are significantly more sensitive to heavy ion induced cataractogenesis than each of the two single heterozygotes, which, in turn, are more sensitive than wild-type controls. It can also be noted that ATM haploinsufficiency has considerable effect on lens opacification even in unirradiated animals, while BRCA1appears to be of less importance in unexposed mice. It is interesting to note that animals heterozygous for Atm develop cataracts about 20 weeks earlier than wild-type animals, even at this very low dose. By contrast, heterozygosity for Brca1 appears to have little effect on cataract onset.

3. Animals singly or doubly heterozygous for Atm and Rad9

It is well established that Atm and Rad9 regulate multiple cellular responses to DNA damage, including cell cycle checkpoints, DNA repair and apoptosis. However, the impact of dual heterozygosity for Atm and Rad9 on radiation cataractogenesis in the intact animal was, until recently, unknown. To address this question, we examined whether mice haploinsufficient for the combination of both these genes might be more susceptible to the cataractogenic effects of ionizing radiation than wild type animals or those haploinsufficient for only one of these genes.

The results established that Atm+/- or Mrad9+/- animals develop spontaneous as well as radiation-induced cataracts with earlier onset and more severity than wild-type controls, which lends considerable support for the concept that radiation cataract requires misrepaired DNA damage and given the roles of Atm and mRad9 in maintaining genomic stability, are consistent with a genotoxic basis for radiation cataractogenesis. Cataracts developed earlier in X-irradiated double heterozygotes than in single heterozygotes, which were more prone to cataractogenesis than wild-type controls. Cataract onset time and progression in single or double heterozygotes were accelerated even in unirradiated eyes. These findings indicate that the cataractogenic effect of combined heterozygosity is greater than for each gene alone and the study is among the first to demonstrate radiation effects of multiple haploinsufficiency in an intact mammal. Such observations are directly relevant to explanations of observed inter-individual differential radiosensitivity in human populations and have important implications for those undergoing radiotherapy or exposed to elevated levels of cosmic radiation, such as the astronaut core.

Summary and Conclusions.

It is notable that the findings from these studies demonstrate, for the first time, the ability of two different heterozygous gene mutations to interact in a manner that increases the frequency of a radiation response. This radiation cataract model is the first higher level organ system in which it is demonstrated that heterozygosity alters the late response of a normal tissue to radiation exposure.

Three genes involved in checkpoint control and/or DNA damage recognition and repair, Atm, Brca1 and mRad9, have been examined to date. Our findings have established that single haploinsufficiency for ATM, mRAD9 or BRCA1 decreases the time of onset for cataract development following irradiation with either x-rays or heavy ions. Furthermore, combined haploinsufficiency, with either Atm/ Rad9 or Atm/Brca1, increases susceptibility for radiation induced cataract formation further still. Quantitative values for the relative biological effectiveness (RBE) of high energy 56Fe ions compared with X-rays, both for wild type and for Atm+/-mice, were determined with a clear trend toward higher RBE’s in haplo-insufficient animals.

Corresponding human homologues for these genes and mutations and/or polymorphisms have been identified in a few percent of the human population. This amounts to a small but significant radiosensitive sub-population. This has wide societal implications and in the context of NASA may account for the unexpected observation of early onset of cataracts in astronauts who have flown in space.

Bibliography Type: Description: (Last Updated: 11/14/2017) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Kleiman NJ. "Radiation Cataract." Radiation Research Society 54th Annual Meeting, Boston, MA, September 21-24, 2008.

Radiation Research Society 54th Annual Meeting, Boston, MA, September 21-24, 2008. http://www.abstractonline.com/viewer/viewAbstract.asp?CKey={9CBD1857-B1BE-4D6A-81BB-8156D607205A}&MKey={469F71A9-9297-46B3-A676-3B5BF986A1D3}&AKey={483E38F8-EC56-48FD-A044-F83F4725E268}&SKey={93F33B40-9FED-462E-9A89-6E1FE4F19A17} , Sep-2008

Abstracts for Journals and Proceedings Kleiman NJ. "Role of genetics in determining risk of radiation cataract." 5th Columbian Congress of SOLACI (Latin American Society of Interventional Heart Specialists), Bogotà, Colombia, September 25-26, 2008.

Conference Proceedings. 5th Columbian Congress of SOLACI (Latin American Society of Interventional Heart Specialists), Bogotà, Colombia, September 25-26, 2008. , Sep-2008

Abstracts for Journals and Proceedings Hall EJ, Smilenov L, Brenner DJ, Kleiman N. "Individual genetic susceptibility." NASA Human Research Program Investigators' Workshop, League City, TX, February 2-4, 2009.

NASA Human Research Program Investigators' Workshop, League City, TX, February 2-4, 2009. http://www.dsls.usra.edu/meetings/hrp2009/pdf/CNSDegenerativeRisks/1016Hall.pdf , Feb-2009

Abstracts for Journals and Proceedings Kleiman NJ. "Haploinsufficiency and radiation cataract." Workshop on Radiation Cataractogenesis, Radiation Effects Research Foundation (RERF), Hiroshima, Japan, March 9-11, 2009.

Workshop on Radiation Cataractogenesis, Radiation Effects Research Foundation (RERF), Hiroshima, Japan, March 9-11, 2009. , Mar-2009

Abstracts for Journals and Proceedings Kleiman NJ. "Haploinsufficiency and radiation cataract." International Atomic Energy Agency and National Heart Association of Malaysia 13th Annual Scientific Meeting, Kuala Lumpur, Malaysia, April 17-19, 2009.

International Atomic Energy Agency and National Heart Association of Malaysia 13th Annual Scientific Meeting, Kuala Lumpur, Malaysia, April 17-19, 2009. , Apr-2009

Abstracts for Journals and Proceedings Hall EJ. "Factors Influencing Risk." 8th Annual Gilbert W. Beebe Symposium, National Academy of Sciences, Washington D.C., December 9, 2009.

8th Annual Gilbert W. Beebe Symposium, National Academy of Sciences, Washington D.C., December 9, 2009. , Dec-2009

Abstracts for Journals and Proceedings Kleiman NJ. "Radiation Cataracts." First ICRP Symposium of the International System on Radiological Protection, Bethesda, MD, October 24-26, 2011.

First ICRP Symposium of the International System on Radiological Protection, Bethesda, MD, October 24-26, 2011. Program and abstracts, p. 21. http://www.icrp.org/docs/Programme%20-%20ICRP%20Symposium%20on%20the%20System%20of%20Radiological%20Protection.pdf , Oct-2011

Articles in Peer-reviewed Journals Kleiman NJ, Elliston CD, Smilenov LR, Worgul BV, Brenner DB, Hall EJ. "Effect of dual heterozygosity for Atm and Brca1 on x-ray induced radiation cataract in mice." Radiation Research, submitted, as of January 2012. , Jan-2012
Articles in Peer-reviewed Journals Kleiman NJ, Elliston CD, Smilenov LR, Worgul BV, Brenner DB, Hall EJ. "Atm and Brca1 Dual Haploinsuffiency Increases Risk for Radiation Cataract after Heavy Ion Exposure in Mice." Advances in Space Research, submitted, as of January 2012. , Jan-2012
Articles in Peer-reviewed Journals Kleiman NJ, Stewart FA, Hall EJ. "Modifiers of radiation effects in the eye." Life Sci Space Res. 2017 Nov;15:43-54. Review. Epub 2017 Jul 18. https://doi.org/10.1016/j.lssr.2017.07.005 , Nov-2017
Articles in Peer-reviewed Journals Suit H, Goldberg S, Niemierko A, Ancukiewicz M, Hall E, Goitein M, Wong W, Paganetti H. "Secondary carcinogenesis in patients treated with radiation: A review of data on radiation-induced cancers in human, non-human primate, canine and rodent subjects." Radiat Res. 2007 Jan;167(1):12-42. Erratum in: Radiat Res. 2007 Jun;167(6):748. PubMed PMID: 17214511 , Jan-2007
Articles in Peer-reviewed Journals Suit H, DeLaney T, Goldberg S, Paganetti H, Clasie B, Gerweck L, Niemierko A, Hall E, Flanz J, Hallman J, Trofimov A. "Proton vs carbon ion beams in the definitive radiation treatment of cancer patients." Radiother Oncol. 2010 Apr;95(1):3-22. Epub 2010 Feb 23. Review. PubMed PMID: 20185186 , Apr-2010
Articles in Peer-reviewed Journals Blakely EA, Kleiman NJ, Neriishi K, Chodick G, Chylack LT, Cucinotta FA, Minamoto A, Nakashima E, Kumagami T, Kitaoka T, Kanamoto T, Kiuchi Y, Chang P, Fujii N, Shore RE. "Radiation cataractogenesis: Epidemiology and biology. Meeting report." Radiat Res. 2010 May;173(5):709-17. PMID: 20426671 , May-2010
Articles in Peer-reviewed Journals Su F, Smilenov LB, Ludwig T, Zhou L, Zhu J, Zhou G, Hall EJ. "Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis." Radiat Oncol. 2010 Feb 22;5:15. PubMed PMID: 20175908 ; http://dx.doi.org/10.1186/1748-717X-5-15 , Feb-2010
Articles in Peer-reviewed Journals Zhou G, Smilenov LB, Lieberman HB, Ludwig T, Hall EJ. "Radiosensitivity to high energy iron ions is influenced by heterozygosity for Atm, Rad9 and Brca1." Adv Space Res. 2010 Sep 15;46(6):681-6. http://dx.doi.org/10.1016/j.asr.2010.02.026 , Sep-2010
Articles in Peer-reviewed Journals Hricak H, Brenner DJ, Adelstein SJ, Frush DP, Hall EJ, Howell RW, McCollough CH, Mettler FA, Pearce MS, Suleiman OH, Thrall JH, Wagner LK. "Managing radiation use in medical imaging: a multifaceted challenge." Radiology. 2011 Mar;258(3):889-905. Epub 2010 Dec 16. Review. PubMed PMID: 21163918 , Mar-2011
Papers from Meeting Proceedings Kleiman NJ. "Radiation Cataract." Radiation Protection. New insights in radiation risk and basic safety standards. European Commission scientific seminar, Luxembourg, October 17, 2006.

In: Radiation Protection. New insights in radiation risk and basic safety standards.Working party on research implications on Health and Safety Standards of the Article 31 Group of experts. Issue 145, p. 81-95, 2007. http://ec.europa.eu/energy/nuclear/radioprotection/publication/doc/145_en.pdf , Nov-2007

Project Title:  Mechanisms of Ocular Cataracts Reduce
Fiscal Year: FY 2010 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/04/2005  
End Date: 09/30/2011  
Task Last Updated: 09/08/2009 
Download report in PDF pdf
Principal Investigator/Affiliation:   Hall, Eric J Ph.D., D.Sc. / Columbia University 
Address:  630 West 168th Street 
Center for Radiological Research 
New York , NY 10032 
Email: ejh1@columbia.edu 
Phone: 212-305-5660  
Congressional District: 15 
Web: http://cpmcnet.columbia.edu/dept/radoncology/crr  
Organization Type: UNIVERSITY 
Organization Name: Columbia University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Brenner, David  Ph.D. Columbia University 
Smilenov, Lubomir  Columbia University 
Kleiman, Norman  Columbia University 
Key Personnel Changes / Previous PI: Personnel unchanged
Project Information: Grant/Contract No. NNJ05HI38G 
Responsible Center: NASA JSC 
Grant Monitor: Cucinott1a, Francis  
Center Contact: 281-483-0968 
noaccess@nasa.gov 
Solicitation / Funding Source: 2004 Radiation Biology NNH04ZUU005N 
Grant/Contract No.: NNJ05HI38G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
Flight Assignment/Project Notes: NOTE: Received no-cost extension to 9/30/2011 per C. Guidry/JSC (8/10)

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

Task Description: Radiation standards in space have followed a somewhat different path from those on the ground. Exposures in space are potentially much higher than terrestrial irradiation due to galactic cosmic radiation, trapped radiation belts near the earth and solar particle events. Radiation exposures in space are relatively difficult to reduce and impossible to eliminate entirely. At the same time, other risks to humans in the hostile environment in space may be more acute or drastic than those of radiation. This puts a different perspective on radiation hazards and is one reason, together with the limited number of individuals involved, why larger annual dose limits have been tolerated for astronauts than are recommended for radiation workers on the ground, (though career limits of risk have been roughly equalized). The purpose of radiation protection is to prevent deterministic effects of clinical significance and limit stochastic effects to levels that are acceptable, modulated by societal concerns. The deterministic effect already observed in some astronauts is an earlier onset of ocular cataracts. The hypothesis upon which this proposal is based is that heavy ions mediate their cataractogenic effect through errors in differentiation resulting from damage and/or misrepair of irradiated cells . Aberrantly dividing and/or differentiating cells in the pre-equatorial region of the lens epithelium eventually migrate to the lens where they become opaque lens fiber cells. We propose to investigate the mechanisms of cataractogenesis by looking at cataract formation in animals haploinsufficient for one or more genes involved in DNA repair and/or checkpoint control.

Research Impact/Earth Benefits: The hypothesis upon which this proposal is based is that heavy ions mediate their cataractogenic effect through errors in differentiation resulting from damage and/or misrepair of irradiated cells. We propose to investigate the mechanisms of cataractogenesis by looking at cataract formation in animals haploinsufficient for one or more genes involved in DNA repair and/or checkpoint control, including Atm, rad9 and Brca1. The research impact of this study will be to provide information on the mechanism of cataract induction in radiosensitive subpopulations.

Task Progress & Bibliography Information FY2010 
Task Progress: To date, increased incidence and earlier onset of cataracts are the only long-term degenerative effects observed in astronauts exposed to space radiation. Furthermore, considerable uncertainty surrounds the relationship between radiation dose and cataract development, which is of concern to the risk assessment community. Previous NASA funded studies from our laboratory demonstrated that mice haplo- insufficient for Atm (one good copy and one bad copy of the Atm gene) develop high-LET (heavy-ion) radiation induced cataracts earlier and with more severity than wild type animals. This leads to speculation that the unexpected observation of cataractogenesis in the astronaut core might be explained by individual genetic susceptibilities and predispositions.

The research reported here seeks to expand the library of genes involved in DNA repair and checkpoint control beyond Atm, and also to investigate the possible importance of mutations in more than one gene. Attention focused on two genes, Brca1 and Rad9, haplo-insufficiency for which had previously been shown to confer radiosensitivity on cells cultured in vitro. In these studies, the endpoints scored were oncogenic transformation in mouse embryo fibroblasts and apoptosis in mouse thymocytes. These systems were chosen because they give rapid results and are relatively inexpensive, but can be used to choose genes that are likely to be worth the long-term investment of studying them with the in more relevant, but labor-intensive and expensive, end-point of cataract development.

Animals heterozygous for Atm, Brca1 or Rad9, as well as wild-type animals, were exposed to either 5 or 25 mGy of 1,000 MeV/amu 56Fe in the BNL NASA Space Radiation Laboratory (NSRL). In addition, double heterozygous animals, Atm/Rad9 and Atm/Brca1, were created by cross-breeding single heterozygotes, and exposed to the same doses of heavy ions. Animals are examined biweekly to classify the extent and stage of lens opacification as it develops, and because the doses used were so low, observations are continued for over a year post-irradiation.

During the past year we have completed the study of Atm combined with Brca1, which involved over 200 animals scored for over a year.

The study of Atm combined with Rad9 is 50% completed. The first batch of 120 animals was irradiated in 2008 and have been examined for almost one year. A second batch is scheduled to be irradiated in the Fall of 2009, with the study ending in late 2010.

To summarize, haplo-insufficiency for both genes studied to date, namely Atm and Brca1, resulted in radiation-induced cataracts that appeared earlier and at a higher grade than in wild type animals. Since mutations and/or polymorphisms are present in the homologues of these genes in the human population, this suggests the existence of a radiosensitive sub-population of a few percent The study of the double heterozygotes also raises an interesting point. Animals heterozygous for both Atm and Brca1 were no more radiosensitive that animals heterozygous for a single gene, suggesting no additive effect as far as these genes are concerned.

There are two important consequences of the existence of a radiosensitive sub-population. First it would distort the shape of the dose-response relationship for end-points such as carcinogenesis. Linearity between dose and effect would no longer be the case if a fraction of the population is radiosensitive. Second, it would be unethical to place a radiosensitive individual in a situation where they may be exposed to a significant dose of radiation. It is entirely possible that other genes will be identified that will add to the potential pool of genes determining the size of the radiosensitive human sub-population.

Bibliography Type: Description: (Last Updated: 11/14/2017) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Hall EJ. "Is there a place for quantitative risk assessment? " Journal of Radiological Protection, 2009 Jun: 29(2A): A171-84. PubMed PMID: 19454800 , Jun-2009
Articles in Peer-reviewed Journals Su F, Smilenov L, Ludwig T, Zhou L, Zhu J, Zhou G, Hall EJ. "Heterozygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis." International Journal of Radiation Biology (Submitted, May 2009). , May-2009
Articles in Peer-reviewed Journals Zhou G, Smilenov LB, Lieberman HB, Hall EJ. "Radiosensitivity to high energy iron ions is influenced by heterozygosity for Atm, Rad9 and Brca1." Advances in Space Research (Submitted, June 2009). , Jun-2009
Articles in Peer-reviewed Journals Neriishi K, Blakely EA, Kleiman NJ, Shore RE, et al. "Meeting Report: Radiation Cataractogenesis Workshop 2009, Hiroshima, Japan." Radiat. Res., (Submitted, July 2009). , Jul-2009
Project Title:  Mechanisms of Ocular Cataracts Reduce
Fiscal Year: FY 2009 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/04/2005  
End Date: 09/30/2010  
Task Last Updated: 08/06/2008 
Download report in PDF pdf
Principal Investigator/Affiliation:   Hall, Eric J Ph.D., D.Sc. / Columbia University 
Address:  630 West 168th Street 
Center for Radiological Research 
New York , NY 10032 
Email: ejh1@columbia.edu 
Phone: 212-305-5660  
Congressional District: 15 
Web: http://cpmcnet.columbia.edu/dept/radoncology/crr  
Organization Type: UNIVERSITY 
Organization Name: Columbia University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Brenner, David  Ph.D. Columbia University 
Smilenov, Lubomir  Columbia University 
Kleiman, Norman  Columbia University 
Key Personnel Changes / Previous PI: Personnel unchanged
Project Information: Grant/Contract No. NNJ05HI38G 
Responsible Center: NASA JSC 
Grant Monitor: Cucinott1a, Francis  
Center Contact: 281-483-0968 
noaccess@nasa.gov 
Solicitation / Funding Source: 2004 Radiation Biology NNH04ZUU005N 
Grant/Contract No.: NNJ05HI38G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
Flight Assignment/Project Notes: NOTE: Received no-cost extension to 9/30/2010 per J. Dardano/JSC (8/09)

Task Description: Radiation standards in space have followed a somewhat different path from those on the ground. Exposures in space are potentially much higher than terrestrial irradiation due to galactic cosmic radiation, trapped radiation belts near the earth and solar particle events. Radiation exposures in space are relatively difficult to reduce and impossible to eliminate entirely. At the same time, other risks to humans in the hostile environment in space may be more acute or drastic than those of radiation. This puts a different perspective on radiation hazards and is one reason, together with the limited number of individuals involved, why larger annual dose limits have been tolerated for astronauts than are recommended for radiation workers on the ground, (though career limits of risk have been roughly equalized). The purpose of radiation protection is to prevent deterministic effects of clinical significance and limit stochastic effects to levels that are acceptable, modulated by societal concerns. The deterministic effect already observed in some astronauts is an earlier onset of ocular cataracts. The hypothesis upon which this proposal is based is that heavy ions mediate their cataractogenic effect through errors in differentiation resulting from damage and/or misrepair of irradiated cells . Aberrantly dividing and/or differentiating cells in the pre-equatorial region of the lens epithelium eventually migrate to the lens where they become opaque lens fiber cells. We propose to investigate the mechanisms of cataractogenesis by looking at cataract formation in animals haploinsufficient for one or more genes involved in DNA repair and/or checkpoint control.

Research Impact/Earth Benefits: The hypothesis upon which this proposal is based is that heavy ions mediate their cataractogenic effect through errors in differentiation resulting from damage and/or misrepair of irradiated cells. We propose to investigate the mechanisms of cataractogenesis by looking at cataract formation in animals haploinsufficient for one or more genes involved in DNA repair and/or checkpoint control, including Atm, rad9 and BRCA. The research impact of this study will be to provide information on the mechanism of cataract induction in radiosensitive subpopulations.

Task Progress & Bibliography Information FY2009 
Task Progress: Our research is directed at understanding how low doses of heavy ion (high-LET) exposure, similar to that received by astronauts in space, results in cataract in a genetically defined mouse model system. More specifically, we seek to understand whether individuals with one good and one bad copy of gene(s) involved in DNA repair and/or cell cycle checkpoint control (Atm, Brca1 or Rad9) are more susceptible to cataract development. These studies provide an opportunity to investigate the influence(s) of genetic factors on radiosensitivity in a rodent model that has great relevance and similarity to human response to radiation exposure and determination of appropriate human exposure guidelines. Findings in this animal model are likely to be important to the development of appropriate guidelines for national space radiation risk policy.

To date, increased incidence and earlier onset of cataract are the only long-term degenerative effects observed in astronauts exposed to space radiation. Furthermore, considerable uncertainty surrounds the relationship between radiation dose and cataract development, which is of concern to the risk assessment community. Previous NASA funded studies from our laboratory demonstrated that mice haplo- insufficient for Atm (one good copy and one bad copy of the Atm gene) develop high-LET (heavy-ion) radiation induced cataracts earlier and with more severity than wild type animals. This leads to speculation that the unexpected observation of cataractogenesis in the astronaut core might be explained by individual genetic susceptibilities and predispositions.

Our group received a multi-year NASA grant funded to investigate the mechanisms of heavy ion induced cataractogenesis in mice that are haplo-insufficient for one or more genes involved in DNA repair and/or checkpoint functions. Animals singly or double heterozygous for Atm, Brca1 and/or Rad9, as well as wildtype animals, were exposed to either 5 or 25 cGy of 1,000 MeV/amu 56Fe in the BNL NASA Space Radiation Laboratory (NSRL). Many of the animals irradiated in mid to late 2007 and early 2008 are still being examined biweekly to classify the extent and stage of lens opacification. For example, we irradiated approximately 80 rad9/ATM in Fall 2007 with 5 cGy of 56Fe and approximately 120 Brca1/ATM mice with 56Fe in Spring 2008 averages below 1.0, a cataract stage half that of the double heterozygous mutants. While it is too early to unfold the data in detail, preliminary results indicate that, even at these low doses of heavy ions, irradiated animals are developing lens opacification characteristic of radiation exposure and that some mutant genotypes develop cataract faster than irradiated wild-type animals. Many more Atm-Brca1 double heterozygous animals appear to have reached stage 1.5 cataracts than either Brca1 or Atm singly heterozygous animals. The degree of opacification in wild-type, control animals still averages below 1.0, a cataract stage half that of the double heterozygous mutants. Throughout the coming year, we will continue to examine these animals as well as begin to examine various measures of DNA damage and repair, cell death, mitochondrial function and other cytological endpoints in lens epithelial cells obtained from irradiated animals at the end of their lifespans.

To summarize, these studies are among the first to study the effect(s) of multiple haplo-insufficiency on biological response in a highly organized tissue. We believe they will shed considerable light on the genetic control and cellular mechanisms of heavy ion induced cataractogenesis. More significantly, our preliminary results suggest that double heterozygotes are more sensitive to the cataractogenic effects of ionizing radiation than single heterozygotes or wild-type controls. This finding is likely to have important implications for both radiosensitive subsets of the human population and for the astronaut core.

Bibliography Type: Description: (Last Updated: 11/14/2017) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Kleiman NJ, Smilenov LB, Hall EJ, Brenner DJ. "Low dose radiation cataract." Low Dose Radiation Research Investigators' Workshop VII, Washington, DC, January 21-23, 2008.

Abstracts, Low Dose Radiation Research Investigators' Workshop VII, Washington, DC, January 21-23, 2008. , Jan-2008

Abstracts for Journals and Proceedings Smilenov LB, Kleiman NJ, Lieberman HB, Zhou G, Hall EJ. "Individual Genetic Susceptibility." Low Dose Radiation Research Investigators' Workshop VII, Washington, DC, January 21-23, 2008.

Abstracts, Low Dose Radiation Research Investigators' Workshop VII, Washington, DC, January 21-23, 2008. , Jan-2008

Abstracts for Journals and Proceedings Hall EJ. " Invited talk: Neutrons Secondary to Proton Therapy: Problems and Solutions." PTCOG Meeting, Jacksonville, FL, May 19-24, 2008.

PTCOG Meeting, Jacksonville, FL, May 19-24, 2008. , May-2008

Abstracts for Journals and Proceedings Hall EJ. "Invited talk: Neutrons secondary to proton therapy: problems and solutions." NIRS-MD Anderson Symposium on Clinical Issues for Particle Therapy, Houston, TX, Mar. 21-22, 2008.

NIRS-MD Anderson Symposium on Clinical Issues for Particle Therapy, Houston, TX, Mar. 21-22, 2008. , Mar-2008

Abstracts for Journals and Proceedings Kleiman NJ, Smilenov LB, Lieberman HB, Hall EJ. "Mechanism of Ocular Cataracts." NASA Human Research Program Investigators' Workshop, League City, TX, February 4-6, 2008.

Abstracts, NASA Human Research Program Investigators' Workshop, League City, TX, February 4-6, 2008. , Feb-2008

Abstracts for Journals and Proceedings Smilenov LB, Kleiman NJ, Lieberman HB, Hall EJ. "Role of heterozygosity for ATM, Rad9 and BRCA1 in cell transformation." NASA Human Research Program Investigators’ Workshop, League City, TX, February 12 -14, 2007.

Abstracts, NASA Human Research Program Investigators’ Workshop, League City, TX, February 12 -14, 2007. , Feb-2007

Abstracts for Journals and Proceedings Kleiman NJ, Hall EJ, Brenner DJ, Lieberman HB, Smilenov LB. "Radiation cataract." 37th COSPAR Scientific Assembly, Montreal, Canada, July 13-20, 2008.

Abstracts, 37th COSPAR Scientific Assembly, Montreal, Canada, July 13-20, 2008. , Jul-2008

Articles in Peer-reviewed Journals Kleiman NJ, David J, Elliston CD, Hopkins KM, Smilenov LB, Brenner DJ, Worgul BV, Hall EJ, Lieberman HB. "Mrad9 and atm haploinsufficiency enhance spontaneous and X-ray-induced cataractogenesis in mice." Radiat Res. 2007 Nov;168(5):567-73. PMID: 17973559 , Nov-2007
Papers from Meeting Proceedings Kleiman NJ. "Radiation cataract." New Insights in Radiation Risk and Basic Safety Standards, scientific seminar held in Luxembourg, 17 October 2006.

In: New Insights in Radiation Risk and Basic Safety Standards. Proceedings of a scientific seminar held in Luxembourg on 17 October 2006. p. 81-95. Radiation Protection 145. , Oct-2006

Project Title:  Mechanisms of Ocular Cataracts Reduce
Fiscal Year: FY 2008 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/04/2005  
End Date: 09/30/2009  
Task Last Updated: 07/20/2007 
Download report in PDF pdf
Principal Investigator/Affiliation:   Hall, Eric J Ph.D., D.Sc. / Columbia University 
Address:  630 West 168th Street 
Center for Radiological Research 
New York , NY 10032 
Email: ejh1@columbia.edu 
Phone: 212-305-5660  
Congressional District: 15 
Web: http://cpmcnet.columbia.edu/dept/radoncology/crr  
Organization Type: UNIVERSITY 
Organization Name: Columbia University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Brenner, David  Ph.D. Columbia University 
Smilenov, Lubomir  Columbia University 
Kleiman, Norman  Columbia University 
Key Personnel Changes / Previous PI: Personnel unchanged
Project Information: Grant/Contract No. NNJ05HI38G 
Responsible Center: NASA JSC 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2004 Radiation Biology NNH04ZUU005N 
Grant/Contract No.: NNJ05HI38G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
Task Description: Radiation standards in space have followed a somewhat different path from those on the ground. Exposures in space are potentially much higher than terrestrial irradiation due to galactic cosmic radiation, trapped radiation belts near the earth and solar particle events. Radiation exposures in space are relatively difficult to reduce and impossible to eliminate entirely. At the same time, other risks to humans in the hostile environment in space may be more acute or drastic than those of radiation. This puts a different perspective on radiation hazards and is one reason, together with the limited number of individuals involved, why larger annual dose limits have been tolerated for astronauts than are recommended for radiation workers on the ground, (though career limits of risk have been roughly equalized). The purpose of radiation protection is to prevent deterministic effects of clinical significance and limit stochastic effects to levels that are acceptable, modulated by societal concerns. The deterministic effect already observed in some astronauts is an earlier onset of ocular cataracts. The hypothesis upon which this proposal is based is that heavy ions mediate their cataractogenic effect through errors in differentiation resulting from damage and/or misrepair of irradiated cells . Aberrantly dividing and/or differentiating cells in the pre-equatorial region of the lens epithelium eventually migrate to the lens where they become opaque lens fiber cells. We propose to investigate the mechanisms of cataractogenesis by looking at cataract formation in animals haploinsufficient for one or more genes involved in DNA repair and/or checkpoint control.

Research Impact/Earth Benefits: The hypothesis upon which this proposal is based is that heavy ions mediate their cataractogenic effect through errors in differentiation resulting from damage and/or misrepair of irradiated cells . We propose to investigate the mechanisms of cataractogenesis by looking at cataract formation in animals haploinsufficient for one or more genes involved in DNA repair and/or checkpoint control, including Atm, rad9 and BRCA. The research impact of this study will be to provide information on the mechanism of cataract induction in radiosensitive subpopulations.

Task Progress & Bibliography Information FY2008 
Task Progress: To date we have completed the first specific aim, namely to establish stocks of mice heterozygous for the Atm and BRCA1, and also to produce double heterozygotes, i.e. animals haploinsufficient for both Atm and BRCA1. Towards completion of the second specific aim, 287 mice have been enrolled in the study since the Spring 2006 BNL run. These include 28 double heterozygotes, 52 Atm heterozygotes, 46 Brca1 heterozygotes and 98 wild type controls. (Approximately half of the wild-type controls are being utilized for histological and immunohistological preparations.) 24 double heterozygotes, 39 Atm herozygotes, 42 Brca1 heterozygotes and 67 wild types were irradiated with either 5 or 25 cGy of 1,000 MeV/n 56Fe (approximately equal numbers of mice received each of the two doses). Mice are examined weekly by slit lamp examination and monthly by Scheimpflug examination. Cataract stage is scored for each mouse and the genotype or irradiation status of each animal is blinded to the observer. Examination will continue for up to 100 weeks post irradiation unless death and/or disease removes the animal from the study. At present, 103 mice have been examined for approximately 68 weeks, 121 mice for 54 weeks and 63 mice for 40 weeks post examination. Preliminary results for average cataract stage in this study can be calculated using the aggregate data from the four genotypes without revealing information about any particular animal. In general, at any time point, average cataract stage for single and double heterozygotes is greater than that of wild type animals and the oldest such animals are presently approaching an average cataract stage of 2.0 (3.0 is considered blinding and any animal with this score is sacrificed.) Unirradiated control animals have average cataract scores in the range of 1.0-1.5. The code will be broken and the data analysed in approximately one year.

Bibliography Type: Description: (Last Updated: 11/14/2017) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Hall EJ, Worgul BV, Smilenov L, Elliston CD, Brenner DJ. "The relative biological effectiveness of densely ionizing heavy-ion radiation for inducing ocular cataracts in wild type versus mice heterozygous for the ATM gene. " Radiat Environ Biophys. 2006 Jul;45(2):99-104. Epub 2006 Jun 24. PMID: 16799786 , Jul-2006
Articles in Peer-reviewed Journals Hall EJ. "Intensity-modulated radiation therapy, protons, and the risk of second cancers." Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):1-7. Review. PMID: 16618572 , May-2006
Articles in Peer-reviewed Journals Travis LB, Rabkin CS, Brown LM, Allan JM, Alter BP, Ambrosone CB, Begg CB, Caporaso N, Chanock S, DeMichele A, Figg WD, Gospodarowicz MK, Hall EJ, Hisada M, Inskip P, Kleinerman R, Little JB, Malkin D, Ng AK, Offit K, Pui CH, Robison LL, Rothman N, Shields PG, Strong L, Taniguchi T, Tucker MA, Greene MH. "Cancer survivorship--genetic susceptibility and second primary cancers: research strategies and recommendations. " J Natl Cancer Inst. 2006 Jan 4;98(1):15-25. Review. PMID: 16391368 , Jan-2006
Articles in Peer-reviewed Journals Hall EJ. "The inaugural Frank Ellis Lecture--latrogenic cancer: the impact of intensity-modulated radiotherapy." Clin Oncol (R Coll Radiol). 2006 May;18(4):277-82. PMID: 16703744 , May-2006
Articles in Peer-reviewed Journals Hall EJ. "Cancer caused by x-rays--a random event?" Lancet Oncol. 2007 May;8(5):369-70. PMID: 17466892 , May-2007
Project Title:  Mechanisms of Ocular Cataracts Reduce
Fiscal Year: FY 2007 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/04/2005  
End Date: 09/30/2009  
Task Last Updated: 07/28/2006 
Download report in PDF pdf
Principal Investigator/Affiliation:   Hall, Eric J Ph.D., D.Sc. / Columbia University 
Address:  630 West 168th Street 
Center for Radiological Research 
New York , NY 10032 
Email: ejh1@columbia.edu 
Phone: 212-305-5660  
Congressional District: 15 
Web: http://cpmcnet.columbia.edu/dept/radoncology/crr  
Organization Type: UNIVERSITY 
Organization Name: Columbia University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Brenner, David J Ph.D. Columbia University 
Smilenov, Lubomir  Columbia University 
Kleiman, Norman  Columbia University 
Key Personnel Changes / Previous PI: We sadly report the death of Professor Basil Worgul during the year. His place is taken on this project by Dr. Norman Kleiman. The rest of the personnel remains unchanged.
Project Information: Grant/Contract No. NNJ05HI38G 
Responsible Center: NASA JSC 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2004 Radiation Biology NNH04ZUU005N 
Grant/Contract No.: NNJ05HI38G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
Task Description: The only non-cancer degenerative effect so far unequivocally observed in astronauts is the early onset of ocular cataracts. Previous studies have shown that mice haplo-insufficient for Atm develop cataracts earlier than wild type animals exposed to either gamma rays or high energy Fe ions. At a large x-ray dose (4 Gy) the Atm heterozygotes developed vision impairing cataracts 10 or more weeks early than the wild-type counterparts. At a lower dose x-ray dose (0.5 Gy) the Atm heterozygotes developed a low grade cataract, while the wild-type did not. We can conclude from this study that (a) Vision impairing cataracts appear earlier in Atm heterozygotes than in wild-type animals; the acceleration by 10 weeks is an appreciable fraction of the life-span of the animal. (b) At lower doses, low grade cataracts appear in Atm heterozygotes where none appear in wild-type animals. For animals exposed to 0.325 Gy of high energy Fe-59, cataracts again appeared earlier in the Atm heterozygotes and the acceleration is similar to that seen for x-rays. Also, at this dose, vision impairing cataracts occur in Atm heterozygotes, but not in wild type animals. These earlier studies indicated that the susceptibility to cataractogenesis shown by Atm heterozygotes is much greater than for cell killing in cells grown in culture from the same animals, suggesting that errors in differentiation, not cell killing, is the mechanism for cataract formation. When dividing cells in the pre-equatorial region of the lens epithelium are damaged by radiation, they differentiate into fibers that are not translucent as they accrete at the posterior pole of the lens. We now have available mice heterozygous for Mrad9, for the BRCA1 and BRCA2 genes, as well as animals that are heterozygous for pairs of genes believed to be in the same DNA repair pathway, for example Atm/Mrad9, Atm/BRCA1. We propose to irradiate these animals carrying these various genetic deficiencies to a fluence of Fe-59 ions corresponding to one particle traversal per cell nucleus, and score the appearance of cataracts over the life-time of the mice. Data from these experiments will (a) Shed light on the genetic factors that control the susceptibility to radiation induced cataracts, and (b) Identify further sub-groups in the population that are radiosensitive to cataractogenesis. AT heterozygotes comprise 1 to 3% of the US population, RAD9 polymorphisms occur with a similar frequency, while 1 in 250 women carry a BRCA mutation. The combination of these genes, and others that may be identified in the future, add up to a small but significant group of individuals that would develop cataracts earlier and of a higher grade than normal individuals following exposure to high energy heavy ions. Laboratory experiments involving cytological and cytopathological endpoints are designed to elucidate the mechanisms of cataractogenesis in wild type and Atm heterozygous animals in an attempt to understand why the small difference in cell killing due to haploinsufficiency for the Atm protein translates into a large and important difference for cataract formation.

Research Impact/Earth Benefits: The hypothesis upon which this proposal is based is that heavy ions mediate their cataractogenic effect through errors in differentiation resulting from damage and/or misrepair of irradiated cells . We propose to investigate the mechanisms of cataractogenesis by looking at cataract formation in animals haploinsufficient for one or more genes involved in DNA repair and/or checkpoint control, including Atm, rad9 and BRCA. The research impact of this study will be to provide information on the mechanism of cataract induction in radiosensitive subpopulations.

Task Progress & Bibliography Information FY2007 
Task Progress: To date we have completed the first specific aim, namely to establish stocks of mice heterozygous for the Atm and BRCA1, and also to produce double heterozygotes, i.e. animals haploinsufficient for both Atm and BRCA1. In the course of two runs at the Brookhaven Alternating Gradient Synchrotron, this year (06A and 06B) a total of 225 animals have been exposed to either 0.05 or 0.25 Gy of 1 Gev/amu 56Fe ions. The animals were approximately equally divided between wild type, Atm+-, BRCA+- and Atm+- / BRCA+- double heterozygotes. All animals undergo slit-lamp examinations weekly to assess the development of cataracts.

Bibliography Type: Description: (Last Updated: 11/14/2017) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Hall EJ. "Intensity-modulated radiation therapy, protons, and the risk of second cancers." Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):1-7. Review. PMID: 16618572 , May-2006
Articles in Peer-reviewed Journals Hall EJ, Worgul BV, Smilenov L, Elliston CD, Brenner DJ. "The relative biological effectiveness of densely ionizing heavy-ion radiation for inducing ocular cataracts in wild type versus mice heterozygous for the ATM gene. " Radiat Environ Biophys. 2006 Jul;45(2):99-104. PMID: 16799786 , Jul-2006
Articles in Peer-reviewed Journals Travis LB, Rabkin CS, Brown LM, Allan JM, Alter BP, Ambrosone CB, Begg CB, Caporaso N, Chanock S, DeMichele A, Figg WD, Gospodarowicz MK, Hall EJ, Hisada M, Inskip P, Kleinerman R, Little JB, Malkin D, Ng AK, Offit K, Pui CH, Robison LL, Rothman N, Shields PG, Strong L, Taniguchi T, Tucker MA, Greene MH. "Cancer survivorship--genetic susceptibility and second primary cancers: research strategies and recommendations. " J Natl Cancer Inst. 2006 Jan 4;98(1):15-25. Review. PMID: 16391368 , Jan-2006
Articles in Peer-reviewed Journals Persaud R, Zhou H, Baker SE, Hei TK, Hall EJ. "Assessment of low linear energy transfer radiation-induced bystander mutagenesis in a three-dimensional culture model. " Cancer Res. 2005 Nov 1;65(21):9876-82. PMID: 16267011 , Nov-2005
Project Title:  Mechanisms of Ocular Cataracts Reduce
Fiscal Year: FY 2006 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 10/04/2005  
End Date: 09/30/2009  
Task Last Updated: 02/08/2006 
Download report in PDF pdf
Principal Investigator/Affiliation:   Hall, Eric J Ph.D., D.Sc. / Columbia University 
Address:  630 West 168th Street 
Center for Radiological Research 
New York , NY 10032 
Email: ejh1@columbia.edu 
Phone: 212-305-5660  
Congressional District: 15 
Web: http://cpmcnet.columbia.edu/dept/radoncology/crr  
Organization Type: UNIVERSITY 
Organization Name: Columbia University 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NNJ05HI38G 
Responsible Center: NASA JSC 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2004 Radiation Biology NNH04ZUU005N 
Grant/Contract No.: NNJ05HI38G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
Human Research Program Gaps: (1) Degen02:What are the adverse outcome pathways associated with degenerative tissues changes in the cardiovascular, cerebrovascular, lens, immune, digestive, endocrine, and other tissue systems? What are the key events or hallmarks, their time sequence, and their associated biomarkers? (IRP Rev J)
Task Description: The only non-cancer degenerative effect so far unequivocally observed in astronauts is the early onset of ocular cataracts. Previous studies have shown that mice haplo-insufficient for Atm develop cataracts earlier than wild type animals exposed to either gamma rays or high energy Fe ions. At a large x-ray dose (4 Gy) the Atm heterozygotes developed vision impairing cataracts 10 or more weeks early than the wild-type counterparts. At a lower dose x-ray dose (0.5 Gy) the Atm heterozygotes developed a low grade cataract, while the wild-type did not. We can conclude from this study that (a) Vision impairing cataracts appear earlier in Atm heterozygotes than in wild-type animals; the acceleration by 10 weeks is an appreciable fraction of the life-span of the animal. (b) At lower doses, low grade cataracts appear in Atm heterozygotes where none appear in wild-type animals. For animals exposed to 0.325 Gy of high energy Fe-59, cataracts again appeared earlier in the Atm heterozygotes and the acceleration is similar to that seen for x-rays. Also, at this dose, vision impairing cataracts occur in Atm heterozygotes, but not in wild type animals. These earlier studies indicated that the susceptibility to cataractogenesis shown by Atm heterozygotes is much greater than for cell killing in cells grown in culture from the same animals, suggesting that errors in differentiation, not cell killing, is the mechanism for cataract formation. When dividing cells in the pre-equatorial region of the lens epithelium are damaged by radiation, they differentiate into fibers that are not translucent as they accrete at the posterior pole of the lens. We now have available mice heterozygous for Mrad9, for the BRCA1 and BRCA2 genes, as well as animals that are heterozygous for pairs of genes believed to be in the same DNA repair pathway, for example Atm/Mrad9, Atm/BRCA1. We propose to irradiate these animals carrying these various genetic deficiencies to a fluence of Fe-59 ions corresponding to one particle traversal per cell nucleus, and score the appearance of cataracts over the life-time of the mice. Data from these experiments will (a) Shed light on the genetic factors that control the susceptibility to radiation induced cataracts, and (b) Identify further sub-groups in the population that are radiosensitive to cataractogenesis. AT heterozygotes comprise 1 to 3% of the US population, RAD9 polymorphisms occur with a similar frequency, while 1 in 250 women carry a BRCA mutation. The combination of these genes, and others that may be identified in the future, add up to a small but significant group of individuals that would develop cataracts earlier and of a higher grade than normal individuals following exposure to high energy heavy ions. Laboratory experiments involving cytological and cytopathological endpoints are designed to elucidate the mechanisms of cataractogenesis in wild type and Atm heterozygous animals in an attempt to understand why the small difference in cell killing due to haploinsufficiency for the Atm protein translates into a large and important difference for cataract formation.

Research Impact/Earth Benefits: 0

Task Progress & Bibliography Information FY2006 
Task Progress: Please note that this is a new grant for the FY 2006 year. The investigator will provide a task progress at the time of the one year anniversary of the grant. If you need more information, please contact the Task Book Help Desk at taskbook@nasaprs.com.

Bibliography Type: Description: (Last Updated: 11/14/2017) 

Show Cumulative Bibliography Listing
 
 None in FY 2006