Department of Energy

Office of Science Financial Assistance Program Notice DE-FG01-04ER04-21; Low Dose Radiation Research Program - Molecular Mechanisms and Pathways

AGENCY: U.S. Department of Energy

ACTION: Notice inviting grant applications.

SUMMARY:The Office of Biological and Environmental Research (OBER) of the Office of Science (SC), U.S. Department of Energy (DOE) and the Office of Biological and Physical Research (OBPR), National Aeronautics and Space Administration (NASA), hereby announce their interest in receiving grant applications for new research to develop a better scientific basis for understanding exposures and risks to humans from low doses or low fluences of ionizing radiation. Research must support the DOE/OBER Low Dose Radiation Research Program, and may include complementary research of direct interest to the NASA/OBPR Space Radiation Health Program of sufficient scientific merit to qualify for partial NASA support. To be considered for funding, research must focus on elucidating exact molecular mechanisms and pathways involved in radiobiological responses to low dose exposure; exclusively phenomenological studies will not be considered. Scientists working in rapidly developing areas of biological sciences not necessarily associated with the study of radiation are also encouraged to consider the contributions that their field of study can make. Research employing genome-wide or proteome-wide high-throughput screening methods is especially encouraged.

DOE/OBER also announces its interest in receiving applications for special grants to support new collaborative work between two or more laboratories, one or more of which is already funded by the DOE Low Dose Program. These "glue grants" are primarily designed to support post-doctoral or graduate-student research that will enable laboratories with complementary expertise to develop and apply innovative new approaches to low dose research. Please review the Supplementary Information sections below for further discussion of programmatic needs, and for details on format for the two types of applications.

DATES: Preapplications (letters of intent), including information on collaborators, areas of research, and a one-page summary of the proposed research, should be submitted by July 15, 2004.

Formal applications submitted in response to this notice must be received by 4:30 p.m., Eastern Time, September 15, 2004, in order to be accepted for merit review and to permit timely consideration for award in Fiscal Year 2005.

ADDRESSES: Preapplications referencing Program Notice DE-FG01-04ER04-21, should be sent to Ms. Kim Laing by E-mail: kim.laing@science.doe.gov, with a copy to Dr. Noelle Metting at: noelle.metting@science.doe.gov.

Formal applications referencing Program Notice DE-FG01-04ER04-21 must be sent electronically by an authorized institutional business official through DOE's Industry Interactive Procurement System (IIPS) at: http://e-center.doe.gov. IIPS provides for the posting of solicitations and receipt of applications in a paperless environment via the Internet. In order to submit applications through IIPS your business official will need to register at the IIPS website. IIPS offers the option of using multiple files, please limit submissions to one volume and one file if possible, with a maximum of no more than four PDF files. The Office of Science will include attachments as part of this notice that provide the appropriate forms in PDF fillable format that are to be submitted through IIPS. Color images should be submitted in IIPS as a separate file in PDF format and identified as such. These images should be kept to a minimum due to the limitations of reproducing them. They should be numbered and referred to in the body of the technical scientific grant application as Color image 1, Color image 2, etc. Questions regarding the operation of IIPS may be e-mailed to the IIPS help desk at: HelpDesk@pr.doe.gov or you may call the help desk at (800) 683-0751. Further information on the use of IIPS by the Office of Science is available at: http://www.science.doe.gov/grants/.

If you are unable to submit an application through IIPS, please contact the Grants and Contracts Division, Office of Science at: (301) 903-5212 or (301) 903-3064, in order to gain assistance for submission through IIPS or to receive special approval and instructions on how to submit printed applications.

FOR FURTHER INFORMATION CONTACT: Dr. Noelle Metting, telephone: (301) 903- 8309, E-mail: noelle.metting@science.doe.gov, Office of Biological and Environmental Research, U.S. Department of Energy, SC-72/Germantown Building, 1000 Independence Avenue SW, Washington, DC 20585-1290. For specific information on NASA/OBPR interests, contact Dr. Walter Schimmerling, telephone (202) 358-2205, E-mail: wschimmerling@hq.nasa.gov, NASA Headquarters, Mail Code UB, Washington, DC 20546-0001.

SUPPLEMENTARY INFORMATION

I. Specifics for the Low Dose Radiation Research Program (DOE)
II. Specifics for Glue Grants (DOE)
III. Specifics for the Space Radiation Health Program (NASA)

I. Specifics for the Low Dose Radiation Research Program (DOE)

The DOE/OBER Low Dose Radiation Research Program has the challenge of conducting research that can be used to inform the development of future national radiation risk policy for the public and the workplace. This research program will be a success if the science it generates is useful to policy makers, standard setters, and the public. Successful applicants will be expected to effectively communicate research results through publication in peer-reviewed journals. Any data and results generated through the investigations that are appropriate to share with the broader scientific community should, where possible, be provided in a format amenable to deposition in databases. Successful applicants will also be encouraged to communicate with the wider community of concerned persons, so that current thinking and the public debate is better able to reflect sound science.

Mechanisms and Pathways. In order to be considered for this solicitation, the proposed project must focus on elucidating exact molecular mechanisms and pathways involved in radiobiological responses to low dose exposure. Proposals to perform exclusively phenomenological studies will not be considered for funding.

Gene knock-out or knock-in technologies have already shown usefulness in studies of protein function and molecular pathways; newer molecular techniques such as RNA interference, SAGE (serial analysis of gene expression), and other sequence-based approaches and proteomics techniques may also prove useful. Another approach for elucidation of molecular pathways might be to characterize topological, physical, and chemical characteristics that underlie cellular responses to low dose radiation exposures. Intracellular organization is undoubtedly necessary in order for the various cellular components to efficiently mediate their appropriate pathways. Hence, studies of cellular internal organization using existing technologies are encouraged.

The linkage of data from low dose experiments to downstream health outcomes that might occur in humans (e.g., carcinogenesis) has not yet been accomplished. Defining the patterns of expression and functions of genes from tissues or tissue constructs containing several different cell types, after low dose exposures, may be critical to making this linkage. Therefore, research projects that extend basic mechanistic research in simple in vitro systems to look at more complex cell microenvironments (thus leading to greater understanding of radiobiological responses in intact human tissue) are strongly encouraged.

Information on regulatory, metabolic, and signaling pathways is growing rapidly, and applications should point out, wherever possible, how the proposed research might clarify or extend this information.

Doses and dose rates. DOE/OBER is chiefly concerned with very low doses of low Linear Energy Transfer (LET) radiation (high energy electrons and protons, x- and gamma-rays). The focus of research should be on doses of low LET radiation that are at or near current workplace exposure limits. In general, research in this program should focus on total radiation doses that are less than or equal to 10 rads (0.1 Gray). Some experiments will likely involve selected exposures to higher doses of radiation for comparisons with previous experiments or for determining the validity of extrapolation methods previously used to estimate the effects of low doses of radiation from observations made at high doses. Low dose rate studies are also desirable, but the total dose delivered must be low.

Not all research on the biological effects of low doses of radiation will be equally useful for the development of radiation risk policy, though the path from basic radiation biology research to radiation risk policy is admittedly not clear at this time. In the present context, the research considered to be most useful will focus on biological responses that are known to be induced at low doses of radiation, have the potential to directly impact (i.e., increase or decrease) subsequent development of cancer or other harmful health impacts, are quantifiable, could potentially be linked to the development of a biologically based model for radiation risk, and could potentially lead to the development of biological predictors (biomarkers) of individual risk.

Alternatively, a biological response of interest could meet all of the above criteria only at high doses but may actually be absent (as opposed to simply undetectable) at low doses of radiation. Since evidence is accumulating that the mechanisms of action after high doses of radiation may be different from the mechanisms of action after low doses, such studies would help define these mechanisms. Defining the doses where these mechanisms shift is of critical importance.

Keeping in mind the above statements of programmatic needs, suggested topics for which the Program desires additional research include, but are not limited to, endogenous oxidative damage versus low dose radiation-induced damage, radio-adaptive responses, bystander effects, and individual genetic susceptibility to low dose radiation exposure. A brief description of each follows:

a) Individual genetic susceptibility to low dose radiation. A major goal of the Low Dose Radiation Research Program is determining the existence of genetic differences that result in increased risk for radiation-induced cancer in sensitive individuals or sub-populations. Knowledge of genetic susceptibility is also one of the Critical Questions used by NASA to define research priorities; this knowledge is required to properly define individual radiation risk for spaceflight crew members. Accordingly, high priority will be given to support of research that seeks to identify patterns of genetic polymorphisms significantly impacting radiation sensitivity or resistance to low dose exposures, and to characterize their mechanism of action. The ability to exploit genome-wide or proteome-wide high-throughput screening methods that have a chance of ultimately detecting complex, multi-gene patterns indicative of or related to susceptibility is of particular interest. Radiation sensitivity is already well known in individuals with particular gene polymorphisms or mutations that affect one or more of their DNA repair systems. It is very likely that many other gene anomalies and combinations of anomalies will be found to be implicated in human susceptibility to disease

In addition to an individual's genetic makeup or genotype, carcinogenesis occurs as a function of all the forces and phenomena that go into the production of that individual's phenotype. These include current and historical aspects of diet, physical exercise, and exposures to chemicals and radiation. Where appropriate, research design should consider these and other external factors that could influence susceptibility to low doses of radiation.

A new resource that is now available to all Low Dose Program investigators, but might be of particular interest to those proposing research in the area of genetic susceptibility, is a tissue repository containing cells from patients who developed second cancers following total body irradiation and hematopoietic stem cell transplantation (HSCT). Presently there are EBV- transformed cell lines from 25 individuals exposed to radiation, which subsequently developed a skin tumor, and an equal number from exposed individuals that have not yet developed a second cancer. A much larger tissue resource will be available in the future. Please contact directly Dr. Jeffrey L. Schwartz, Associate Professor of Radiation Oncology, University of Washington, (206) 598-4091, E-mail: jschwart@u.washington.edu, for collaborative opportunities.

b) Endogenous oxidative damage in relation to low dose radiation induced damage. A key goal of this research program is the study of similarities and differences between endogenous oxidative damage and damage induced by low levels of ionizing radiation, in order to distinguish any associated health risks. This information will underpin our interpretation of all other biological effects of exposure to low doses of ionizing radiation. Although qualitative descriptions of differences and/or similarities between the types of damage induced under both conditions have been useful in the design and interpretation of experiments in other parts of the program, there is also a need for quantification of the levels of damage induced by normal oxidative processes and incremental increases due to low dose irradiation.

c) Radio-Adaptive Response Induction. This is the ability of a low dose of radiation to induce cellular changes that alter the level of subsequent radiation-induced or spontaneous damage. New research is sought to characterize the exact molecular mechanisms that are involved in radiation induced adaptive response. There is overwhelming evidence that the phenomenon does exist, although its applicability to different cell tissue types has not been fully explored, nor has quantification over a range of priming doses, dose rates, and time constants of action been completed. Nevertheless, it is crucial to focus on mechanism. The presumed DNA damage sensors: poly(ADP-ribose) polymerase (PARP), DNA-dependent protein kinase (DNA-PK), the protein product of the ataxia telangiectasia mutated (ATM) gene, and the tumor suppressor, p53, have each been individually implicated in the induction pathway, as have such apoptosis-related enzymes as Ras, ceramid-activated protein kinase, phospholipase-C, and phosphatidilinostol 3-kinase. There is evidence that the final mode(s) of action could be DNA repair up-regulation, heightened immunity, and/or heightened anti-oxidant production. However, no clear consensus of opinion on the mechanisms of adaptive response has emerged. High priority will be given to studies to discover the exact molecular mechanisms involved in all steps of the induction of radio-adaptive response.

d) Bystander effects. These are biological responses observed in cells that are not directly traversed by radiation but are neighbors of an irradiated cell. New research is sought to characterize the exact molecular mechanisms that are involved in radiation induced bystander effects. Multiple studies of cell monolayers in a wide variety of human and rodent cell types and strains have presented clear evidence for an effect; bystander cells have already been shown to respond with gene induction and/or production of clastogenic changes such as mutations, sister chromatid exchanges, chromosomal aberrations, oncogenic transformation, and apoptotic cell death. However, ongoing studies are only beginning to address the issue of whether different levels of bystander effects occur in three-dimensional tissues in contrast to corresponding monolayer cultures. Hence, additional proposals that address effects in tissues, or in tissue-like models, will receive high priority. Investigators are also encouraged to propose bioimaging for in situ quantification in tissues

The DOE Low Dose Program is currently funding several projects that have developed micro- irradiation devices capable of delivering low doses of low LET radiation to individual cells or to specific parts of individual cells. Investigators are encouraged to use these irradiators, as appropriate, through collaborative means, and funds are available to assist in the collaborative use of these or comparable tools (see also the information on glue grants, below). Information on the microbeam irradiators can be found at: http://lowdose.tricity.wsu.edu.

II. Specifics for Glue Grants (DOE)

The Low Dose Radiation Research Program is also interested in receiving applications for the purpose of supporting collaborative work between two laboratories, one of which should be currently funded by the Program. These small grants are primarily designed to support post-doctoral or graduate-student research that will enable laboratories with complementary expertise to develop and apply innovative or collaborative approaches to low dose research, although comparative studies between laboratories already using similar experimental approaches are also encouraged. At least one of the applicant partners must hold a DOE grant focusing on low dose studies, and both applicant partners must have at least 1 year of support remaining on their core grants at the time of award (~November 2004). Collaborative glue grants can be set up with laboratories funded by such diverse agencies as DOE, NIH/NCI, NASA, DOD, EPA, the European Union, Canada, France, or Japan, but in any case the proposed research must be of interest to the DOE Low Dose Radiation Research Program. Applications for these small grants should review the sections above on programmatic needs, and must also follow the instructions in IIPS for electronic submission. Please note: the Project Description for the glue grant application should not exceed ten pages.

III. Specifics for the Space Radiation Health Program (NASA)

The NASA/OBPR Space Radiation Health Program is charged with providing input for the determination of health risks to humans visiting the space radiation environment. NASA is especially interested in human exposure to low fluences of high-energy particulate ionizing radiation (protons and heavy ions). Applications whose principal focus is on low LET radiation are encouraged to include complementary research with high-energy particulate ionizing radiation that leverages progress, resources, and technology used for the low LET radiation research. Investigators with currently funded low dose projects may also apply for supplementary funding to address closely related research of interest to NASA.

The primary area of emphasis of the NASA/OBPR Space Radiation Health Program is the development of mechanistic insights into biological effects of space radiation that account for radiation risks. Applications are required to be hypothesis-driven and are expected to obtain their data in ground-based experimental radiobiology studies with protons and high-energy heavy ion beams in the energy range corresponding to space radiation. This is mainly a ground-based program using accelerator facilities to simulate space radiation. In addition to the research topics already described above this includes research on non-phenomenological predictors of late cell and tissue effects and the control and modification of radiation effect mechanisms

A short description of the current Space Radiation Health Strategic Program may be found at: http://spaceresearch.nasa.gov/common/docs/1998_radiation_strat_plan.pdf. Activities of OBPR, including research opportunities, descriptions of previous tasks, and other relevant information can be found at: http://SpaceResearch.nasa.gov. A description of the ground-based facilities and experimental program at Brookhaven National Laboratory can be found at: http://server.c-ad.bnl.gov/esfd/nsrl/index.html. The proton therapy facilities at Loma Linda University Medical Center are described at: http://www.llu.edu/llu/ci/nasa/ http://research.hq.nasa.gov/code_u/bcpr/index.cfm. Scientists working in rapidly developing areas of biological sciences not necessarily associated with the study of radiation are particularly encouraged to consider the contributions that their field of study can make to Radiation Health. Applications are required to provide evidence for expertise in radiation, either by reference to the Principal Investigator's work or by inclusion of active collaborators expert in radiation research. Hypotheses should be substantiated by presentation of preliminary data wherever feasible, or by adequate references to the published literature. Experimental applications should include a clear discussion of the relevant aspects of the required radiation dosimetry and an estimate of the statistical power of the expected results.

Research applications to which NASA will assign high priority:

a. Studies that increase the confidence in the accuracy of extrapolating the probability of radiation-induced genetic alterations or carcinogenesis from rodents to humans.
b. Determination of carcinogenic risks following irradiation by protons and HZE particles.
c. Determination if exposure to heavy ions at the level that would occur in deep space poses a risk to the integrity and function of the central nervous system.
d. Studies likely to result in the development of biological countermeasures in humans that could lead to prevention or intervention (including genetic or pharmacological agents) against effects of radiation damage in space.

Research that can lead to future space flight investigations will be welcome, and should take into account the impact of gender, age, nutrition, stress, genetic predisposition, or sensitivity to other factors of importance in managing space radiation risks. However, it should be noted that this announcement does not solicit space flight experiments.

NASA envisions that the selected applications will be structured and operated in a manner that supports the country's educational initiatives and goals (including historically black colleges and universities and other minority universities), and in particular the need to promote scientific and technical education at all levels. NASA envisions that the selected applications will support the goals for public awareness and outreach to the general public. The selected investigators are invited to participate in NASA-funded educational programs.

The applications represent an opportunity to enhance and broaden the public's understanding and appreciation of radiation effects, as specified in the DOE Low Dose Program emphasis on communication of research results and the OBPR Policy for Education and Public Outreach. Therefore, all investigators are strongly encouraged to promote general scientific literacy and public understanding of radiation induced health risk research through formal and/or informal education opportunities. If appropriate, applications should include a clear and concise description of the education and outreach activities proposed. Examples include such items as involvement of students in the research activities, technology transfer plans, and public information programs that will inform the general public of the benefits being gained from the research, and/or plans for incorporation of scientific results obtained into educational curricula consistent with educational standards.

Where appropriate, the supported institution will be required to produce, in collaboration with NASA, a plan for communicating to the public the value and importance of their work.

The particles of interest to the Space Radiation Health Program are protons with energies between 20 and 1000 MeV, and nuclei of elements with atomic numbers between He and Fe, with energies between 50 and 3000 MeV/nucleon. Fluences of interest are of the order of 1-2 particles per cell; studies with higher fluences will need to be justified by compelling arguments, including an explanation of how the results can be applied in the low fluence regime. NASA has developed facilities for use of protons at Loma Linda University Medical School and high-energy heavy ion beams at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory. Applications should not budget for the use of beams at these facilities, which is paid by NASA. NASA will cooperate with DOE to provide the range of technical resources available for experimentation and analysis of experimental results at Brookhaven.

Program Funding

It is anticipated that $2 million will be available from DOE/OBER for new basic research awards during FY 2005, contingent upon the availability of funds. Multi-year funding of grant awards is expected, and is also contingent upon the availability of appropriated funds, progress of the research, and continuing program need. Additional funds of up to $0.5M will be available from NASA for joint funding of new research in Fiscal Year 2005, also contingent upon the availability of funds. Funds will be available from DOE to assist in the collaborative use of certain microbeam irradiators. NASA provides beam time at the NSRL and the Loma Linda proton accelerator; investigators will not be required to pay for the beam time. It is expected that most awards will be from 1 to 3 years and will range from $100,000 to $500,000 per year (total costs). Glue grant awards should range between $75,000 and $110,000 per year, and run from 1 to 3 years.

Collaboration

Applicants are encouraged to collaborate with researchers in other institutions, such as universities, industry, non-profit organizations, federal laboratories and Federally Funded Research and Development Centers (FFRDCs), including the DOE National Laboratories, where appropriate, and to incorporate cost sharing and/or consortia wherever feasible. Additional information on collaboration is available in the Application Guide for the Office of Science Financial Assistance Program that is available via the Internet at: http://www.sc.doe.gov/grants/Colab.html.

Merit and Relevance Review

Applications will be subjected to scientific merit review (peer review) and will be evaluated against the following evaluation criteria listed in descending order of importance as codified at 10 CFR 605.10(d):

1. Scientific and/or Technical Merit of the Project.
2. Appropriateness of the Proposed Method or Approach.
3. Competency of Applicant's Personnel and Adequacy of Proposed Resources.
4. Reasonableness and Appropriateness of the Proposed Budget.

The Application

(PLEASE NOTE INFORMATION BELOW ON PAGE LIMITS)

Information about the development and submission of applications, eligibility, limitations, evaluation, selection process, and other policies and procedures may be found in the Application Guide for the Office of Science Financial Assistance Program and 10 CFR Part 605. Electronic access to the Guide and required forms is made available via the World Wide Web: http://www.science.doe.gov/grants/guide.html. DOE is under no obligation to pay for any costs associated with the preparation or submission of applications if an award is not made.

Adherence to type size and line spacing requirements is necessary for several reasons. No applicants should have the advantage of providing more text in their applications by using small type. Small type may also make it difficult for reviewers to read the application. Applications must have 1-inch margins at the top, bottom, and on each side. Type sizes must be 10 point or larger. Line spacing is at the discretion of the applicant but there must be no more than 6 lines per vertical inch of text. Pages should be standard 8 1/2" x 11" (or metric A4, i.e., 210 mm x 297 mm). Applications must be written in English, with all budgets in U.S. dollars.

Applicants are asked to use the following ordered format:

• Face Page (DOE F 4650.2 (10-91))
• Project Abstract Page; single page only, should contain:
  • Title
  • PI name
  • Abstract text should concisely describe the overall project goal in one sentence, and limit background/significance of project to one sentence. Short descriptions of each individual aim should focus on what will actually be done.
• Relevance Statement; single page only, should identify DOE- or NASA-relevant research that each specific aim is intended to address
• Budget pages for each year and a summary budget page for the entire project period (using DOE F 4620.1)
• Budget Explanation
• Budget pages and budget explanation for each collaborative subproject, if any.
• Project Description, 20 pages or less, exclusive of attachments. Applications with Project Descriptions longer than 20 pages will be returned to applicants and will not be reviewed for scientific merit. (NOTE: Project Descriptions for Glue Grants should not exceed 10 pages.) The project description should be a clear statement of the work to be undertaken and should include: objectives for the period of the proposed work and expected significance; relation to the longer-term goals of the principal investigator of the project; and relation to the present state of knowledge in the field, to work in progress by the investigator under other support, and work in progress elsewhere. The statement should outline the general plan of work, including the broad design of experiments to be undertaken, and an adequate description of experimental methods and procedures.
• Literature Cited
• Biographical Sketches (please limit to 2 pages per senior investigator, consistent with NIH guidelines)
• Facilities and Resources description
• Current and Pending Support for each senior investigator
• Letters of Intent from collaborators (if applicable)

The Office of Science, as part of its grant regulations, requires at 10 CFR 605.11(b) that a recipient receiving a grant to perform research involving recombinant DNA molecules and/or organisms and viruses containing recombinant DNA molecules shall comply with the National Institutes of Health "Guidelines for Research Involving Recombinant DNA Molecules", which is available via the World Wide Web at: http://www.niehs.nih.gov/odhsb/biosafe/nih/rdna-apr98.pdf, (59 FR 34496, July 5, 1994), or such later revision of those guidelines as may be published in the Federal Register.

DOE policy requires that potential applicants adhere to 10 CFR 745 “Protection of Human Subjects” or such later revision of those guidelines as may be published in the Federal Register. DOE requirements for reporting, protection of human and animal subjects and related special matters can be found on the World Wide Web at: http://www.science.doe.gov/grants/Welfare.html.

The Catalog of Federal Domestic Assistance number for this program is 81.049, and the solicitation control number is ERFAP 10 CFR Part 605.

Martin Rubinstein
Acting Director
Grants and Contracts Division
Office of Science

Posted on the Office of Science Grants and Contracts
Web Site June 7, 2004.