Full Text CA-96-010 MECHANISMS OF GENOMIC INSTABILITY FROM THE EXPOSURE OF MAMMALIAN CELLS TO HIGH-LET IONIZING RADIATIONS NIH GUIDE, Volume 25, Number 10, March 29, 1996 RFA: CA-96-010 P.T. 34 Keywords: Health, Radiation Effects Human Genome Genetics Biology, Molecular National Cancer Institute National Aeronautics and Space Administration Letter of Intent Receipt Date: April 24, 1996 Application Receipt Date: June 14, 1996 PURPOSE The Division of Cancer Biology of the National Cancer Institute (NCI) and the Life and Biomedical Sciences and Applications Division of the National Aeronautics and Space Administration (NASA) invite research project grant (R01) applications from interested investigators for studies of the basic molecular mechanisms of long-term (heritable) genomic instability (GI) that is induced in mammalian (or suitable model eukaryotic) cells in organisms exposed to various forms of high-linear-energy-transfer (high-LET) radiation. The primary purpose and interest of both agencies in this Request for Applications (RFA) is to define and understand GI from chronic low-dose exposure of mammalian cells to high energy nuclei of high atomic number (referred to as HZE) particles (e.g., iron) and to high-energy protons, which are likely to be major sources of human exposure to high-LET radiation during extended space flight. It is also of interest to delineate the mechanistic basis for GI from chronic low-dose exposure of mammalian cells to low-energy neutrons or alpha particles (a surrogate for radioactive radon daughters) that are important sources of human exposure in environmental and certain occupational settings. In addition, both agencies have a continuing interest in the possible use of molecular changes that may accompany radiation-induced GI as biomarkers of human exposure to high-LET. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Mechanisms of Genomic Instability from the Exposure of Mammalian Cells to High-LET Ionizing Radiations, is related to the priority areas of biomedical and environmental health research. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit institutions, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA is a one-time solicitation and will be supported through the National Institutes of Health (NIH) investigator-initiated research project grant (R01). The applicant will have the sole responsibility for planning, directing, and executing the proposed research. The total project period for an application submitted in response to this RFA may not exceed four years. At the end of the four-year RFA support period, competitive continuation applications will compete with all other unsolicited applications and be reviewed by a standing Division of Research Grants (DRG) Study Section. The anticipated average direct costs for an application in response to this RFA will be approximately $130,000, although applications with greater or lesser direct costs than this figure will be considered, depending on the nature of the proposed research. The anticipated date of award for the RFA is April 1, 1997. FUNDS AVAILABLE The intent of this research initiative is to fund approximately 10 individual research grants, with total program costs (direct plus indirect) not to exceed $2 million for the first year. It is planned that some portion of these funds (i.e., not to exceed $500,000) may be set-aside to procure beam-time and dosimetry support for HZE and high-energy proton studies at designated sites. Support for this RFA is provided in the financial plans of the NCI and NASA. However, award of grants responding to this RFA will be contingent on the availability of funds at the time the awards are made and also on the receipt of a sufficient number of grant applications of high scientific merit. RESEARCH OBJECTIVES Background A striking phenotypic characteristic of high-LET-induced GI in primary human or rodent cells is the long-term accumulation of genetic abnormalities (e.g., chromosomal aberrations) among progeny of irradiated cells. Most of the other changes associated with radiation-induced GI also involve genes (e.g., point and deletion mutations) or chromosomes; however, none has been studied to the same degree as have cytogenetic effects. Nevertheless, a number of studies that utilize a variety of biological systems and exposure conditions (e.g., primary and immortalized human and rodent cell lines, other eukaryotes, both high- and low-LET forms of ionizing radiation) suggest that radiation-induced GI may be characterized by: (1) eventual acquisition of a mutator phenotype by progeny cells, (2) extensive gene amplification (an early event) followed by generally increasing levels of genetic instability in duplicated sequences (e.g., insertions, deletions), (3) evidence for abnormally high rates of recombination during expression of GI, (4) possible non-random or "hotspot" associations of chromosomal instability and progressive expression of GI, and (5) evidence that the genetic instability associated with GI leads to neoplastic transformation in rodent cells. The mechanistic basis (or bases) for GI induced by either high- or low-LET radiations is unknown. However, it appears that a sizable fraction of mammalian cells that survive exposure to high-LET radiation can transmit the GI phenotype to their progeny. This comparatively high rate of GI induction among progeny of high-LET irradiated mammalian cells would appear to rule out a simple explanation for induction of GI based on radiation-induced forward mutations at individual loci. While all forms of ionizing radiation probably are capable of inducing GI, the limited studies with the high-LET radiations thus far examined suggest that they are far more potent than are low-LET gamma and x rays as inducers of GI. Single exposures of primary human or murine cells to comparatively low, non-killing doses of high-LET may be sufficient to induce significant expression of GI. By contrast, low-LET radiations appear to either not induce GI (e.g., most studies with primary mammalian cells) or to do so only after exposure to comparatively high doses of radiation (e.g., >1Gy). A fundamental question with respect to this RFA is whether the long-term expression of high-LET-induced GI ultimately results in elevated rates of mutagenesis and neoplastic transformation among progeny of irradiated primary human and rodent cell lines compared to background rates in non-irradiated cells. There is limited evidence that neutron-induced GI in progeny of primary murine mammary cells does, in fact, precede and then give rise to elevated rates of mutagenesis and neoplastic transformation compared to non-irradiated mammary cells otherwise treated in the same experimental way. There is little comparable information for most of the high-LET radiations of interest to this RFA; i.e., high-energy HZE particles, high-energy protons and alpha particles. In order to address the need for more basic information on the radiobiology of these forms of high-LET radiation, this RFA will permit a wide range of research activities, including, but not limited to, the following objectives: o Analysis of the role of the radiation-induced cell-cycle check points on the expression of GI; o The identification of DNA-sequences and specific genes that exhibit instability during the expression of GI, the analysis of the mutational changes that such DNA sequences undergo and their underlying generating mechanisms; o Molecular studies to determine if there is a cytogenetic mechanism(s) to account for both the progressive chromosomal and genetic instability observed in cells expressing radiation-induced GI; o Analysis of the role of recombination and DNA repair on the expression of radiation-induced GI; o Studies with preneoplastic cell lines, in vivo (implanted) and in vitro, to determine temporal and molecular relationships of radiation-induced GI to neoplastic transformation of non-immortalized cells; o The temporal and molecular relationships of radiation- induced GI to the acquisition and expression of a "mutator" phenotype among the progeny of irradiated cells. Beam time and dosimetry support for HZE and high-energy-proton studies supported by this RFA will be provided for qualified applicants at designated sources with high-LET radiation exposure capabilities (see below). Comparable exposure and dosimetry capabilities for alpha particles, neutrons or other sources of ionizing radiation must be provided for by the respondents. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS Special instructions to applicants regarding implementation of NIH policies concerning inclusion of females and minorities in clinical research study populations are not applicable. Dosimetry and Beam Time for HZE Particles and High Energy Protons The National Aeronautics and Space Administration (NASA) conducts a ground-based program focused on mechanistic studies with the potential to enable extrapolation of scientific research results to human beings in space. In pursuit of this program, NASA has signed Memoranda of Agreement (MOA) with ground-based laboratories where energetic beams of protons and some atomic nuclei that constitute galactic cosmic rays (GCR) are available: (1) proton beams at the Loma Linda University Medical Center (protons with energies up to 250 MeV), and (2)the Alternating Synchrotron at Brookhaven National Laboratory (beams of iron and other heavy nuclei, with energies from 1 to 10 GeV/nucleon). Use of the Brookhaven facility has been negotiated by NASA in the framework of the Space Radiation Health Program, and successful respondents to this RFA will be considered to be part of the Space Radiation Health Program. Applicants should not budget separately for use of beam time and logistical support (e.g., dosimetry) for HZE studies carried out at this facility; funds for such beam time will be obtained from the set-aside monies indicated above, if necessary, or from other sources, if possible. Similar arrangements are intended for use of the beam time at Loma Linda University Medical Center for high-energy proton studies. It should be noted that no such agreements currently exist with other sources of radiation that may be relevant to this RFA (e.g., alpha particles, neutrons) and investigators requiring these sources should budget for their use. User facilities have been developed at Brookhaven for radiation-biology research, including cell cultures and small animals. Beams with energies as low as 1 GeV/nucleon have been extracted with beam spots up to 16 cm diameter, center to edge uniformity of 15%, and dose rates up to 11 Gy/min. A physics and dosimetry group is available at Brookhaven for investigators requiring their assistance. Use of the Brookhaven facilities will be coordinated by a laboratory-appointed panel and scheduled in accordance with available beam time and other laboratory resources. Applicants should not budget separately for use of the physics and dosimetry group as it is included in the set-aside funding for dosimetry and logistical support at BNL. It is expected that similar arrangements, taking advantage of existing in-house expertise, will be negotiated with Loma Linda University Medical Center, in the framework of the MOA with that institution. If exposures not available at Loma Linda or Brookhaven are needed for studies proposed in response to this RFA, applicants must indicate in their application how such exposures will be accomplished, provide evidence that the sources will be available for their use and indicate how the dosimetry and other physical characteristics of the radiation fields will be measured. LETTER OF INTENT Prospective applicants are asked to submit, by April 24, 1996, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to either: Richard A. Pelroy, Ph.D. Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, Suite 530 - MSC 7391 Rockville, MD 20852-7391 Telephone: (301) 496-9326 FAX: (301) 496-1224 Email: pelroyd@epndce.nci.nih.gov, or Walter Schimmerling, Ph.D. NASA Space Radiation Health and Radiation Biology Programs NASA Headquarters/Code UL 300 E Street, S.W. Washington, DC 20546-001 Telephone: (202) 358-2205 FAX: (202) 358-4168 Email: wschimmerling@hq.nasa.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for this RFA. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov; and from the NCI and NASA staff listed under INQUIRIES. The RFA label available in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the first page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier Service) At the time of submission, two additional copies of the application must be sent to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute Executive Plaza North, Suite 636 6130 Executive Boulevard - MSC 7405 Bethesda, MD 20892 Rockville, MD 20852 (express/courier service) Applications must be received by June 14, 1996. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review by a chartered study section unless the applicant withdraws the pending application. Also, DRG will not accept any application in response to this RFA that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by the DRG for completeness and by the NCI for responsiveness. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, DRG staff may contact the applicant to determine whether to return the application to the applicant or submit it as is for review in competition with other unsolicited applications at the next review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer-review group convened by the NCI in accordance with NIH peer-review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally in the upper half of applications under review, will be discussed, assigned a priority score, and receive a second-level review by the National Cancer Advisory Board. Review Criteria o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA Awards will be made on the basis of scientific merit, as determined by peer review, the degree that an application meets program priorities and the possible need to achieve programmatic balance to meet the overall objectives of the RFA. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquires regarding programmatic issues to: Richard A. Pelroy, Ph.D. Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, Suite 530 Rockville, MD 20852-7391 Telephone: (301) 496-9326 FAX: (301) 496-1224 Email: pelroyd@epndce.nci.nih.gov, or Walter Schimmerling, Ph.D. NASA Space Radiation Health and Radiation Biology Programs NASA Headquarters/Code UL 300 E Street, S.W. Washington, DC 20546-001 Telephone: (202) 358-2205 FAX: (202) 358-4168 Email: wschimmerling@hq.nasa.gov Direct inquiries regarding fiscal issues to: Ms. Marie N. Moyer Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243 - MSC 7150 Bethesda, MD 20892 Telephone: (301) 496-7800, Ext 225 FAX: (301) 496-8601 Email: moyerm@gab.nci.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and to promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental state of the American people. .
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