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 301/435-0714,
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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