Full Text CA-93-02

THE REGULATION, FUNCTION AND SPECIFICITY OF PROTEINS INDUCED IN
MAMMALIAN CELLS EXPOSED TO IONIZING RADIATION

NIH GUIDE, Volume 21, Number 38, October 23, 1992

RFA:  CA-93-02

P.T. 34

Keywords: 
  Proteins and Macromolecules 
  Gene Regulation 
  Gene Products 


National Cancer Institute

Letter of Intent Receipt Date:  December 10, 1992
Application Receipt Date:  February 10, 1993

PURPOSE

The Division of Cancer Etiology of the National Cancer Institute
(NCI) invites grant applications from interested investigators
through an announcement of Request for Applications (RFA) for studies
of the function and regulation of proteins differentially expressed
in mammalian cells exposed to ionizing radiation.  The RFA will
emphasize direct analysis of the genes and gene products associated
with ionizing irradiation of mammalian cells.

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,
The Function, Regulation and Specificity of Proteins Induced in Cells
Exposed to Ionizing Radiation, is related to the priority area of
biomedical research.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001- 00474-0) or
"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

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 and local
governments, and eligible agencies of the Federal government.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

This RFA is a one-time solicitation and will be supported through the
National Institutes of Health (NIH) traditional research project
grant (R01).  The applicant will have the sole responsibility for
planning, directing, and executing the proposed research.  Awards
will be administered under Public Health Service grants policy as
stated in the PHS Grants Policy Statement, DHHS Publication No.
(OASH) 90-50,000 revised October 1, 1990.  The total project period
for each application submitted in response to the present RFA should
not exceed four  years.  Competitive continuation applications will
compete with all other unsolicited applications and be reviewed by a
standing Division of Research Grants study section.

FUNDS AVAILABLE

The intent of this research initiative is to fund approximately six
individual research grants, with total program costs not to exceed
$1,000,000 for the first year.  This funding level will be dependent
on receipt of a sufficient number of grant proposals of high
scientific merit.  Support for this RFA is provided for in the
financial plans of the NCI.  However, award of grants responding to
this RFA will be contingent on the availability of funds at the time
the awards are made.

RESEARCH OBJECTIVES

Background

Recent evidence suggests that mammalian cells possess a specific and
limited set of radiation modulated proteins (RMPs) that are
differentially expressed in response to ionizing irradiation.  The
overall process of RMP structural gene expression appears to be
tightly regulated, mainly at the level of gene transcription, and
demonstrates a radiation dose-response (e.g., from less than 20 cGy
to over 300 cGy).  The molecular lesion(s) that initiates this
process is not known.  Many RMPs have been detected only as peptides
or as new gene transcripts (herein called uncharacterized RMPs) and
appear to be specifically induced by ionizing irradiation and not by
other agents known to induce stress-related proteins (e.g., heat,
hypoxia, ultraviolet light, chemical carcinogens).  Few, if any, of
the cDNAs corresponding to the uncharacterized RMPs have been cloned.
Accordingly, there is little detailed molecular and biochemical
information on the functions carried out by the uncharacterized RMPs
or on the genetic and regulatory mechanisms that control their
expression.  However, there is circumstantial evidence suggesting
that increased expression of several of the uncharacterized RMPs is
correlated with cellular recognition of radiogenic lesions to DNA,
the repair of ionizing-radiation-induced DNA damage, and possibly
with the radiation-induced arrest of the cell cycle suggesting
intimate involvement in classical radiologic endpoints of DNA-repair
and inhibition of DNA-synthesis, gene transcription, and cell
division.

Objectives

Because of advances in the technology for detection of minute
quantities of gene products, both transcripts and proteins, it should
be feasible to directly study the genes expressed in mammalian cells
exposed to ionizing radiation.  Likewise, it should be possible to
construct cDNA libraries from irradiated human or rodent cells that
correspond to the structural genes of the uncharacterized RMPs.  Such
libraries will be essential for the isolation and subsequent
molecular and biochemical analyses of the uncharacterized RMP
structural genes and proteins.  This RFA will permit a wide range of
research activities, including, but not limited to, the following
objectives:

o  Studies to determine the biochemical and molecular functions
carried out by the uncharacterized RMPs, to relate them to poorly
understood radiologic endpoints in mammalian cells such as
radiation-induced arrest of the cell cycle, repair of radiation
damaged DNA, radiation-induced mutagenesis, transformation, and cell
survival;

o  Research to identify the radiogenic lesions that trigger the
differential expression of the uncharacterized RMPs;

o  Analysis of the genetic organization of the uncharacterized RMP
structural genes and the mechanisms of regulation that govern their
expression;

o  Determination of the effects of radiation quality on differential
expression of the uncharacterized RMPs, specifically, the efficacy of
high-LET radiation should be compared with low LET radiation for
inducing the uncharacterized RMPs.

STUDY POPULATIONS

Special instructions to applicants regarding implementation of NIH
policies concerning inclusion of females and minorities in clinical
research study populations are not applicable to this RFA.

LETTER OF INTENT

Prospective applicants are requested to submit, by December 10, 1992,
a letter of intent to respond to the RFA that includes a descriptive
title of the proposed research, collaborations and/or collaborative
agreements, the name and address of the Principal Investigator, the
names of other key personnel, the participating institutions, and the
number and title of the RFA in response to which an application may
be submitted.  The letter of intent helps NCI staff to estimate the
review workload and to avoid possible conflict of interest in the
review.  The letter of intent does not bind the respondent to respond
formally to the RFA, nor is it required in order to respond.  The
letter of intent does not enter into the review of subsequent
applications.

The letter of intent is to be sent to:

Richard A. Pelroy, Ph.D.
Radiation Effects Branch
National Cancer Institute
Executive Plaza North, Suite 530
Bethesda, MD  20892
Telephone:  (301) 496-9326
FAX:  (301) 496-1224

APPLICATION PROCEDURES

Applications are to be submitted on PHS 398 (rev. 9/91) available at
most institutional offices of sponsored research, and may be obtained
from the Office of Grants Inquires, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 449, Bethesda,
MD 20892, telephone (301) 496-7447.  The format and instructions
applicable to regular research grant applications must be followed in
preparing a grant in response to the RFA.

The RFA label available in the application form PHS 398 must be
affixed to the bottom of the face page. Failure to use this label
could result in delayed processing of a grant application, and
possibly preventing it from reaching the review committee in time for
review.  In addition, the number and title of the RFA should be typed
on line 2a of the face page of the application and YES must be
checked.  A signed, typewritten original grant application, including
the checklist, and three signed, exact photocopies, must be mailed,
in one package, to the Division of Research Grants at the address
below.  The photocopies must be clear and single-sided.

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 848
5333 Westbard Avenue
Bethesda, MD  20892

Applications must be received by February 10, 1993.  If an
application is received after that date, it will be administratively
withdrawn from consideration.  If the application submitted in
response to this RFA is substantially similar to a grant application
already submitted to the NIH for review, but has not yet been
reviewed, the applicant will be asked to withdraw either the pending
application or the new one.  Simultaneous submission of identical
applications will not be allowed, nor will essentially identical
applications be reviewed by different review committees.  Therefore,
an application cannot be submitted in response to this RFA that is
essentially identical to one that has already been 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.  Animal and human
subject approval clearances, when applicable, should be submitted
with the application to expedite the review process.

REVIEW CONSIDERATIONS

Review Procedures

Upon receipt, applications will be reviewed by the Division of
Research Grants for completeness.  Incomplete applications will be
returned to the applicant without further consideration.  Review of
the responsiveness of applications is an NCI program staff function.
Applications will be judged to determine how well they meet the goals
and objectives of the program as described in the RFA. Applications
that are judged non-responsive will be administratively withdrawn,
and the proposed Principal Investigator and institutional business
official will be notified.  If an application is judged
non-responsive to this RFA, it may be submitted as an investigator
initiated regular research grant (R01) at the next receipt date.

If the number of applications is large compared to the number of
awards to be made, the NCI may conduct a preliminary scientific peer
review to eliminate those that are clearly not competitive for award.
The NCI will withdraw from further competition those applications
judged to be noncompetitive and notify the Principal Investigator and
institutional business official.

Those applications judged to be both competitive and responsive will
be further evaluated, using the review criteria shown below, for
scientific and technical merit by an appropriate peer review group
convened by the Division of Extramural Activities, NCI.  The second
level of review by the National Cancer Advisory Board considers the
special needs of the Institute and the priorities of the National
Cancer Program.

Review Criteria

Applications should be responsive to the stated purpose and objective
of the RFA.  Those factors considered to be important for review will
include:

o  The scientific merit and innovation of proposed research

o  A demonstrated knowledge of the applicable science and competence
with relevant methodology

o  Adequacy of facilities and special resources relevant to the RFA

o  Cost effectiveness of the proposal

o  Quality of scientific collaboration

o  Technical merit of proposed methods

AWARD CRITERIA

The anticipated date of award is September 15, 1993.  Responsiveness
to the objectives of the RFA, programmatic balance and scientific
merit will be major criteria for making award decisions.

INQUIRIES

Written and telephone inquires concerning the objectives and scope of
this RFA are encouraged and may be directed to Dr. Richard A. Pelroy
at the address listed under LETTER OF INTENT.

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.393, Cancer Cause and Prevention Research.  Awards
are made under authorization of Public Health Service Act, Section
301(c) and Section 402 (Public Law 78-410, as amended; 42 USC 241; 42
USC 282) and administered under PHS grants policies and Federal
regulations 42 CFR Part 52 and 45 CFR Part 74. This program in not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.

.

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