Full Text CA-97-012
 
IMPROVED TECHNOLOGIES FOR PRODUCTION OF FULL-LENGTH HUMAN cDNA
 
NIH GUIDE, Volume 26, Number 1, January 10, 1997
 
RFA:  CA-97-012
 
P.T. 34

Keywords: 
  Biology, Molecular 
  Nucleic Acids 
  Gene Cloning 

 
National Cancer Institute
 
Letter of Intent Receipt Date:  February 15, 1997
Application Receipt Date:  April 29, 1997
 
PURPOSE
 
The Technology Development Branch of the Cancer Diagnosis Program,
Division of Cancer Diagnosis, Treatment, and Centers at the National
Cancer Institute (NCI) invites applications for the development and
application of innovative technologies for efficiently generating
representational, full length cDNA libraries.  Full length cDNAs are
those clones that contain a copy of the entire mRNA sequence from
which they were derived.  Representational libraries are those
libraries that contain at least one cDNA for every mRNA species
present in the starting tissue.
 
Ultimately, this new technology must provide an efficient,
cost-effective method for generating full length, representational
cDNA libraries from tissue samples.  These libraries will provide
access to full length clones for those investigators who have
previously identified important partial clones in other libraries.
In addition the clones from these libraries will provide new gene
sequences which will aid in gene discovery and gene function
assessment.  Therefore, investigators may propose to develop novel
technologies initially on a small scale or they may propose to
further develop existing efficient technologies into a
high-throughput system.  The most desirable technologies will be
those that are easily exportable to the research community.
 
In order to encourage applications proposing innovative, high-risk
projects, exploratory/experimental research grant (R21s) will be used
to support meritorious applications.  A total of $2.5 million will be
available to support approximately 10 awards.
 
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 Request
for Applications (RFA) Improved Technologies for Production of
Full-Length Human cDNA, is related to the priority area of cancer.
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 nonprofit organizations, public and private, such as
universities, colleges, hospitals, laboratories, units of State and
local governments, and eligible agencies of the Federal government.
Applications may be from single institutions but collaborative
studies are also encouraged. Racial/ethnic minority individuals,
women and persons with disabilities are encouraged to apply as
principal investigators.
 
MECHANISM OF SUPPORT
 
Support for this program will be through the National Institutes of
Health (NIH) exploratory/experimental research grant (R21) awards.
The total project period for applications submitted in response to
the present RFA may not exceed three years.  The anticipated award
date is September 1, 1997.
 
This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all
investigator-initiated applications and will be reviewed according to
the customary peer review procedures.  Except as otherwise noted in
this RFA, awards will be administered under PHS grants policy as
stated in the Public Health Service Grants Policy Statement, DHHS
Publications No. (OASH) 94-50,000, revised April 1, 1994.
 
FUNDS AVAILABLE
 
It is anticipated that a total of $2.5 million (total costs) will be
available.  Approximately 10 awards are expected to be made from the
total pool of applications received.  The number of awards made will
be contingent upon the quality of applications received and the
availability of funds.
 
RESEARCH OBJECTIVES
 
Background
 
The rapid increase in our understanding of tumor biology coupled with
the technology and data emerging from the human genome project offer
the opportunity for a change in the way cancer research is done.  It
is becoming clear that cancer is not a single disease but many, and
that cancers arise from the gradual accumulation of genetic changes
in single cells.  It is not clear which changes and how many changes
are required to cause an invasive cancer.  Defining which genes are
involved in the initiation and progression of cancer remains a
challenge.
 
An immediate benefit from the human genome project has been the large
scale generation and sequencing of over 500,000 human expressed
sequence tags (EST).  EST are valuable in that they allow a rapid
preliminary identification of a large number of expressed genes.
They are limited in that the clones themselves often represent only
partial genes. Often the partial clone is not adequate to assess the
gene's biological function.  In addition, few of the libraries
currently being sequenced are from tumor or other cancer related
tissues.  Cost-effective, representational full length cDNA libraries
are necessary to facilitate the identification of genes involved in
cancer initiation and progression.
 
The NCI has established the Cancer Genome Anatomy Project (CGAP) to
capitalize on the technology and data emerging from the human genome
project and refocus it in the direction of cancer research.  CGAP has
two main foci: first, the development of a complete index of genes
expressed in tumors and second, the development of new technologies
that will facilitate high throughput analysis of molecular
alterations in cancer cells and dissemination of these technologies
to basic and clinical researchers. The initial effort of CGAP is to
generate and sequence cDNA libraries from four targeted tumor sites:
breast, prostate, colon and lung.  Though these libraries will be
useful in identifying genes involved in cancer, they rely on current
technology which does not guarantee complete representation or full
length clones.
 
Current technology allows the production of representational
libraries of partial genes or production of more limited libraries of
full length clones, which are generally enriched for shorter genes.
In addition, technology exists to create normalized (reduced
redundancy) cDNA libraries. However, it is not currently possible to
efficiently generate representational libraries of full length cDNAs.
In order to derive the maximum benefit from libraries currently being
developed and to find expressed genes not present in the initial
libraries, new technologies for generating full length
representational cDNA libraries are necessary.
 
Objectives
 
This RFA is intended to support the development and/or the
implementation of technologies that generate representational
libraries of full length cDNAs from tissues that will contribute to
the understanding of cancer at the molecular level.  Investigators
may propose to create novel technologies or adapt existing
technologies for the generation of representational libraries of full
length cDNA clones.  They may also propose feasibility studies
designed to generate libraries from appropriate tissues using the
developed technologies.  Preferred technologies will be those that
are efficient (including, but not limited to, normalization
techniques), scalable for high-throughput and easily transferred to
other cancer researchers.
 
A primary goal of CGAP is the compilation of a complete index of all
genes expressed in tumors.  In order to understand the significance
of individual genes or gene expression levels, it will be necessary
to have libraries from cancerous and nonneoplastic tissue from the
same organs for comparison.  Therefore, investigators may propose to
generate individual libraries or to generate libraries that are
enriched for genes differentially expressed from appropriate tissues
after successful completion of the technology development phase of
the project.  Appropriate tissues are those that will provide
information about the initiation and/or progression of cancers,
including but not limited to tumors of different stages, tumor vs.
nonneoplastic tissue, etc.  In all cases, approaches must be
described for demonstrating that the clones in the libraries encode
the entire sequence of the mRNA from which they were derived and
contain a representative sample of the original mRNA population of
the selected tissue.
 
In addition, the NCI is interested in stimulating the development of
innovative technologies that may be supported by limited preliminary
data.  In order to judge the feasibility of the proposed studies, it
is necessary to establish criteria for scientific progress.
Therefore, in their applications, investigators must propose
specific, quantifiable milestones which can be used to measure the
progress of the studies.  Although the details are left to the
investigator, the milestones proposed must consist of clear, well
defined criteria for measuring progress.  They must be appropriate
for the proposed studies and as specific as possible.  Investigators
should also propose a clear time line for successfully completing the
proposed milestones.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their sub-populations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 20, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.
 
Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
 
LETTER OF INTENT
 
Due to the specialized nature of this program, it is strongly
recommended that prospective applicants contact NCI staff to discuss
research objectives.  Prospective applicants are asked to submit, by
February 15, 1997, 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:
 
Jennifer Couch, Ph.D.
Division of Cancer Treatment, Diagnosis and Centers
National Cancer Institute
6130 Executive Boulevard, Room 513, MSC 7388
Bethesda, MD  20892-7388
Telephone:  (301) 496-1591
FAX:  (301) 402-1037
Email:  couchj@dcbdcep.nci.nih.gov
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Division of
Extramural Outreach and Information Resources, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910,
telephone 301/710-0267, e-mail: ASKNIH@odrockm1.od.nih.gov and from
the program administrator listed under INQUIRIES.
 
The RFA label available in the PHS 398 (rev. 5/95) application form
must be affixed to the bottom of the face page of the application.
Failure to use this label could result in delayed processing of the
application such that it might 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, SUITE 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
 
To expedite the review process, at the time of submission, send two
additional copies of the application to:
 
MS. TOBY FRIEDBERG
REFERRAL OFFICER
NATIONAL CANCER INSTITUTE
6130 EXECUTIVE BOULEVARD, ROOM 636A, MSC 7405
BETHESDA, MD  20892-7405
ROCKVILLE, MD  20852 (for overnight/courier service)
Telephone:  (301) 496-3428
FAX:  (301) 402-0275
 
Applications must be received by April 29, 1997.  If an application
is not received by this 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, unless the
applicant withdraws the pending application.  The DRG will not accept
any application that is essentially the same as one already reviewed.
This does not preclude the submission of a substantially revised
application, but such applications must include an introduction
addressing the previous critique.
 
REVIEW CONSIDERATIONS
 
Upon receipt, applications will be reviewed for completeness by the
DRG and for responsiveness by the NCI program staff. 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 for review in competition
with unsolicited applications at the next review cycle.  Applications
proposing the use of currently available technologies for the
generation of cDNA libraries form tumor tissues will not be
responsive to this RFA.  Applications that fail to include the
description of appropriate mileposts will also not be responsive.
 
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 the review
criteria stated below.  As part of the initial merit review, a
process may be used by the initial review group in which applications
will be determined to be competitive or non-competitive based on
their scientific merit relative to other applications received in
response to the RFA.  Applications judged to be competitive will be
discussed and will be assigned a priority score.  All applicants will
receive a summary statement consisting of the reviewer's written
comments. Summary statements for competitive applications will also
contain a summary of the review committee's discussion.  The second
level of review will be provided by the National Cancer Advisory
Board.
 
Review criteria for RFAs are essentially the same as those for
unsolicited research grant applications and include the following:
 
o  scientific and technical merit of research plans and novelty of
proposed research
 
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research
 
o  qualifications and research experience of the Principal
investigator and staff, particularly but not exclusively, in the area
of the proposed research
 
o  appropriateness of the proposed budget and duration in relation to
the proposed research
 
o  availability of the resources necessary to perform the research
 
The initial review group will also examine the provisions for the
protection of human and animal subjects, the safety of the research
environment, and conformance with the NIH Guidelines for the
Inclusion of Women and Minorities as Subjects in Clinical Research.
 
Additional considerations specific to this RFA include the following:
 
o  the degree to which the technology meets the ultimate objective of
creating representational libraries of full length cDNA clones from
appropriate tissues
 
o  efficiency and cost-effectiveness of the proposed technology.
 
o  the appropriateness of the time-frame and mile posts proposed by
the investigator to evaluate the progress of the technology
development and/or implementation
 
AWARD CRITERIA
 
The anticipated date of award is September 30, 1997.  The following
criteria will be considered in making funding decisions:  the quality
of the proposed project as determined by peer review; the
responsiveness of the proposed project to the goals of this RFA; and
the availability of funds.
 
INQUIRIES
 
Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants are welcome.
 
Direct inquiries regarding programmatic issues to:
 
Jennifer Couch, Ph.D.
Division of Cancer Treatment, Diagnosis and Centers
National Cancer Institute
6130 Executive Boulevard, Room 513, MSC 7388
Bethesda, MD  20892-7388
Telephone:  (301) 496-1591
FAX:  (301) 402-1037
Email:  couchj@dcbdcep.nci.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Ms. Theresa Mercogliano
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 243, MSC 7150
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800, ext. 243
FAX:  (301) 496-8601
Email:  MERCOGLT@GAB.NCI.NIH.GOV
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.394, Cancer Detection and Diagnostic Research.
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 Part 74 and Part 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 recipients to provide a
smoke-free workplace and promote the non-use of all tobacco products.
This is consistent with the PHS mission to protect and advance the
physical and mental health of the American people.  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.
 
.

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