Full Text HL-97-004
NIH Guide, Volume 26, Number 5, February 14, 1997
RFA: HL-97-004
P.T. 34

  Behavioral/Social Studies/Service 

National Heart, Lung and Blood Institute
National Human Genome Research Institute
National Cancer Institute
National Institute of Mental Health
National Institute of Child Health and Human Development
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute on Drug Abuse
National Institute on Alcohol Abuse and Alcoholism
National Institute on Deafness and Other Communication Disorders
National Institute of Dental Research
National Institute of Environmental Health Sciences
National Institute of Neurological Disorders and Stroke
Letter of Intent Receipt Date:  March 28, 1997
Application Receipt Date:  April 23, 1997
The purpose of this Request for Applications (RFA) is to expand the
Rat Genome Project by soliciting applications for research projects
to accomplish three objectives:  1) arraying and distributing
existing rat cDNA libraries, 2) developing Expressed Sequence Tags
(ESTs) from those libraries, and 3) mapping a subset of those ESTs.
The overall goal of this effort is to construct a rat gene catalog
and an EST map that will facilitate the mapping of genes in the rat
and increase the value of the rat as a biomedical research model.
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,
Rat Gene Catalog And Expressed Sequence Tag (EST) Map, is related to
many priority areas.  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).
Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
companies, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal Government.
Applications from social/ethnic minority individuals, women, and
persons with disabilities are encouraged.  Applications from foreign
institutions will not be accepted.  However, subcontracts to foreign
institutions are allowable, with sufficient justification.
This RFA will use the National Institutes of Health (NIH) individual
research project grant (R01) mechanism.  Applications that address
any one or all of the objectives listed above are encouraged.
Because the NIH wishes to retain maximum flexibility in organizing
the best possible overall program, it is possible that, in the case
of an application proposing to accomplish more than one objective,
only one component would be funded.  Therefore, applicants who
propose to address more than one of the objectives should organize
the application in individual sections, each of which describes the
approach proposed for a single objective; individual budgets should
also be proposed for each objective.  A summary budget for the entire
application must also be included and the cover page should state the
total funds requested (direct and total costs).  All investigators
funded under this initiative will be expected to work together
cooperatively so that resources developed will be of maximum
usefulness to the community.
This RFA is an initiative of the Institutes listed above. However,
the awards will be made by the National Heart, Lung, and Blood
Institute (NHLBI) and will be managed by the NHLBI with the National
Human Genome Research Institute (NHGRI) and the other participating
$3.5 million (including direct and indirect costs) is available for
year -01.  Anticipated funds available for year -02 are between $1.2
and $2.5 million.  An exact dollar figure will be provide to those
applicants that submit a letter of intent.  It is anticipated that
three to six awards may be made.  Proposed funding levels are subject
to change due to budgetary, administrative, and/or scientific
The rat is an important experimental model for studying many human
diseases, such as hypertension, cancer, behavioral disorders,
diabetes, drug abuse, alcoholism, cranio-facial and dental disorders,
and obesity.  As a result, the existing body of knowledge about
physiological mechanisms in this animal is large and the advantages
include the ease of breeding, and the ability to generate inbred
congenic rat strains.  Because of its large size, the rat is
preferred to the mouse for studies of anatomy, physiology and
pharmacology.  Examples include studies of the chemical senses and of
intricate neuronal pathways in the brain.
In 1995, a consortium of NIH Institutes and Centers funded a four-
year Rat Genome Project, the purpose of which is to construct genomic
resources that will enhance genetic studies of the rat.  The goals of
the Rat Genome Project are 1) to construct a 6,000 marker genetic map
of the rat genome, 2) to produce physical mapping reagents that will
be useful for both isolating rat genes and for constructing a
physical map of the rat genome, and 3) to construct cDNA libraries
from different rat tissues.  This project has made significant
progress to date.  An early-stage genetic map has been constructed
(the first 1,250 markers and a framework map will be released by the
Whitehead Institute Genome Science and Technology Center in March,
1997), rat YAC and PAC libraries have been constructed, and twelve
normalized cDNA libraries are nearing completion.  In addition to
these resources, a radiation hybrid panel for the rat has been
prepared by a European consortium and is also available commercially.
While the genetic and physical map resources currently being
constructed will be extremely useful to investigators using the rat
as a model to study human diseases, isolating rat genes of relevance
to a particular disease is still not routine and investigators
pursuing such efforts would benefit from additional resources.  As
there are no current plans to sequence the entire rat genome,
constructing an index of a significant number of genes, and
determining the map positions of as many as possible, would greatly
increase the usefulness of the rat as a model system for studying
human disease, health and behavior.  A useful approach to
constructing such a gene catalog and map has been demonstrated for
the human genome.  Schuler et al., (Science 274:540 (1996)) recently
used a catalog of human genes to construct a map of more than 16,000
of them.  These genes were identified using short sequences called
Expressed Sequence Tags (ESTs) from cDNA clones.  The present RFA
seeks to support a similar project in the rat.  Not only will
sequencing rat ESTs lead to the identification of a significant
number of new genes from this organism, but because of the synteny
between the rat genome and both the human and the mouse genomes (a
mouse EST project has also recently begun), comparisons of the gene
maps from all three organisms will add to the usefulness of the
information on each.
Objectives and Scope
There are three objectives of this RFA.  The first is to array and
distribute, rapidly, efficiently and at low cost, the twelve
normalized cDNA libraries that have been produced by the Rat Genome
Project.  The second is to produce ESTs from rat cDNA, and the third
is to construct a gene EST map, including a framework of existing
genetic markers.
Arraying and distribution of cDNA libraries
Twelve normalized rat cDNA libraries are being prepared by Dr. Bento
Soares at Columbia University.  In order to increase the usefulness
of these libraries to the research community and to readily provide
the cDNAs to EST sequencing and mapping projects, the cDNA clones
need to be arrayed and distributed.  Applications are sought to array
the cDNA clones and to establish a distribution mechanism to provide
unrestricted access to both individual clones and to the arrayed
libraries.  Applicants may contact Dr. Soares (e-mail:
cuc@cuccfa.ccc.columbia.edu or (212)960-2313) regarding access to the
existing libraries.
Rat EST Sequencing
The strategy of sequencing short sequences from cDNAs in order to
identify human genes was first demonstrated by Venter and his
colleagues (Adams et al., Science 252:1651 (1991)).  A large
collection of human ESTs has now been deposited in public databases.
cDNAs in current libraries are not full-length, but as a rule
represent only a portion of the gene from which they were derived.
As a result, multiple clones in a library can be derived from the
same gene.  Therefore, the sequence fragments in the existing EST
collection have to be analyzed to identify clusters or distinct
genes.  The product of this effort is the unique set or human gene
catalog (Schuler et al., Science 274:540 (1996)).  Sequence from the
3' end of each cDNA to be mapped was converted to a gene-specific
sequenced tagged site (STSs) for mapping.  As EST projects in other
organisms have begun, there has been discussion about the value of
using a combination of sequencing strategies, i.e., sequencing more
5' than 3' ends of clones or sequencing complete clone inserts, in
order to most efficiently identify as many genes as possible.  To
create a gene catalog for the rat, applicants are free to propose the
sequencing of 5' ends of clones only, 3' ends of clones only, both 5'
and 3' ends of clones, full-length inserts or any combination of
these elements of clones from the rat cDNA libraries.  Rationale
should be offered for the choice of strategy.  Applicants are
encouraged to propose the most efficient and cost-effective strategy
that will contribute the largest number of genes to the rat gene
Rat EST Map
As stated above, a rat genetic map is currently under construction at
the Whitehead Institute GESTEC Center (http:\\www-genome.wi.mit.edu).
A rat YAC library has been constructed and is available from Research
Genetics, Inc. (http:\\www.resgen.com), a rat PAC library is
available from Pieter De Jong at Roswell Park Cancer Institute (e-
mail: pieter@dejong.med.buffalo.edu or (716) 845-8449). Additionally,
DNA from cells in a radiation hybrid panel will shortly be available
from Research Genetics, Inc. Applications are sought for projects
that will use these, or other physical mapping resources, to
construct a gene map of the rat genome.  In order for the map to be
cross-referenced to the emerging genetic map, and to provide markers
in regions of low gene density, it is desirable for applicants to
build the gene map on a framework of rat genetic markers. Efficient,
cost-effective strategies for constructing the most useful physical
map, which need not include mapping all of the ESTs, are sought.
This RFA does not specify the number of ESTs that should be sequenced
or mapped or the strategy for EST/cDNA sequencing. Rather, the
investigator should propose a strategy that will balance the
sequencing and mapping objectives with the funds available to produce
the most useful resource for the community of researchers using the
rat as a model organism. As mentioned above, a proposal may address
one or more than one of the objectives of this RFA, e.g., only
sequencing or both sequencing and mapping.  In each case, the level
of sequencing and/or mapping proposed must be justified in terms of
the usefulness of the resource it will provide for researchers.  Each
objective of this RFA will be considered individually by the NIH,
which will select for funding those applications that, as a group,
will have the greatest potential to yield the best, most efficient
and most cost-effective strategy for accomplishing the aim of each
objective and to work together to meet the overall objectives of the
Rat Genome Program.  In the rapidly advancing field of genomic
research, it is prudent to anticipate that improved technology might
greatly decrease the costs of either sequencing or mapping (or both)
during the course of the effort.  Applicants should address the
impact that changes in technology might have on the throughput and
costs proposed.
Data and Resource Sharing
The sharing of materials and data in a timely manner has been an
essential element in the rapid progress made in construction and use
of the human, mouse and rat genetic maps.  Public Health Service
(PHS) policy requires that investigators make the results and
accomplishments of funded activities publicly available.  The
advisors to the NIH and the DOE genome programs have developed a set
of "NIH-DOE Guidelines for Access to Mapping and Sequencing Data and
Material Resources" (available at
data_release.html) that address the special needs of genome research.
Those guidelines call for material and information from genome
research to be made available within six months of the time the data
or materials are generated; more rapid sharing is encouraged and has
become the norm in the genome community.  Applications submitted in
response to this RFA should include detailed plans for sharing data
and materials generated through the grant.  Where appropriate,
grantees may work with the private sector in making unique resources
available to the larger biomedical research community at a reasonable
cost.  The plans proposed for sharing and data release will be
reviewed for adequacy by NIH staff prior to award of the grant and
the proposed sharing plan will be made a condition of the award.
Investigators may request funds to defray the costs of sharing
materials or submitting data in their application. Such requests must
be adequately justified.
During the course of the grant period, technologies will improve,
genomic technologies will evolve, and the rate of progress and focus
of work supported by the grant(s) may change.  It is expected that
the Principal Investigator(s) will make any necessary adjustment in
scientific direction to accommodate the changing environment.  In
order to ensure that the project(s) remains focused on appropriate
goals, maintains excellent coordination with the other projects
funded under this RFA, incorporates new technological advances and
makes sufficient progress, scientific and programmatic visits to the
grantees will be conducted at a frequency to be negotiated with the
awardees.  In addition, applications should include travel funds for
the P.I. and the other key investigators in the grant to meet
annually with NIH staff in the Washington D.C. area.
Prospective applicants are asked to submit, by March 28, 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.  Any applicant planning to
submit an application for more than $500,000 direct cost in any one
year must contact the NHLBI staff listed under the INQUIRIES section
in order for the application to be accepted by NIH.
Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains allows Institute staff to estimate the potential
review workload and to avoid conflict of interest in the review.
The letter of intent is to be sent to:
James C. Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220 - MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3460
Email:  james_scheirer@nih.gov
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  Applications kits are available at
most institutional offices of sponsored research and may be obtained
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, email:
ASKNIH@odrockm1.od.nih.gov; and from the program administrator listed
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 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:
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application
must also be sent to Dr. James Scheirer, as listed under the LETTER
OF INTENT section.
Applications must be received by April 23, 1997.  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, 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 substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.
Upon receipt, applications will be reviewed for completeness by DRG
and for responsiveness to the RFA by NIH program staff.  Incomplete
applications will be returned to the applicant without further
consideration.  If the application is not responsive to the RFA, NIH
staff will 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.
Those applications that are complete and responsive will be evaluated
in accordance with the criteria stated below for scientific/technical
merit by an appropriate peer review group convened by the NHLBI and
the NHGRI.  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 be assigned a priority score.  All applicants will receive a
summary statement consisting of the reviewer's written comments
essentially unedited.  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 Heart, Lung, and Blood Advisory Council and by the National
Advisory Councils/Boards of the other Institutes involved.
Review criteria will include the following:
o  scientific and technical merit of the research proposed to meet
the objectives of this RFA;
o  the value of the proposed resource to the scientific community;
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  availability of the resources and technology necessary to perform
the research;
o  adequacy of facilities and resources and the level of
institutional commitment;
o  appropriateness of the proposed budget and duration in relation to
the proposed research.
The anticipated date of award is September 30, 1997. Factors that
will be used to make award decisions are as follows:
o  Quality of the proposed project as determined by peer review;
o  Promise of the proposed program to accomplish the goals of this
RFA and address the need of the participating Institutes as regards
their interest in the rat as a model organism;
o  Cost effectiveness of the proposed strategy;
o  Quality of the plans to cooperate with other projects that may be
funded under this RFA;
o  Nature and extent of the plans for sharing and distributing data
and resources in a timely manner;
o  Availability of funds.
Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Stephen C. Mockrin, Ph.D. or Susan E. Old, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7940
Bethesda, MD  20892-7940
Telephone:  (301) 435-0477
FAX:  (301) 480-1336
Email:  sm60d@nih.gov or so40y@nih.gov
Jane L. Peterson, Ph.D.
Large Scale Sequencing
National Human Genome Research Institute
Building 38A, Room 610 - MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email:  petersoj@odder.nchgr.nih.gov
Grace L. Shen, Ph.D,
Hematology and Oncology for Extramural Program
National Cancer Institute
6130 Executive Boulevard, Room 501, MSC 7381
Rockville, MD  20892-7531
Telephone:  (301) 496-7815
FAX:  (301) 496-8656
Email:  gs35r@nih.gov
Ljubisa Vitkovic, Ph.D.
Division of Neuroscience and Behavioral Science
National Institute of Mental Health
5600 Fishers Lane, Room 11C-06
Rockville, MD  20857
Telephone:  (301) 443-5288
FAX:  (301) 443-4822
Email:  vitkovic@helix.nih.gov
Steven L. Klein, Ph.D.
Developmental Biology, Genetics and Teratology Branch National
Institute of Child Health and Human Development 6100 Executive
Boulevard, Room 4B01, (MSC 7510)
Bethesda, MD  20892-7510
Telephone:  (301) 496-5541
FAX:  (301) 402-4083
Email:  kleins@hd01.nichd.nih.gov
Joan T. Harmon, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases National
Institute of Diabetes and Digestive and Kidney Diseases Building 45,
Room 5AN-18G, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8813
FAX:  (301) 480-3503
Email:  joan_harmon@nih.gov
Thomas P. Jacobs, Ph.D.
Division of Stroke, Trauma and Neurodegenerative Disorders National
Institute of Neurological Disorders and Stroke 7750 Wisconsin Avenue,
Room 8A13
Bethesda, MD  20892-9155
Telephone:  (301) 496-4226
FAX:  (301) 480-1080
Email:  tj12g@nih.gov
Theresa Lee, Ph.D.
Division of Basic Research
National Institute on Drug Abuse
5600 Fishers Lane, Room 10A-19
Rockville, MD  20857
Telephone:  (301) 443-6300
FAX:  (301) 594-6043
Email:  tl37h@nih.gov
Robert Karp, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-2239
FAX:  (301) 594-0673
Email:  rkarp@willco.niaaa.nih.gov
Kenneth A. Gruber, Ph.D.
Division of Human Communication
National Institute on Deafness and Other Communication Disorders 6120
Executive Boulevard, Suite 400C, MSC 7180
Rockville, MD  20892-7180
Telephone:  (301) 402-3458
FAX:  (301) 402-6251
Email:  kenneth_gruber@nih.gov
Eleni Kousvelari, Ph.D.
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN 18A
Bethesda, MD  20892-6402
Telephone:  (301) 594-2427
FAX:  (301)480-8318
Email:  kousvelari@de45.nidr.nih.gov
William A. Suk, Ph.D., M.P.H.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-0797
FAX:  (919) 541-2843
Email:  suk@niehs.nih.gov
This program is described in the Catalog of Federal Domestic
Assistance No. 93.837, Heart and Vascular Diseases.  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.  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 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 health of the
American people.

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