Full Text HL-95-014

GENETIC MAP AND LARGE INSERT LIBRARY FOR THE RAT GENOME

NIH GUIDE, Volume 23, Number 43, December 9, 1994

RFA:  HL-95-014

P.T. 34

Keywords: 
  Genetics 
  0755044 


National Heart, Lung and Blood Institute
National Center for Human Genome Research
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 Center for Research Resources
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

Letter of Intent Receipt Date:  February 15, 1995
Application Receipt Date:  March 15, 1995

PURPOSE

The purpose of this Request for Application (RFA) is to solicit
applications to construct a genetic map of the rat genome with a
resolution of 0.43 cM or better and a large-insert DNA clone library
of rat genomic DNA.

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), Genetic Map and Large Insert Library for the
Rat Genome, 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 "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 for-profit and non-profit
organizations, public and private, such as universities, colleges,
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.

Collaborations and consortia are encouraged.  In such collaborations,
the respective contributions should be well-integrated into the
design of the application to encourage cross-fertilization of ideas
and rapid application of the research to practical purposes.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research grant (R01) mechanism.  The total project period for
applications submitted in response to the present RFA may not exceed
five years.  The anticipated award date is September 30, 1995.  This
RFA is a one-time solicitation.

This RFA is an initiative of the Institutes and Centers listed above.
However, the awards will be made by the National Heart, Lung, and
Blood Institute (NHLBI) and managed through the NHLBI with the
collaboration of the participating Institutes and Centers.

FUNDS AVAILABLE

A maximum of about $11.06 million (including direct and indirect
costs) over a five year period will be awarded.  Approximately $3.2
million may be available for the first year, $2.4 million for the
second year, $1.82 million for the third year, $1.82 million for the
fourth year, and $1.82 million for the fifth year.  Funding is
subject to the availability of funds.  It is anticipated that one to
two awards will be made.  Applications for building either the
genetic map or the large insert clone library alone will be accepted,
as well as those proposing to accomplish both aims of this RFA.

RESEARCH OBJECTIVES

Background

For many years, the rat has been an important experimental model for
studying human diseases such as hypertension, cancer, behavioral
disorders, diabetes, drug abuse, alcoholism, cranio-facial and dental
disorders, and obesity, among others.  The rat offers many advantages
in this regard because of the existing body of knowledge about
physiological mechanisms, the ease of breeding, and the ability to
generate inbred congenic rat strains.  Because of its large size in
comparison with the mouse, the rat is widely used in studies of
anatomy, physiology and pharmacology of the chemical senses and more
generally, of intricate neuronal pathways in the brain.

The usefulness of the rat as a model system is hampered, however, by
the lack of high-resolution genetic and physical maps of the rat
genome.  A number of groups working with the rat as a model system
have constructed useful genetic maps, but only in genomic regions of
interest.  Investigators attempting to locate particular genes in an
unmapped region must construct detailed maps, thus slowing the
progress of their research.  Such extensive individual mapping
efforts would no longer be required if a high resolution genetic map
were available.  The technology to construct such maps has been
developed through efforts that have developed 5,000 marker genetic
maps of the human and mouse genomes respectively.  This technology
can now be applied in a cost-effective and efficient way to construct
maps of the genomes of other mammals.

Similar progress has also been made in the technology for building
another genomic resource that is useful in gene analysis, a large
insert clone library.  A number of vectors have been developed for
making libraries of large DNA fragments.  Additionally, there is
considerable information about the depth of coverage needed to
maximize the usefulness of a clone library and the best ways to
format it for wide usage.

The present initiative, to build a genetic map and a large-insert
clone library for the rat genome, is intended to take advantage of
recent technological advances and experience in mapping and library
construction in order to begin constructing mapping resources of use
for studies involving the rat.

Objectives and Scope

The first objective of this RFA is to solicit applications for
research projects that will use state-of-the-art methods, and will
develop any necessary new technologies, to construct a genetic map of
the rat genome consisting of 6,000 easy-to-use polymorphic markers,
and to do so rapidly, efficiently and at low cost.  Applications are
also being sought to construct a high quality, large-insert clone
library of the rat genome that can be generally used by many
investigators as a physical resource for obtaining DNA in any region
of interest.  Applications submitted in response to this RFA to
accomplish either one or both of these goals will be
investigator-initiated and should be forward-thinking, proposing a
project design that will rapidly incorporate new approaches to map
and library construction.  In developing the research strategy,
applicants should consider and address the following:

Construction of the Genetic Map

The rat strains to be used for constructing the map.  As this RFA is
an interdisciplinary effort involving several of the Institutes and
Centers of the NIH, rat strains that will be most useful to the
widest community of researchers should be selected.  A clear
justification for selection of the strains and how they will be used
must be presented.  After the map has been constructed, applicants
may wish to consider genotyping the one available battery of
recombinant inbred rats (J. Kunes and J. Zicha, Physiol Res
42:225-233, 1993) with a subset of markers at intervals of 5 cM or
less;

The strategy for map construction.  The completed map should consist
of at least 6,000 polymorphic markers displaying a high degree of
variation among strains that are commonly used in biomedical
research,  yielding a map of 0.43 cM or less average resolution.  The
research plan should include a rationale for the type of marker that
will be used, the number of markers that will be mapped at high odds
and a realistic and well-justified estimate of the unit cost for
making and mapping a genetic marker in the rat.  Although the human
and mouse genetic mapping efforts have been highly successful in
making maps of microsatellite repeats, applications for this RFA are
not limited microsatellites.  Other types of markers are currently
being developed and a plan to build a useful map of the rat genome
using such markers would be appropriate as long as completion of a
high quality, widely useful genetic map of the rat that meets the
criteria described above is a reasonable expectation during the five-
year period of the proposed grant and the technology for assaying the
markers is or can be economically made available to the rat research
community.  The current status of the rat genome map should be
discussed and the possibility of integrating existing markers
addressed.  The overall mapping plan must include a discussion of
expected, quantifiable milestones that can be used to assess yearly
progress, e.g., the number of markers that can be generated and
mapped each year;

Data management.  Projects of this magnitude require informatics
support for management of the data and map construction.  A thorough
description of the informatics plan for the project will be critical
in evaluation of the proposal.

Construction of a Large Insert Library

The strategy for construction of a large insert clone library.
Selection of the vector and source of DNA with which this library
will be built should be justified in terms of its usefulness to
research employing the rat model.  Issues of library depth,
representation, and format should also be discussed.  Prior
experience in building such libraries and the rationale for the
strategy selected should be thoroughly discussed.

Data and Resource Sharing

Plans for the availability and distribution of the data and resources
developed through the grant.  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 and mouse 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" that address the special
needs of genome research.  These 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.

Post-award Management

During the course of the grant period, mapping and cloning
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 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, incorporates new technological advances
and makes sufficient progress, scientific and programmatic visits to
the grantee will be conducted at a frequency to be negotiated with
the awardee.  In addition, Applications should include travel funds
for the P.I. and the other investigators in the grant to meet yearly
with NIH staff in the Washington area.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 15, 1995, 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 per year
must have contacted one of the NIH staff listed under INQUIRIES
before submitting the application or it will be returned to the
applicant.

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 IC 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 Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 557
Bethesda, MD  20892
Telephone:  (301) 594-7478
FAX:  (301) 594-7407

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/710-0267.

The RFA label available in the PHS 398 (rev. 9/91) 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 2a 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
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to Dr. Scheirer at the address listed under
INQUIRIES.

Applications must be received by March 15, 1995.  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 announcement 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.

REVIEW CONSIDERATIONS

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 NCHGR.  As part of the initial merit review, a process (triage)
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 and Centers
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 map 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.

AWARD CRITERIA

The anticipated date of award is September 30, 1995.  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 needs of the participating Institutes and Centers
as regards their interest in the rat as a model organism;

o  Nature and extent of the plans for sharing distributing data and
resources in a timely manner;

o  Availability of funds.

INQUIRIES

Written and telephone 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.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Federal Building, Room 4C10
7550 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-1613
FAX:  (301)402-2044
Email:  SM60d@nih.gov

Jane L. Peterson, Ph.D.
Mammalian Genomics Branch
National Center for Human Genome Research
Building 38A, Room 610, MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email:  jane_peterson@occhost.nlm.nih.gov

Grace L. Shen, Ph.D,
Hematology and Oncology for Extramural Program
National Cancer Institute
Executive Plaza North, Room 501
6130 Executive Boulevard, MSC 7381
Rockville, MD  20892-8531
Telephone:  (301) 496-7815
FAX:  (301) 496-8656
Email:  sheng@dcbdcep.nci.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:  lv5@cu.nih.gov

Steven Kaminsky, Ph.D.
Developmental Biology Genetics and Teratology Branch
National Institute of Child Health and Human Development
Building 61E, Room 4B01D, MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 496-5541
FAX:  (301) 402-4083
Email:  tky@cu.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 6401
Bethesda, MD  20892-6401
Telephone:  (301) 594-7565
FAX:  (301) 594-9011
Email:  joanh@dvsgate.niddk.nih.gov

Louise Ramm, Ph.D.
Deputy Director
National Center for Research Resources
Building 12A, Room 4009, MSC 5662
Bethesda, MD  20892-5662
Telephone:  (301) 496-6023 or (301) 594-7906
FAX:  (301) 402-0006
Email:  louiser@ep.ncrr.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:  tlee@aoada.ssw.dhhs.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) 443-4223
FAX:  (301) 594-0673
Email:  rkarp@willco.niaaa.nih.gov

Ralph F. Naunton, M.D.
Division of Human Communication
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Suite 400C
6120 Executive Boulevard, MSC 7180
Rockville, MD  20892-7180
Telephone:  (301) 496-1804
FAX:  (301) 402-6251
Email:  nauntonr%nidcd-eps%nih@fedtcp.ninds.nih.gov

Norman S. Braveman, Ph.D.
Assistant Director for Program Development
National Institute of Dental Research
Building 45, Room 4AN24B, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-2089
FAX:  (301) 480-8381
Email:  bravemann@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

Direct inquiries regarding fiscal matters to:

Mr. Thomas G. Turley
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A12B
Bethesda, MD  20892
Telephone:  (301) 594-7434
FAX:  (301) 594-7492

AUTHORITY AND REGULATIONS

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 Public Health Service (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.

.

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