MUTANT MOUSE REGIONAL RESOURCE CENTERS

Release Date:  January 22, 1999

RFA:  RR-99-001 - (Reissued as RFA-RR-09-003)

P.T.

National Center for Research Resources

Letter of Intent Receipt Date:  February 23, 1999
Application Receipt Date:  March 25, 1999

PURPOSE

In response to recommendations of the NIH meeting on "Priority Setting for Mouse
Genomics and Genetics Resources" and to pressures created by the great increase
in the numbers of genetically altered mice used by the biomedical research
community, the National Center for Research Resources (NCRR) invites applications
for cooperative agreements (U42) to support Mutant Mouse Regional Resource
Centers (MMRRCs). These Centers will enhance the availability of, and help to
ensure the quality of, genetically altered mice. The MMRRCs will be coordinated
and linked electronically, and will include a coordinated database characterizing
the animals. Each MMRRC will be capable of maintaining and providing animals,
cryopreserving, storing and reconstituting embryos, and of supporting these
activities with the necessary administrative and quality control infrastructure.
Because of their regional nature, responsiveness to specific needs, and
interrelatedness, these Centers will help ensure the continued supply of
characterized mutant mice in an efficient and cost effective manner.

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), MUTANT
MOUSE REGIONAL RESOURCE CENTERS, is related to the priority areas of immunology,
reproductive biology, atherosclerosis, carcinogenesis, and infectious diseases.
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 202-512-1800).

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. Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program will be an
"Animal (Mammalian and Nonmammalian) Model, and Animal and Biological Materials
Resource Cooperative Agreement" (U42), an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NCRR scientific and/or
programmatic involvement with the awardees is anticipated during the performance
of the activity. Under the cooperative agreement, the NCRR's purpose is to
support and/or stimulate the recipient's activity by involvement in, and
otherwise working jointly with the award recipient in a partnership role, but it
is not to assume direction, primary responsibility, or a dominant role in the
activity. Details of the responsibilities, relationships and governance of the
activities to be funded under cooperative agreements are discussed later in this
document.

The NCRR anticipates two or three cooperative awards for MMRRCs with budgets that
may not exceed $750,000 each in direct costs in the first year. In addition, it
is anticipated that one award will be made for an Informatics Coordinating Center
(ICC) with a budget that may not exceed $450,000 in direct costs in the first
year.

FUNDS AVAILABLE

The NCRR anticipates making awards for two or three  MMRRCs and one ICC for
project periods of up to five years.  Approximately $3.0 million total costs is
expected to be set aside for funding these activities in the initial year. The
number of awards and the level of support will depend upon receipt of a
sufficient number of applications of high scientific merit. Although this program
is provided for in the financial plans of the NCRR, awards pursuant to this RFA
are contingent upon the availability of funds for this purpose in fiscal year
1999. The anticipated award date is September 30,1999. At the present time, the
NCRR has not determined whether or how this solicitation will be continued beyond
the present RFA.

RESEARCH OBJECTIVES

Background

Advances in the technologies that allow investigators to create transgenic and
targeted mutant mice, which have proven to be extremely powerful biomedical
research tools, have led to an explosive expansion in the use of these
genetically altered animal research models. Large numbers of new mutant mouse
strains are being developed and characterized by investigators from around the
world. These animal models are often made available to other investigators for
collaborative or independent biomedical research uses, but often the demands for
distribution and maintenance of mice are beyond the physical and/or financial
resources of the initial investigator. This may impose undesirable limits on the
scientific exploitation of potentially valuable animal models. In addition,
unique mouse strains may become unavailable or disappear.

Objectives and Scope

In response to the critical nationwide need for making mutant mice available to
the biomedical research community, the NCRR will establish a cooperative network
of MMRRCs. The MMRRCs must have three basic characteristics. First, each MMRRC
must have research components to generate new information that is relevant to the
resource. Second, each MMRRC must serve the needs of investigators in a variety
of research areas where work is sponsored by NIH categorical Institutes. If the
mouse user community targeted is very narrow scientifically or limited to the
applicant institution, support for the resource should be sought from the
appropriate NIH categorical Institute. Third, each MMRRC must be willing to make
mice available to investigators on a local, regional, and national basis. It is
expected that some of the costs specifically associated with the establishment,
improvement, or expansion of supply and long-term mouse resource maintenance
should be recovered from users through a charge schedule acceptable to the NIH.
The MMRRCs will be responsible for:

o  Support for the establishment and maintenance of animal facilities, both
barrier and traditional, for the husbandry of various hybrid and inbred strains
and for genetically selected or altered lines of mice;

o  Cryopreservation capabilities, storage facilities, and expertise for the
reconstitution of cryopreserved embryos and gametes;

o  Phenotypic characterization of induced mutants with regard to development,
function and pathology, including surveillance for infectious and environmental
factors in animals and in germplasm;

o  Genetic quality control. Facilities and expertise to analyze the genetic
integrity of stocks being maintained, imported and exported must exist on site;

o  Maintenance of a local electronic database for live animals and for
cryopreserved germplasm.  The local database must be connected through an
integrated network with all of the other institutional MMRRCs and with the ICC;

o  An administrative structure responsible for directing all of the activities
at the MMRRC and for cooperative interactions with other institutional MMRRCs and
with the ICC.

The Informatics Coordinating Center (ICC) will be responsible for designing and
developing the necessary software, installing an electronic network linking the
MMRRCs, and maintaining the database.  The ICC database should be updated
continuously and must include the live mouse and cryopreserved germplasm
inventory at each MMRRC.  The coordinated management of these inventories in a
cost and resource efficient manner is the prime objective of the ICC.

SPECIAL REQUIREMENTS

The cooperative agreements (U42s) will require cooperation between the NCRR
representative (NCRR Program Administrator) and the Principal Investigators (PIs)
of the individual projects in order to assure smooth interactions among
cooperating organizations.  The NCRR Program Administrator will assist in
coordinating the activities of the awardees and in facilitating exchange of
information.

TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the U42 award
statement, and will be provided to the PI and the awardee institutional official
at the time of award.

These special Terms of Award are in addition to, and not in lieu of, otherwise
applicable OMB administrative guidelines, HHS Grant Administration Regulations
at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration
policy statements.  [Part 92 applies when state and local governments are
eligible to apply as a "domestic organization."]

The administrative and funding instrument to be used for this program will be an
"Animal (Mammalian and Nonmammalian) Model, and Animal and Biological Materials
Resource Cooperative Agreement" (U42), an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NCRR scientific and/or
programmatic involvement with the awardees is anticipated during the performance
of the activity. Under the cooperative agreement, the NCRR's purpose is to
support and/or stimulate the recipient's activity by involvement in, and
otherwise working jointly with the award recipient in a partnership role, but it
is not to assume direction, primary responsibility, or a dominant role in the
activity. Details of the responsibilities, relationships and governance of the
activities to be funded under cooperative agreements are discussed later in this
document.

1. COLLABORATIVE RESPONSIBILITIES

Coordinating Committee(CC)

The NCRR Program Administrator and awardees are responsible for forming a CC as
defined below.  The CC is responsible for reviewing the plans for development of
the MMRRCs proposed in the individual applications of awardees.  They will
develop uniform procedures for quality control in mouse husbandry and in the
maintenance of animal facilities, shipping and receiving animals and germplasm,
cryopreservation and reconstitution of embryos and gametes, phenotypic
characterization, gametic quality control, maintenance of a local electronic
database, and administrative direction and reporting procedures.  The CC will
also review and approve the operating procedures proposed by individual awardee
organizations in order to ensure that they are compatible with the overall goals
of the RFA.  The CC is also responsible for selecting members and coordinating
the activities of the MMRRC Advisory Panel (AP) as described below.

The CC will initially consist of the Principal Investigator of each MMRRC and the
ICC with the NCRR Program Administrator. Additional members can be added by
action of the CC.  The structure of the CC should be established at the first
meeting as noted below.  The Chair of the CC will be responsible for coordinating
the Committee activities, for preparing meeting agendas, and for scheduling and
chairing meetings.  The NCRR Program Administrator attends and participates in
all meetings of the CC and should be informed of any major interactions.  The CC
must prepare an annual progress report which will include individual reports from
each awardee.  Each awardee is responsible for timely preparation of this report.

At its initial meeting, the Committee will elect a chairperson (who may not be
the NCRR Program Administrator). The CC will determine whether additional CC
representation is required. Depending on availability of appropriate expertise,
the MMRRCAP described below could be constituted as a sub-committee of the CC.

The CC will meet three times in the first year to map strategies, to develop
operating procedures and to evaluate progress.  The initial meeting will be held
as soon as possible after funding. Two additional meetings will be held during
the first year of operation and there will be at least two meetings per year
thereafter. Meetings may be held at any of the participating organizations or at
another convenient location. These meetings are aimed at coordinating the
activities of the participating laboratories, establishing new policies and
priorities, and reviewing progress.  The NCRR Program Administrator will
participate in the discussions at these meetings.

The NCRR Program Administrator, as a member of the CC, will assure that operating
policies are acceptable to the NCRR. An arbitration system, as detailed below,
will be available to resolve disagreements between awardees and NCRR staff.

Mutant Mouse Regional Resource Center Advisory Panel (MMRCAP)

The MMRRCAP is responsible for reviewing and approving requests from
investigators both to have mutant strains accepted and to decide which individual
MMRRC is the most appropriate site.  The decisions as to whether to accept live
animals or cryopreserved germplasm and whether to maintain live animals or only
cryopreserved germplasm will also be determined by the MMRRCAP.  The composition
of the MMRRCAP will be determined by the CC.  Members must have appropriate
expertise in molecular genetics which might include clinicians, laboratory
researchers, statisticians or other experts that the CC determines are needed. 
The NCRR Program Administrator is a member (but not the Chairperson)of the
MMRRCAP. Members of the CC may also serve on the MMRRCAP but may not be in the
majority.

2. AWARDEE RIGHTS AND RESPONSIBILITIES

o  Awardees will have primary and lead responsibilities for the project as a
whole, including selection and maintenance of mutant mouse strains, mouse
husbandry, gamete and embryo cryopreservation and revitalization, microbiological
and genetic monitoring, data quality control and reporting to the ICC, research
to enhance the resource, preparation of publications, as well as collaboration
with the other awardees with assistance from the NCRR Program Administrator.

o  Awardees must comply with the operating policies and procedures developed by
the CC.

o  The ICC will serve as the central repository and distribution center for
electronic data on all strains of mutant mice maintained in the MMRRCs. Data on
the numbers and locations of live mice, including their ages and sex, plus the
numbers and locations of cryopreserved embryos and gametes must be submitted
electronically by the MMRRCs to the ICC in a timely manner using procedures and
computer software developed by the ICC. An electronic inventory of the mouse
resources will be maintained and constantly updated by the ICC. The ICC will
design and maintain a public web site to advertise the availability of mutant
mice and to indicate the procedures for requesting these resources.  All requests
from the research community for live mice and cryopreserved material will be
directed to the ICC, which will be responsible for authorizing the distribution
from the appropriate MMRRC. The ICC will follow the policy guidelines developed
by the CC and by the MMRRCAP. Upon request, the ICC will report to the CC or
MMRRCAP on the details of policy implementation, and will aid these groups in
their decision making.

o  Awardees will retain custody of, and have primary rights to, the data
developed under these awards, subject to Government rights of access consistent
with current HHS, PHS, and NIH policies.  Investigators conducting biomedical
research frequently develop unique research resources.  The policy of the PHS is
to make available to the public the results and accomplishments of the activities
that it funds.  All awardees must adhere to PHS policy for the distribution of
unique research resources produced with PHS funding that was published in NIH
Guide for Grants and Contracts (NIH Guide, Vol. 25, No. 23, July 12, 1996), and
is available at the following Internet address:
https://grants.nih.gov/grants/guide/notice-files/not96-187.html.

o  Effective conduct of the MMRRC goals will require considerable electronic
communication of data and other information among the MMRRC and ICC participants. 
Awardees are responsible for assuring that the activities supported under the
cooperative agreement will not be adversely affected by Year 2000 problems as
detailed in "Notice Regarding the Year 2000 Computer Problem" that was published
in the NIH Guide for Grants and Contracts, April 3, 1998, and is available at the
following Internet address: 
https://grants.nih.gov/grants/guide/notice-files/not98-046.html

3. NCRR PROGRAM ADMINISTRATOR RESPONSIBILITIES

o  The NCRR Program Administrator will coordinate and facilitate the programs
supported by these cooperative agreements, will attend and participate as a
voting member in all meetings of the CC and MMRRCAP, and will provide liaison
between them and the NCRR.

o  The NCRR Program Administrator will ensure that there is effective
communication between the MMRRCs and the ICC.

o  The NCRR Program Administrator will assist the CC in developing and drafting
operating policies and procedures for dealing with recurring situations that
require coordinated action, e.g. standardized cryopreservation techniques,
genetic and microbiological monitoring.

o  The NCRR Program Administrator may review the operations of individual U42
grants for compliance with the operating policies developed by the CC, and may
recommend withholding of support, suspension, or termination of an award for lack
of progress or failure to adhere to policies established by the CC.

4. ARBITRATION PROCEDURES

An arbitration panel of external consultants will be created as needed to resolve
any irreconcilable differences of opinion related to scientific/programmatic
matters between the NCRR Program Administrator and the CC with respect to
implementation of a proposed operating policy.  The panel will include one member
selected by the CC, one member selected by the NCRR, and a third member chosen
by the other two members of the arbitration panel.  These special arbitration
procedures in no way affect the awardee's right to appeal an adverse
determination in accordance with PHS regulations at 42 CFR Part 50, subpart D and
HHS regulations at 45 CFR Part 16.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 23, 1999, 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
this RFA.  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 will allow NCRR staff to estimate the potential review workload and
avoid conflict of interest in the review. The letter of intent is to be sent to:

Neal B. West, Ph.D.
Comparative Medicine area
National Center for Research Resources
6705 Rockledge Drive, Room 6030
Bethesda, MD  20892-7965
Telephone:  (301) 435-0744
FAX:  (301) 480-3819

APPLICATION PROCEDURES

To promote the development of a collaborative program among the award recipients,
a number of issues need to be addressed in the applications. Applicants must
include their specific plans for responding to the "Terms and Conditions of
Award" section. Applicants should state their willingness to collaborate and
share data freely with the other MMRRCs and with the ICC, to serve on the CC and
to be bound by its decisions, and to be able and willing to share data and
communicate with each other and with the NCRR in an internet environment.
Applicants should also describe how they will comply with the decisions of the
CC, and how they will fulfill the responsibility of the MMRRC components to work
together cooperatively.

Applicants should detail the specialized or unique facilities, fundamental
infrastructure, research and mouse husbandry expertise, and core resources and
services that are available to support the planned MMRRC, and should propose any
additional equipment, specialized caging, and personnel requirements needed to
participate in the cooperative group. If facilities at more than one institution
are required, applicants should thoroughly describe them and obtain the
appropriate assurances. Applicants for the ICC should describe the personnel and
the computer hardware and software available, and should propose additional needs
related to the proposed cooperative group activities. The roles and expertise of
all key personnel, collaborators, and consultants who are associated with the
application should be well documented.

Each applicant should describe their plans for interfacing with the CC and
MMRRCAP and should propose their views on how the CC and MMRRCAP activities
should be carried out in the context of the Collaborative Responsibilities
described above. Applicants should submit budget requests that include travel to
required CC meetings and/or telephone conferences. The MMRRCAP will meet with the
CC at least once yearly and each MMRRC and the CC should include travel funds for
one MMRRCAP member in their budget requests.

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 and 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: [email protected].
Application kits are also available at:
https://grants.nih.gov/grants/funding/funding.htm and from the program administrator
listed under INQUIRIES.

The RFA label available in the PHS 398 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:

CENTER FOR SCIENTIFIC REVIEW
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:

Neal B. West, Ph.D.
Comparative Medicine area
National Center for Research Resources
6705 Rockledge Drive, Room 6030
Bethesda, MD  20892-7965
BETHESDA, MD  20817 (for express/courier service)

Applications must be received by March 25, 1999.  If an application is received
after that date, it will be returned to the applicant without review.  The Center
for Scientific Review (CSR) 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 CSR 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 CSR and
responsiveness by the NCRR.  Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.  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 NCRR in
accordance with the review criteria stated below.

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 the top half of the applications under
review, will be discussed, assigned a priority score, and receive a second level
by the National Research Resources Advisory Council.

Review Criteria

Applicants are encouraged to submit and describe their own ideas about how to
meet the Objectives and Scope described above for the cooperative network of
MMRRCs. The review group will assess the scientific merit of the applications and
related factors, including:

Significance
Does this resource address an important problem?  If the aims of the application
are achieved, how will scientific knowledge be advanced?  What will be the effect
of the resource-related studies on the concepts or methods that drive this field?

Approach
Are the conceptual framework, design, methods, and analyses adequately developed,
well-integrated, and appropriate to the aims of the project?  Does the applicant
acknowledge potential problem areas and consider alternative tactics?

Innovation
Does the project employ novel concepts, approaches or methods?  Is the project
original and innovative?  Does the project challenge existing paradigms or
develop new methodologies or technologies?  Will the approaches proposed advance
the field of mouse resource development?

Investigators
Are the investigators appropriately trained and well suited to carry out this
work?  Is the work proposed appropriate to the experience level of the Principal
Investigator and other researchers?

Environment
Are the facilities for mouse maintenance and experimentation appropriate to
support the endeavor?  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

The Informatics Coordinating Center will be supported by a separate U42 grant
that may or may not be located at a site that has animal facilities.  The review
criteria described above will still be applied with the exception of the
requirement for mouse facilities under Environment.

The initial review group will also examine the provisions for the protection of
animal subjects and the safety of the research environment.

AWARD CRITERIA

Applications recommended by the National Research Resources Advisory Council will
be considered for award based upon scientific merit as determined by peer review,
availability of funds, and programmatic priorities including the geographical
distribution of the applicants.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.  An Applicant
Information Meeting (AIM) to assist applicants unfamiliar with the requirements
for "Animal (Mammalian and Nonmammalian) Model, and Animal and Biological
Materials Resource Cooperative Agreement" (U42) applications and to clarify any
issues or questions from potential applicants will be held at 1 P.M. on February
23, 1999 in Bethesda, MD.  For additional information regarding the AIM, call
(301) 435-0744.  A summary of the presentations and issues discussed will be
provided upon request for those unable to attend.

Direct inquiries regarding programmatic issues to:

Neal B. West, Ph.D.
Comparative Medicine area
National Center for Research Resources
6705 Rockledge Drive, Room 6030
Bethesda, MD  20892-7965
Telephone:  (301) 435-0744
FAX:  (301) 480-3819
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Joellen M. Harper
Office of Grants Management
National Center for Research Resources
One Rockledge Centre, Room 6086
Bethesda, MD  20892-7965
Telephone: (301) 435-0844
FAX:  (301) 480-3777
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.306.  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 promote the non-use of tobacco products.  In addition, Public
Law 103-277, 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

Department of Health and Human Services

National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892