COMPARATIVE MOUSE GENOMICS CENTERS CONSORTIUM

Release Date:  December 16, 1999

RFA:  ES-00-005

National Institute of Environmental Health Sciences

Letter of Intent Receipt Date: May 12, 2000
Application Receipt Date: July 20, 2000

PURPOSE

The National Institute of Environmental Health Sciences (NIEHS) 
invites applications for cooperative agreements (U01s) from 
groups of investigators who are capable of, and interested in, 
becoming components of the Comparative Mouse Genomics (CMG) 
Centers Consortium.  The purpose of implementing this 
Consortium is to develop mouse models for studying the 
biological function of genetic variants of DNA repair and cell 
cycle control genes found in the human population.  Mutant 
mice, protocols, assays, assessment criteria, and other 
materials and information generated in projects funded under 
this RFA will be made available to the wider biomedical 
community for further investigation or application.  To 
accomplish this, the NIEHS will select, as components of the 
Consortium, groups of investigators whose scientific and 
technical expertise will enable them to derive the models, 
characterize them thoroughly, and validate them for various 
aspects of basic, clinical or applied research.  The approaches 
used for generating, characterizing, and validating the mice 
will reflect the blend of experience and creativity of the CMG 
Consortium component groups, and will be originated by these 
investigators.  They will contribute to the CMG Consortium 
their collective knowledge of mouse genetics, experimental 
genetic manipulation of mice and phenotypic and genotypic 
analyses of the resulting strains, genomics, animal husbandry, 
mouse and human pathology.

Through formation of the CMG Consortium, the component groups 
will have access to resources, information, technologies, 
ideas, and expertise that are beyond the scope of any single 
research team.  The goals of the CMG Consortium are: 1) to 
choose which models to derive de novo; 2) to choose which mouse 
models to characterize fully for their relevance to 
environmental health; and 3) to define the standards by which 
to validate the models for their relevance to human disease.  

The activities of the CMG Consortium will be coordinated with: 
(1) the National Center for Research Resources (NCRR)-Sponsored 
Mutant Mouse Regional Resource Centers
(See RFA: RR 99-001, 
http://grants.nih.gov/grants/guide/rfa-files/RFA-RR-99-001.html), 
(2) the facilities established in 
response to RFA MH-99-007 AMouse Mutagenesis and Phenotyping: 
Nervous System and Behavior (see 
http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-99-007.html), 
and (3) RFA HD-99-007 AMouse Mutagenesis and 
Phenotyping: Developmental Defects@ (see 
http://grants.nih.gov/grants/guide/rfa-files/RFA-HD-99-007.html 
). The NCRR centers are being developed as regional 
distribution facilities capable of husbandry, cryopreservation, 
phenotypic characterization, genetic quality control, and 
maintenance of a mouse resource database.  Further information 
about NIH initiatives on mouse genomics and genetics resources 
is available at the following Internet site: 
http://www.nih.gov/science/models/mouse.

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), Comparative Mouse 
Genomics Centers Consortium, is related to the priority area of 
environmental health.  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) 
http://odphp.osophs.dhhs.gov/pubs/hp2000.

ELIGIBILITY REQUIREMENTS

Cooperative agreement (U01) 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, eligible 
agencies of the Federal government, and small businesses.  
Applications may represent a single institution, or may involve 
several institutions or organizations.  Applications will not 
be accepted from foreign institutions, however, foreign 
institutions may establish sub-contract arrangements with 
domestic applicant institutions.  Applications from minority 
individuals, women, and persons with disabilities as principal 
investigators are encouraged.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this 
program will be a cooperative agreement (U01), an "assistance" 
mechanism (rather than an "acquisition" mechanism), in which 
substantial NIEHS scientific and/or programmatic involvement 
with the awardee is anticipated during performance of the 
activity.  Under the cooperative agreement, the NIEHS purpose 
is to support and/or stimulate the recipient's activity by 
involvement in, and otherwise working jointly with, the award 
recipient in a partner role, but it is not to assume direction, 
prime responsibility, or a dominant role in the activity.  
Details of the responsibilities, relationships and governance 
of the study to be funded under cooperative agreement(s) are 
discussed later in this document under the section "Terms and 
Conditions of Award.@

Grants funded under this program must be interdisciplinary 
efforts bringing together investigators from different 
scientific disciplines.  In order to be funded, each applicant 
must successfully meet the requirements as stated below:

o  Applicants must include expertise in transgenic 
technologies, mouse genetics and pathology, genomics, 
biostatistics, and at least two researchers with scientific 
expertise in the biology of the genes and gene products 
targeted for study (DNA repair and/or cell cycle control 
genes).

o  Applicants must include an administrative core to include: 
an information transfer activity, a Steering Committee liaison 
activity, and a technology transfer activity.

FUNDS AVAILABLE

The NIEHS anticipates making up to five U01 awards for project 
periods of five years.  U01 application budgets may not exceed 
$700,000 direct costs in the first budget period.  Should an 
applicant plan to include subcontracts to other institutions or 
organizations, only the direct costs associated with the 
subcontracts will be used to tally the direct costs that apply 
toward the cap of $700,000.  For further budget information, 
see the "APPLICATION PROCEDURES" section.  The NIEHS intends to 
commit $5 million dollars (Total Costs, including facilities 
and administrative costs) to fund applications in response to 
this RFA.  The number of U01 awards and level of support depend 
upon receipt of a sufficient number of U01 applications of high 
scientific merit.

Although this program is provided for in the financial plans of 
the NIEHS, U01 awards pursuant to this RFA are contingent upon 
the availability of funds for this purpose in fiscal year 2001. 
 The anticipated award date is April 1, 2001. 

It is possible that new applications in other categories of 
genes (i.e., apoptosis and cellular differentiation, signal 
transduction mechanisms, and drug metabolizing enzymes) may be 
supported in future years, depending upon the success and the 
needs of the CMG Consortium, and the availability of funds.
 
RESEARCH OBJECTIVES

Background

In March 1998, the NIH Director convened an External Advisory 
Group on Priority Setting for Mouse Genomics and Genetics 
Resources.  The full report of this meeting can be obtained 
from the NIH web site 
(http://www.nih.gov/welcome/director/reports/mgenome.htm). 
Following some of the recommendations of this group, the NIEHS 
proposes the establishment of Comparative Mouse Genomics  (CMG) 
Centers Consortium to address specifically the functional 
analysis of human genes associated with human-exposure 
diseases. 

The NIEHS Environmental Genome Project (see 
http://www.niehs.nih.gov/envgenom/home.htm) is founded on the 
sound scientific concept that the genetic makeup of an 
individual person is major factor in human disease resulting 
from exposure to environmental agents.  The project long-term 
goal is to characterize specific genetic variations, or 
polymorphisms, that contribute to either resistance or 
susceptibility to environmentally induced diseases.  NIEHS is 
collaborating with other NIH institutes in the discovery of 
single nucleotide polymorphisms in approximately 500 genes that 
might be relevant to understand human diseases resulting from 
exposure to environmental agents.  NIEHS has decided to 
concentrate on studying the biological significance of the 
genetic variants in five categories of genes: DNA repair, cell 
cycle control, drug metabolizing enzymes, apoptosis and 
differentiation, and signal transduction mechanisms responsible 
for the regulation of the other categories of genes.  

To understand the functional significance of human polymorphic 
variants in the environmental responsive genes (ERG), the NIEHS 
will support the development of new research centers, to 
produce novel transgenic and knockout mouse models which will 
mirror specific human ERG polymorphic variants found in the 
general population. 

For the purposes of responding to this RFA, a research group 
will focus its activities on the development of novel models in 
DNA repair and/or Cell Cycle Control genes.

Objectives and Scope

Although many mice have been designed or engineered to ask 
specific mechanistic questions about the functions of single 
genes, the constraints of limited time and funding often do not 
permit an in-depth, comprehensive analysis and characterization 
of their phenotype and genotype. The NIH supports many 
individual projects that involve the derivation or study of 
mice that develop specific diseases.  However, at the present 
time, the NIH does not support a coordinated, collaborative 
effort to produce highly accurate mouse models of 
environmentally induced human diseases, particularly for the 
early design, derivation, characterization, and validation 
phases of model building, and to ensure that the models and the 
data relevant to them are readily available to the research 
community for further investigation or application.

The intent of this initiative is to assemble from U01 grants, a 
cross-disciplinary, multi-institutional Consortium whose 
component teams of investigators will derive or refine mouse 
models of environmentally-relevant human diseases, provide a 
comprehensive analysis of their phenotype and genotype, and 
validate them for their use by the research community for a 
variety of investigations.  The CMG Consortium should improve 
access to information, resources, ideas, expertise, and 
technology beyond the scope of any single group, and should 
impact the entire scientific community.

The CMG centers, working under the umbrella of a consortium, 
will function as centralized facilities for:

o  Comparative alignment of human-mouse sequence analyses.
o  Development of cloning-sequencing-vector construction 
strategies.
o  Production of transgenic and knockout animals and 
maintenance of breeding colonies.
o  Development, characterization, maintenance, and distribution 
of ES cell lines.
o  Identification of mouse lines suitable for tissue-specific 
and inducible mutagenesis.
o  Validation of the Cre-Lox system, and other novel approaches 
for targeted mutagenesis. 
o  Development and distribution of relevant databases and other 
materials.  A plan to make these animals and materials 
available to the scientific community must be included in the 
application.

The transgenic and knockout mice expressing specific genes 
produced by the CMG Consortium might be used by the scientific 
community-at large to study disease sequelae due to specific 
insults, including: exposure to environmental agents, viruses, 
nutritional factors, pharmacological drugs, and other physical 
and chemical stresses.  This comparative genomics strategy of 
using transgenic technologies to study human gene function has 
a high potential to be successful due to the increasingly 
detailed knowledge of functional homologies of proteins encoded 
by mouse and human genes. 

The CMG Consortium, when implemented from the component funded 
U01 grants, will through its Steering Committee: 
o  set the priorities for the models which should be derived,
o  select those which should be comprehensively characterized 
and refined,
o  determine the parameters by which the models will be 
validated (standards for pathology, genotype, phenotype, etc.),
o  identify technological impediments for accurate model 
design,
o  select strategies for implementation or development to 
surmount them,
o  determine when a model is sufficiently characterized and 
validated so that the model itself, and all available 
accompanying data, can be distributed to the research community 
for individual investigator-initiated projects.

To implement this initiative, the NIEHS will select up to five 
multi-disciplinary teams.  Each team will be a self-assembled 
group of collaborating investigators (at one or several sites) 
with specific expertise in transgenic technology development 
and scientific knowledge in DNA repair and/or cell cycle 
control genes.  It is anticipated that an applicant team will 
incorporate an appropriate mix of expertise, including, but not 
limited to: transgenic technologies, mouse genetics and 
genomics, mouse pathology; animal husbandry, and mouse models 
of human disease, computational and structural biology, 
bioinformatics, statistics, and expertise on the cellular and 
molecular biology of the genes and gene products chosen for 
investigation.

SPECIAL REQUIREMENTS FOR THE RFA

I.  Definitions

ARBITRATION PANEL:  A panel that is formed to review any 
scientific or programmatic disagreement (within the scope of 
the U01 award), between U01 awardees and the NIEHS.  The panel 
will be composed of three members: one selected by the
Steering Committee (without NIEHS staff voting), or by an 
individual U01 awardee in the event of an individual 
disagreement; a second member selected by the NIEHS; and, the 
third member selected by the two prior selected members.

AWARDEE:  The institution to which a cooperative agreement 
(U01) is awarded.

COOPERATIVE AGREEMENT (U01):  An "assistance" mechanism (rather 
than an "acquisition" mechanism), in which substantial NIEHS 
scientific and/or programmatic involvement with the awardee is 
anticipated during performance of the activity.  Under the 
cooperative agreement, the NIEHS purpose is to support and/or 
stimulate the recipient's activity by involvement in, and 
otherwise working jointly with, the award recipient in a 
partner role, but it is not to assume direction, prime 
responsibility, or a dominant role in the activity.

CONSORTIUM:  The Comparative Mouse Genomics Centers Consortium, 
which will have as its components the funded U01 grants. 

MOUSE TASK FORCE:  A committee of NIEHS/NIH staff.  The task 
force will meet regularly to review the progress of the 
Consortium, and to recommend to the NIEHS Program Director new 
scientific and technological advances that could enhance the 
goals of the Consortium.  Non-government experts may be added 
to the Task Force to enhance the scientific expertise of the 
group.

NIEHS PROGRAM DIRECTOR:  A scientist administrator of the NIEHS 
extramural staff.  The NIEHS Program Director will provide 
normal stewardship for the U01 grants awarded under this RFA, 
as well as have substantial scientific and programmatic 
involvement to assist, guide, coordinate, and participate in 
the conduct of the Consortium activities.  The NIEHS Program 
Director will evaluate and implement the advice and 
recommendations of the Steering Committee for allocating NIH 
support.

PRINCIPAL INVESTIGATOR (PI):  The investigator who is 
designated by the applicant organization to direct the project 
to be supported by the U01 grant in response to this RFA.  The 
PI will assume responsibility and accountability to the 
applicant organization officials and to the NIEHS for the 
performance and proper conduct of the research supported by the 
U01 in accordance with the terms and conditions that are stated 
in the RFA.  The PI will coordinate the activities of the U01 
with the Consortium, and will be one of two investigators from 
the U01 to serve as a voting member of the Steering Committee.

STEERING COMMITTEE:  This committee will be the main governing 
body of the Consortium.  Its voting members will include the PI 
and an additional senior investigator from each U01, and up to 
three members of the Mouse Task Force.  The Steering Committee 
will meet twice a year.  The initial planning meeting will take 
place in the Research Triangle Park, NC, with subsequent 
meetings at a location that the Steering Committee selects and 
with which the NIEHS concurs.  NIEHS/NIH representation on the 
Steering Committee will never make up a majority of the total 
number.

II.  Special Application Format

The PHS 398 application must be used for this RFA, and the 
format must be modified as described under "APPLICATION 
PROCEDURES."

III.  Terms and Conditions of Award

The following terms and conditions will be incorporated into 
the U01 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."]

1.  The administrative and funding instrument used for the 
applicants to this program is a cooperative agreement (U01), an 
"assistance" mechanism (rather than an "acquisition" mechanism) 
in which substantial NIH scientific and/or programmatic 
involvement with the awardee is anticipated during performance 
of the activity.  Under the cooperative agreement, the NIH 
purpose is to support and/or stimulate the recipient's activity 
by involvement in and otherwise working jointly with the award 
recipient in a partner role, but it is not to assume direction, 
prime responsibility, or a dominant role in the activity.  
Consistent with this concept, the dominant role and prime 
responsibility for the activity resides with the awardee(s) for 
the project as a whole, although specific tasks and activities 
in carrying out the studies will be shared among the awardees 
and the NIEHS through the Steering Committee.

2.  Awardee Rights and Responsibilities

The PI will coordinate project activities scientifically and 
administratively at the awardee institution and at the other 
sites that may be supported by sub-contracts to this award.  
The PI of a U01 grant will have primary authority and 
responsibility to define objectives and approaches, and to 
plan, conduct, analyze, and publish results, interpretations, 
and conclusions of studies conducted under the terms and 
conditions of the cooperative agreement award.

The PI will assume responsibility and accountability to the 
applicant organization officials and to the NIEHS for the 
performance and proper conduct of the research supported by the 
U01 in accordance with the terms and conditions of the award.

o  The PI, and another senior investigator from the U01, will 
serve, as voting members of the Steering Committee, and will 
attend the Steering Committee meetings.

o  The PI will be responsible for accepting and implementing 
the goals, priorities, procedures, and policies agreed upon by 
the Steering Committee.

o  The PI of a U01 will be responsible for close coordination 
and cooperation with the other components of the Consortium, 
the Steering Committee, and with the NIEHS staff.

o  The PI will submit periodic progress reports in a standard 
format, as agreed upon by the Steering Committee.

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.  

o  All awardees must adhere to PHS policy for the distribution 
of unique research resources produced with PHS funding that was 
published in the NIH Guide for Grants and Contracts (NIH Guide, 
Vol. 25, No. 23, July 12, 1996), and is available at the 
following Internet address: 
http://grants.nih.gov/grants/guide/notice-files/not96-184.html  
Awardees specific plans for distribution of data 
and mouse models, produced as a result of their participation 
in this Consortium, will be incorporated into the Terms and 
Conditions of the Awards.

The NIEHS reserves the right to require the transfer of 
appropriate mouse stocks, related reagents, and pertinent data 
that are generated as the result of participation in research 
supported under these awards to an eligible third party, in 
order to preserve the mouse models and data about them and/or 
to continue the research.  Third parties supported under these 
awards must be informed of this right.

Effective conduct of the Consortium goals will require 
considerable electronic communication of data and other 
information among the Consortium components and between the 
components and the NIEHS.  Awardees are responsible for 
developing or enhancing their Internet communication tools to 
ensure effective communication among the different components 
that form the U01 grant (such as, sub-contracts, individual 
core facilities at the institution), the Consortium members, 
and with NIEHS.

3.  NIEHS Extramural Staff Responsibilities

The NIEHS Program Director will provide normal stewardship for 
the U01 awards under this RFA, as well as have substantial 
scientific and programmatic involvement to assist, guide, 
coordinate, and participate in the conduct of the Consortium 
activities.  The NIEHS Program Director will coordinate and 
facilitate the Consortium programs, will attend and participate 
in all meetings of the Consortium Steering Committee, and will 
provide liaison between the Steering Committee, the Consortium, 
and the NIEHS/NIH.  The Program Director will also coordinate 
the activities of the Consortium with the activities of the 
other facilities established under the Trans-NIH mouse genetics 
and genomics initiatives.

The NIEHS Program Director will regularly consult with the 
Mouse Task Force on the scientific progress of the Consortium. 
 The Mouse Task Force members will have access to progress 
reports and other relevant information submitted by U01 
awardees.

The NIEHS Program Director will assist the Steering Committee 
in developing and drafting operating policies and policies for 
dealing with recurring situations that require a coordinated 
action.  

The NIEHS Program Director will review the scientific progress 
of individual U01 grants, and review them for compliance with 
the operating policies developed by the Steering Committee.  
The Program Director may recommend withholding support, 
re-allocating support among awardees, and suspension or 
termination of a U01 award for lack of scientific progress or 
failure to adhere to policies established by the Steering 
Committee.

NIEHS/NIH staff with relevant scientific expertise, or who 
manage research grant programs that relate scientifically to 
the goals of the Consortium will form the Mouse Task Force.  
The Group will meet regularly to review the progress of the 
Consortium, and to recommend to the NIEHS Program Director 
scientific developments and opportunities that may enhance the 
achievement of the Consortium goals.

4.  Collaborative Responsibilities

Steering Committee

The representatives from the U01 grants that comprise the 
Consortium and representatives from the Mouse Task Force will 
be responsible for forming a Steering Committee as defined 
below.  An arbitration system, as detailed below, will be 
available to resolve disagreements between the NIEHS Program 
Director and the members of the Steering Committee.

The Steering Committee will be the main governing board of the 
Consortium.  It will function to set priorities for model 
derivation, define the parameters for model validation, 
identify technological impediments to success and strategies to 
overcome them, and decide when models should be made available 
to the research community for individual investigator-initiated 
projects.

The Steering Committee will be composed of the PI and a Co-PI 
or other senior investigator from each U01 and up to three 
members of the Mouse Task Force.  The two investigators from 
each U01 and the members of the Mouse Task Force will each have 
one Steering Committee vote.  The chairperson, who will be 
someone other than an NIEHS/NIH staff member, will be selected 
by the Steering Committee.  The NIEHS Program Director is not a 
member of the Steering Committee, but will facilitate creation 
of the group and will attend all meetings.  NIH staff may not 
serve as the Committee chair.

The Steering Committee may, when it deems it to be necessary, 
invite additional, non-voting scientific advisors to the 
meetings at which research priorities and opportunities are 
discussed.  The NIEHS reserves the right to augment the 
scientific or consumer expertise of the Consortium when 
necessary.

There will be two Steering Committee meetings annually.  The 
initial planing meeting will be organized by NIEHS, but 
subsequent meetings will be organized by the Steering 
Committee.  The committee=s chair will schedule the meetings and 
will be responsible for developing meeting agendas (in 
collaboration with the Program Director), chairing the 
meetings, and producing Steering Committee=s reports. 

The first meeting of the Consortium will be a Planning Meeting, 
which will take place in the Research Triangle Park, NC very 
shortly after award of the U01 grants.  At the Planning 
Meeting, the Steering Committee will be formed and select a 
chairperson from among the members who represent the U01 
awardees.  

At the Planning Meeting, the Steering Committee may:
o  draft a charter to detail policies and procedures, a process 
for monitoring compliance with the policies and procedures, and 
a process for recommending that the NIEHS Program Director act 
on evidence of non-compliance of any Consortium component with 
Steering Committee policies;
o  agree upon the terms of the charter;
o  discuss the models and approaches that were proposed in the 
U01 applications, and any relevant new information, and set 
initial priorities for the models to be derived and for new 
technologies to be developed;
o discuss and set initial genotypic and phenotypic parameters 
required to characterize the models and to define their 
comparability to human diseases;
o  discuss and set initial standards for validating the models 
for further biological studies.
o  discuss and set procedures for recommending to the Program 
Director, themes or scientific areas for solicitation of pilot 
projects from Consortium members, and establish guidelines for 
providing peer review of such pilot studies.

At their first meeting each year, the Steering Committee may 
formulate plans for any workshops or symposia to be held.  It 
will discuss and recommend to the Program Director areas or 
themes for pilot projects.  The pilot projects will be peer 
reviewed following the procedures established by the Steering 
Committee, and awards will be made with funds set aside for 
this program.

At the second and subsequent meetings, the Steering Committee 
will: 1) refine the Consortium scientific objectives, 2) define 
the characterization and validation strategies, and 3) identify 
available models with sufficient promise for further testing, 
or define those human diseases for which models must be created 
de novo.

At any time during the Consortium project, the Steering 
Committee may examine the characterization and validation data 
for models derived by the Consortium components, and decide 
when a model is sufficiently validated that it may be 
distributed to the research community for further 
investigations or applications. 

The Steering Committee may recommend one or several workshops a 
year, or at different frequencies, to which non-Consortium 
participants may be invited to enable the Consortium to explore 
scientific or technological innovation that occurs during the 
course of the project.  These meetings will serve to inform the 
research community of the progress made toward derivation or 
refinement of models, their characterization and validated 
uses, and any technological advances related to design and 
derivation of mouse models.  The organization of the workshops 
and symposia will be the responsibility of the Consortium 
members.  NIEHS may provide supplemental funds to the selected 
host institution, after the receipt of an appropriate 
application and reviewed by the Steering Committee.

Applicants must budget for travel and per diem expenses for 
Steering Committee meetings.  In the first year, applicants 
should plan for two investigators, the principal investigator 
and an additional senior investigator, to attend a Planning 
Meeting and two Steering Committee meetings.  In the second and 
subsequent years, applicants should plan for the PI and another 
investigator to attend two Steering Committee meetings per 
year.

Applicants must budget for travel and per diem expenses for 
participation in Consortium workshops and symposia.  Applicants 
should plan that at least five investigators will attend a 
workshop or symposium every year in years two through five.

The Steering Committee may establish subcommittees.  The NIEHS 
Program Director and the other NIEHS/NIH staff who are Steering 
Committee members may serve on subcommittees, as they deem 
appropriate.

5.  Arbitration Process

Any disagreement that may arise on scientific/programmatic 
matters (within the scope of the U01 award), between U01 
awardees and the NIEHS may be brought to arbitration.  An 
arbitration panel will be composed of three members: one 
selected by the Steering Committee (without NIH representatives 
voting), or by the individual U01 awardee in the event of an 
individual disagreement; a second member selected by the NIEHS; 
and, the third member selected by the two prior selected 
members.  For U01 awardees, this special arbitration procedure 
in no way affects the awardee's right to appeal an adverse 
action that can otherwise be appealed in accordance with the 
PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation 
at 45 CFR Part 16.

6.  Yearly Milestones and Evaluations

Awardees will finalize yearly milestones at the time of their 
awards.  The awardees= milestones will be provided to the 
Steering Committee.  It is expected that the milestones will be 
adjusted annually at the award anniversary dates, both to 
incorporate a group=s scientific accomplishments and progress in 
the field in general, as well as to reflect the recommendations 
of the Steering Committee.  In accord with the procedures 
described above, NIH may withhold or reduce funds for projects 
that substantially fail to meet their milestones or to maintain 
their research activities as state-of-the-art.

Specific issues related to cooperative agreements must also be 
addressed as follows:

Plan to Share Research Resources and Intellectual Property 
Rights

NIH is interested in ensuring that the research resources 
developed through this RFA become readily available to the 
research community.  Applicant institutions should present 
their intellectual property policies and practices.  A 
description of plans for handling intellectual property 
resulting from the studies or for commercialization of any 
discoveries should be included in the application.  This is 
expected to include an elaboration of the applicant=s 
anticipated plans to generate, or not generate, patents and/or 
exclusive or non-restrictive licensing of biomaterials and 
other patentable subject matter created with funds provided 
under this RFA.  This plan is also expected to include 
disclosure of any pre-existing intellectual property rights, 
including options to for-profit research sponsors, that are 
associated with biomaterials and data that might be generated.

The initial review group will make an administrative comment on 
the adequacy of the proposed plan for sharing and data access. 
NIEHS Program Staff will consider the adequacy of the plan in 
determining whether the grant shall be awarded.  The sharing 
plan as approved, after negotiation with the applicant when 
necessary, will be a condition of the award.  It is expected 
that this plan include all elements of the guidelines developed 
by NIH and the Department of Energy (DOE) to 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 collected, and are available at: 
http://www.nhgri.nih.gov:80/Grant_info/Funding/Statements/.

Where appropriate, awardees may work with the private sector to 
make unique resources available to the biomedical research 
community at a reasonable cost.

Applicants are reminded that the awardee institution is 
required to disclose each subject invention to NIH within two 
months after the inventor discloses it in writing to the 
awardee institutional office responsible for patent matters.  
The awarding Institute reserves the right to monitor awardee 
activity in this area to ascertain if patterns or patent 
applications are adversely affecting the goals of this RFA.
 
RESEARCH INVOLVING HUMAN SUBJECTS

The primary objective of this RFA is to derive mouse models for 
environmental health research.  Therefore, there may be 
instances in which applicants must collect or use pathology 
specimens derived from human subjects, or clinical or 
epidemiological data from projects involving human subjects, to 
inform the design of the models or to derive the standards that 
validate them as models of human diseases.  In those instances, 
the NIH policies below apply and must be addressed in the 
application. 


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 policy results from the NIH Revitalization Act 
of 1993 (Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects 
should read the "NIH Guidelines for Inclusion of Women and 
Minorities as Subjects in Clinical Research", which were 
published in the Federal Register of March 28, 1994 (FR
59 14508-14513) and in the NIH Guide for Grants and Contracts, 
Vol. 23, No. 11, March 18, 1994, and are available at the 
following Internet address: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING 
HUMAN SUBJECTS

It is the policy of the NIH that children (i.e., individuals 
under the age of 21) must be included in all human subject 
research, conducted or supported by the NIH, unless there are 
scientific and ethical reasons not to include them.  This 
policy applies to all initial (Type 1) applications submitted 
for receipt dates after October 1, 1998.  All investigators 
proposing research involving human subjects should read the 
"NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects" that was 
published in the NIH Guide for Grants and Contracts, March 6, 
1998, and is available at the following Internet address:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html 
and http://grants.nih.gov/grants/funding/children/children.htm.

LETTER OF INTENT

Prospective applicants are asked to submit by May 12, 2000, a 
letter of intent that includes: 1) a descriptive title of the 
proposed research; 2) the name, mailing address, telephone 
number, and email address of the Principal Investigator, 3) 
identities of other key personnel and participating 
institutions, and 4) 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 subsequent applications, 
the information allows NIEHS staff to estimate the potential 
review workload and to avoid conflict of interest in the 
review.

The letter of intent is to be sent (by mail, FAX, or email) to:

J. Patrick Mastin, Ph.D.
Scientific Review Administrator
Scientific Review Branch
Office of Program Operations
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P. O. Box 12233, 111 Alexander Drive
Research Triangle Park, North Carolina 27709
Tel. 919-541-1446
Fax: 919-541-2503
E-mail: mastin@niehs.nih.gov

APPLICATION PROCEDURES

Applicants for U01 grants must use the research grant 
application form PHS 398 (rev. 4/98), with the modified format 
that is described below.  Application 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 
301/435-0714, Email: GrantsInfo@nih.gov. 

1.  General Application Format Instructions

Administrative Core

It is the intent of this RFA to support cutting edge research 
activities integrated into an interdisciplinary program.  To 
ensure this goal, NIEHS requires the establishment of an 
Administrative Core. The Administrative Core will provide 
supportive structure sufficient to ensure accomplishment of the 
following: 
o  planning and coordination of research activities,
o  fiscal and resource management planning, 
o  information dissemination planning, 
o  technology transfer planning. 

This core will provide leadership, ensure the integration of 
the program, and serve as a resource to the program in 
administrative matters.  It is anticipated that this core will 
be composed of the principal investigator, a co-principal 
investigator, and an administrative staff.  One individual 
would be assigned the responsibility for information transfer 
and dissemination.  This individual would be the point of 
contact for NIEHS staff for coordinating written documents 
about the program.

To further support the program=s goal in technology transfer, 
NIEHS recommends that the program designate an individual to 
promote technology transfer for the program.  The 
responsibilities of this person would be to seek opportunities 
for applying research findings with appropriate audience. This 
may exist as a formal technology transfer activity, where the 
person would coordinate with the institution=s established 
office of technology transfer, or less formal arrangements 
where the individual would seek opportunities for partnership 
in advancing the science from the laboratory into application.

The principal investigator will be the liaison between the 
program, the Steering Committee, and the NIEHS.  The 
responsibilities of the principal investigator and co-principal 
investigator are detailed elsewhere in this document.

Research Plan

An integrated application, presenting a comprehensive and 
cross-disciplinary team approach, should be prepared in 
response to this RFA. The form PHS 398 should be modified as 
follows.  The "Research Plan", sections a. to d., should be 
divided into four parts.  The number of pages allowed for the 
"Research Plan" is increased from 25 to 40 pages; budget pages, 
budget justifications, and letters from collaborators and 
consultants and their biosketches are not included in this 
limit.  

For U01 applicants who do not request funds to support the 
activities in a particular part of the application, the 
applicants should indicate the source of funds (institutional, 
R01, P01, P30, etc.) that permit them to accomplish the project 
goals.  The U01 applications should also have individual 
budgets for any sub-contracts proposed. The sub-contract budget 
should be a separate page, and the sub-contract indirect costs 
should be calculated and listed in the usual place as part of 
the direct costs in the composite budget.  However, only the 
direct costs associated with each sub-contract will count 
toward the direct cost cap of $700,000 on the budget for the 
first year.  The total costs for the U01 applications are not 
capped. 

Part 1.  INFRASTRUCTURE.  In this part of the "Research Plan", 
applicants should detail the specialized or unique facilities, 
fundamental infrastructure, research expertise, and core 
resources and services that are available to support the 
planned mouse model derivation, characterization, and 
validation.  If facilities at more than one institution are 
required, applicants should thoroughly describe them, and 
obtain the appropriate assurances.  The roles and expertise of 
all key personnel, collaborators, and consultants who are 
associated with this part of the application should be well 
documented; letters from collaborators and consultants and 
their biosketches should directly follow this part of the 
application.

Part 2.  MODEL DERIVATION.  In this part of the "Research 
Plan," applicants should describe their rationale for the 
design and derivation of a new mouse model or models, or for 
altering and improving an existing model or models, based on 
their experience with mouse models of human disease, and their 
knowledge of basic and clinical research.  Applicants should 
clearly explain their choice of genes to study.  However, the 
models presented in the applications that are funded will be 
reviewed by the Steering Committee to determine which ones the 
Consortium will use.

Applicants should describe the extent to which they plan to 
characterize any models they derive or refine; the methods that 
they will use to characterize the models; the rationale for 
choices of methods; and, how generally applicable the methods 
are, or will be, for all mouse models.  In this part as well, 
applicants are expected to identify the standards they will 
apply to validate a model or models; the rationale for the 
choices; how generally applicable the validation standards are, 
or will be, for all mouse models; and, the purpose(s) for which 
they anticipate their models may be used.  The roles and 
expertise of all key personnel, collaborators, and consultants 
who are associated with this part of the application should be 
thoroughly documented; letters from collaborators and 
consultants and their biosketches should directly follow this 
part of the application.

Applicants must include expertise in transgenic technologies, 
mouse genetics and pathology, genomics, biostatistics, and at 
least two researchers with scientific expertise in the biology 
of the genes and gene products targeted for study (DNA repair 
and/or cell cycle control genes).

Part 3.  NEW TECHNOLOGY.  In this part of the "Research Plan," 
applicants should define new technological approaches they will 
use, or any technology that they propose to develop, to achieve 
the goals of model derivation or refinement, characterization, 
and validation.  The roles and expertise of all key personnel, 
collaborators, and consultants who are associated with this 
part of the application should be thoroughly documented. 
Letters from collaborators and consultants and their 
biosketches should directly follow this part of the 
application.

Part 4.  INTERACTIONS WITH OTHER CONSORTIUM COMPONENTS.  In 
this part of the "Research Plan," applicants should describe 
how they believe their unique blend of experience can 
contribute to the collective efforts of the Consortium.  They 
should identify potential pilot projects for research or 
technology development that they believe should be goals of the 
Consortium after it has been assembled from the U01 components. 
 Applicants should not plan to budget any funds for collective 
Consortium pilot projects.  During the second and subsequent 
years of the program, Consortium members will be able to submit 
applications for pilot studies to be funded from the set aside 
funds.  Pilot project funds will be used to pursue scientific 
goals, such as high-risk technology development, that should be 
joint efforts pursued by the Consortium.  At its first meeting 
every year, the Steering Committee will recommend to the 
Program Director scientific areas or themes for solicitation of 
pilot projects for that year. The pilot projects submitted by 
Consortium members will be peer reviewed following procedures 
established by the Steering Committee, and those judged to be 
highly meritorious will be funded from the set aside funds.  
The number of pilot projects to be awarded each year will be 
determined by the quality to the applications and the 
availability of funds for that purpose.

In this part of the "Research Plan," applicants should describe 
their experience with, and capability for, Internet-based 
communication, and their ideas about how to facilitate 
electronic communication and other interactions among the 
Consortium components and the NIEHS. 

Applicants should state their willingness to collaborate and 
share data freely with the other Consortium components, to 
participate in planning and attending workshops and symposia, 
to serve on the Steering Committee and be bound by its 
decisions, particularly those which relate to setting 
priorities for model development and the standards for 
characterization and validation, and to be able and willing to 
share data and communicate with each other and the NIEHS in an 
Internet environment.  Applicants should also describe how they 
would comply with the involvement of the NIEHS Program 
Director, and how they will fulfill the responsibilities of 
Consortium components to work together cooperatively.

Additional Materials to Include in the Application

Applicant institutions should submit in an APPENDIX their 
intellectual property policies and practices.  A description of 
the plans to share materials and data, as well as plans for 
handling intellectual property resulting from the studies or 
for commercialization of any discoveries, should be included in 
this section.

The RFA label available in the PHS 398 (rev. 9/95) 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, "Comparative Mouse Genomics Centers Consortium", and 
number, RFA ES-00-005 must be typed on line 2 of the face page 
of the application form and the YES box must be marked. The RFA 
number must be typed on the label as well.

The sample RFA label is available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified 
to allow for this change.  Please note this is in pdf format.


U01 applicants should submit a typewritten, signed 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 signed photocopies of 
the application must also be sent to:

J. Patrick Mastin, Ph.D.
Scientific Program Administrator
Scientific Review Branch
Office of Program Operations
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P. O. Box 12233, 111 Alexander Drive, EC-24
Research Triangle Park, North Carolina 27709

Applications must be received by July 20, 2000.  If a U01 
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 U01 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 a substantial revision of an 
application already reviewed, but such an application must 
follow the guidance in the PHS Form 398 application 
instructions for the preparation of revised applications, 
including an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

General Considerations

All U01 applications will be judged on the basis of the 
scientific and technical merit of the proposed project and the 
documented ability of the investigators to meet the "RESEARCH 
OBJECTIVES" of the RFA as presented in the four components of 
the Research Plan.  Although the technical merit of the 
proposed protocol is important, it will not be the sole 
criterion for evaluation of a study.  Other considerations, 
such as the multi-disciplinary nature of the studies, the 
appropriateness of the proposed Administrative Core, and the 
adequacy of the proposed plan for sharing and data access will 
be part of the evaluation criteria.

Review Method

Upon receipt by the Center for Scientific Review (CSR), U01 
applications will be reviewed for completeness; incomplete 
applications will be returned to the applicant without further 
consideration.  Complete applications will be reviewed for 
responsiveness by NIEHS staff.  If an application is not 
responsive to the RFA, NIEHS staff will contact the applicant 
to inform him/her of that decision and will return the 
application.

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 NIEHS in 
accordance with the review criteria stated below.  There will 
be no site visits.  As part of the initial merit review, a 
process will be used by the initial review group in which 
applications 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, and assigned a priority score. 
 All applications will receive a second level review by the 
National Advisory Environmental Health Sciences Council.

Review Criteria

The criteria to be used in the evaluation of grant applications 
are listed below.  To put those criteria in context, the 
following information is contained in instructions to the peer 
reviewers.

The goals of NIH-supported research are to advance our 
understanding of biological systems, improve the control of 
disease, and enhance health.  The reviewers will comment on the 
following aspects of the application in their written critiques 
in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  
Each of these criteria will be addressed and considered by the 
reviewers in assigning the overall score weighting them as 
appropriate for each application.  Note that the application 
does not need to be strong in all categories to be judged 
likely to have a major scientific impact and thus deserve a 
high priority score.  For example, an investigator may propose 
to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

Applicants are encouraged to submit and describe their own 
ideas about how best to meet the goals of the Consortium, and 
are expected to address issues identified under "SPECIAL 
REQUIREMENTS FOR THE RFA."  The peer review group will comment 
on each of the four sections of the Research Plan 
(Infrastructure, Model Derivation, New Technology, and 
Interactions with Other Consortium Components).  The peer 
review group will assess the merit of the applications and 
related factors, including:

1.  Significance:  Do the model or models proposed for 
derivation/characterization/validation address an important 
need for the environmental health research community.  What is 
the immediacy of the research opportunity?  Over the project 
period, is there potential for the group to develop models 
other than those specified in the application?

2.  Approach:  Are the conceptual framework, design, methods, 
and analyses adequately developed and appropriate to the aims 
of the project?  Does the applicant acknowledge potential 
problem areas and consider alternative tactics?  Can these 
approaches be used to derive mouse models for other diseases in 
addition to those proposed?  Are the parameters chosen to 
characterize the model(s) sufficient and appropriate?  Are 
these parameters generally applicable to all mouse models?  Are 
the standards chosen to validate the model(s) for its relevance 
to a human disease adequate? Are these standards generally 
applicable to all mouse models?

3.  Innovation:  Does the project employ novel concepts, 
approaches or method? Is the project original and innovative?  
Does the project challenge existing paradigms or develop new 
methodologies or technologies?  Will the approaches advance the 
field of mouse transgenics or other model development?

4. Investigators:  Are the principal investigator and his/her 
collaborators appropriately trained and well suited to carry 
out this work?  To what extent do these investigators have the 
necessary complementary skills?  Have collaborations been 
established or consultants identified to provide the 
appropriate depth and breadth of scientific expertise required 
for the project?  Will this team of investigators contribute 
unique skills to the overall Consortium?

Factors considered to be important for review include 
demonstrated expertise in transgenic technologies, mouse 
genetics, genomics, and pathology, as applied to the design and 
derivation of mouse models of human disease; a multi-
disciplinary team of collaborators; substantial interactions 
among collaborating researchers; demonstration of appropriate 
facilities and resources; willingness to share data and 
reagents freely. 

In addition, the reviewers will take into consideration the 
demonstrated expertise of the applicant group in the biology of 
the gene and gene products chosen for investigation.  

For example, a group proposing development of models involving 
DNA repair genes, should demonstrate substantial expertise in 
the field of DNA repair, including, but not limiting to, having 
a minimum of two researchers with current external funding 
(preferable from NIH) and current peer review publications.

5.  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 and incorporate the best use of collaborative 
arrangements?  Is there evidence of institutional support?

Additional Considerations

6.  Interactions:  Are there adequate plans for effective 
interaction and coordination between Consortium components and 
the NIEHS?  Do the investigators state their willingness to 
collaborate extensively and share information fully?  

Do the investigators state their willingness to abide by the 
priorities and policies agreed upon by the Steering Committee? 
 Have the applicants proposed sound strategies for 
communication among themselves, with the other Consortium 
components, and with the NIEHS?

7.  Budget:  Does the apportionment of the budget among 
fundamental infrastructure, model development, 
characterization, and validation, and technology development 
indicate that the applicants understand the requirements of 
managing this sort of model-building enterprise?  

AWARD AND SELECTION CRITERIA

The NIEHS intends to choose the programs which will 
collectively provide for the Consortium the most creative 
approaches to mouse model design, and the range of research 
experience, technology, and resources to ensure that the models 
that are validated as appropriate for various aspects of 
research are derived rapidly.

U01 applications recommended by the National Advisory 
Environmental Health Sciences Council (NAEHSC) will be 
considered for award based upon: (a) scientific and technical 
merit, (b) importance of the proposed models for enhancing 
NIEHS mission,  (c) the adequacy of the proposed plans for 
sharing resources and data access, and (d) the availability of 
funds.

SCHEDULE

Letter of Intent Receipt:  May 12, 2000
Application Receipt Date:  July 20, 2000
Review by NAEHSC:  February 2001
Earliest Award Date:  April 1, 2001

INQUIRIES

Due to the unusual application format and complexity of this 
RFA, the NIEHS encourages potential applicants to take the 
opportunity to clarify any issues or questions.  Written and 
telephone inquiries concerning the RFA are welcome.

Direct inquiries regarding programmatic issues to:

Jose M. Velazquez, Ph.D.
Scientific Program Administrator
Chemical Exposures and Molecular Biology Branch
Office of Program Development
National Institute of Environmental Health Sciences
P.O. Box 12233, 111Alexander Drive
Research Triangle Park, NC 27709
Telephone:  (919)541-4998 
FAX:  (919) 316-4606
Email:  Velazqu1@niehs.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Laura Williams
Grants Management Specialist
Grants Management Branch
Office of Program Operations
National Institute of Environmental Health Sciences
P. O. Box 12233, 111 Alexander Drive
Research Triangle Park, North Carolina 27709
Telephone:  (919) 541-7629
FAX:  (919) 541-2860
Email:  Willia27@niehs.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic 
Assistance No.93.113,93.114, and 93.15.  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 Parts 52 and 45 CFR Part 74 [and 
Part 92 when applicable for State and Local governments].  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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