MOUSE MUTAGENESIS AND PHENOTYPING: NERVOUS SYSTEM AND BEHAVIOR

Release Date:  March 31, 1999

RFA:  MH-99-007

P.T.

National Institute of Mental Health
National Institute of Neurological Disorders and Stroke
National Institute on Aging
National Institute on Deafness and Other Communication Disorders
National Institute on Drug Abuse
National Eye Institute
National Institute on Alcohol Abuse and Alcoholism

Public Briefing Date: June 21, 1999
Letter of Intent Receipt Date:  August 2, 1999
Application Receipt Date:  October 14, 1999

PURPOSE

The purpose of this request for applications (RFA) is to establish facilities for
large-scale mutagenesis and phenotyping of nervous system functions and complex
behaviors in the laboratory mouse.  Neuroscience-focused mutagenesis and
phenotyping facilities established by this RFA are expected to serve as a
national resource by producing a bank of mouse strains that harbor a wide range
of mutations affecting murine nervous system function and behavior.  Data and
biomaterials produced in projects supported under this RFA will be made widely
available to the scientific community.

A companion RFA entitled, "Phenotyping the Mouse Nervous System and Behavior:
MH-99-006," available at http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-99-006.html, 
solicited applications that focused on the development of standardized
criteria and high-throughput phenotyping assays to assess a comprehensive range
of murine nervous system functions and complex behaviors.  These assays will be
widely distributed to the scientific community and available for application in
projects supported under this RFA.

The activities of facilities established under this RFA will be coordinated with
those supported under RFA HD-99-007, "Mouse Mutagenesis and Phenotyping:
Developmental Defects," available at http://grants.nih.gov/grants/guide/rfa-files/RFA-HD-99-007.html, 
and with those of future related facilities.  Further
information about NIH initiatives on mouse genomics and genetics resources are
available at http://www.nih.gov/science/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 RFA - Mouse Mutagenesis and
Phenotyping: Nervous System and Behavior - is related to one or more priority
areas. Applicants may obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

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 will not be accepted from foreign institutions. 
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators (PIs).

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) cooperative agreement
(U01) award mechanism, an "assistance" mechanism, which is distinguished from a
regular research grant in that substantial scientific and/or programmatic
interaction between NIH program staff and the awardees is anticipated.  The
cooperative agreement is used when participation by NIH staff is warranted to
support and/or stimulate the recipient's activity by involvement in or otherwise
working jointly with the award recipient in a partner role; NIH staff will not
assume direction, prime responsibility, or a dominant role in the activity. 
Details of the responsibilities, relationships, and governance of the studies
funded under cooperative agreements are discussed later in this document under
"Terms and Conditions of Award."  If there are multiple facilities to be
supported, each will be awarded as a separate U01.

For administrative reasons all applications received in response to this
solicitation will be initially assigned to NIMH.  After discussions among the
participating NIH Institutes, applications will be reassigned to the Institute(s)
that is programmatically most appropriate.  Because the scope of some of the
research projects proposed in response to this RFA encompasses the interests of
several Institutes, applications may receive dual assignments based on
established PHS guidelines.  Awards will be made and managed by NIMH and/or the
other participating Institutes.

FUNDS AVAILABLE

This RFA is a one-time solicitation.  It is anticipated that $5.5 million
(including direct and indirect costs) will be available for this initiative in
Fiscal Year 2000, during which it is anticipated that 2 to 4 awards will be made. 
The total project period for an application submitted in response to this RFA may
not exceed 5 years.  Awards pursuant to this RFA are contingent upon the
availability of funds for this purpose.  The amount of funding for this
initiative may be increased if a large number of highly meritorious applications
are received and if funds are available.  Only applications that are found to be
of the highest scientific merit will be considered for funding, and not all of
the funding will be spent if there are not enough highly meritorious
applications.  Funding in future years will be subject to the availability of
funds.

For the purpose of accomplishing the goals of this RFA, the facility may include
investigators at more than one site, and subcontracts may be included in the
budget to support investigators at sites other than the awardee institution.

RESEARCH OBJECTIVES

Background

With the impending elucidation of the complete sequence of both the mouse and
human genomes, the next challenge will be to conduct large-scale functional
analyses of these genomes to greatly enhance our understanding of mammalian
biology.  The laboratory mouse plays a pivotal role in human functional genomics,
insofar as mouse strains carrying mutations have provided useful models for human
diseases. Despite an apparent large collection of mouse mutations, the genetic
bases of nervous system functions and complex behaviors are still poorly
understood.  This is in part true because there have not been systematic, large-
scale efforts to identify mutations across the genome via systematic mutagenesis,
and comprehensive phenotypic and genetic analyses of the resulting mouse strains.

Creation of additional genomic and genetic resources to facilitate functional
analysis of murine biology is of widespread interest, and will make the mouse an
even more useful model for the research community.  In order to help define and
establish priorities for generating such resources, the NIH Director convened a
meeting of a distinguished group of scientists in March 1998, and a follow-up
meeting in October 1998.  Summaries of the two meetings can be found at
http://www.nih.gov/welcome/director/reports/mgenome.htm and
http://www.nih.gov/welcome/director/reports/mgenom3.htm (links to these
summaries, as well as all relevant information regarding NIH initiatives on mouse
genomics and genetics resources, are available at
http://www.nih.gov/science/mouse/).  A recent article (J. Battey et al., Nature
Genetics 21:73, 1999, available at http://www.nih.gov/science/mouse/reports/actionplan.html) 
summarizes a proposed action plan by NIH for implementation of these recommendations.

Large-scale, genome-wide mutagenesis is a powerful approach for the analysis of
gene function, and has historically played a major role in the evolution of our
understanding of the biology of viruses, bacteria, fungi, the nematode,
Caenorhabditis elegans, the fruit fly, Drosophila melanogaster, and most
recently, the zebrafish, Danio rerio.  In all three of the metazoan species so
studied, genome-wide mutagenesis has made important contributions to our
understanding of the development and cellular functions of the nervous system. 
Two routes, phenotype-driven and genotype-type driven, are currently being used
to develop large-scale mutagenesis efforts.  Phenotype-driven approaches
typically utilize pseudo-randomly acting chemical agents such as N-ethyl-N-
nitrosourea (ENU), procarbazine, or chloroambucil, to generate mice with
phenotypes of interest.  Recovery of novel phenotypes is a starting point from
which the relevant genes and biochemical, anatomical and physiological pathways
are subsequently elucidated.  Although considerable effort is needed to find the
genes underlying novel phenotypes in mice, this approach has been successfully
used to identify genes encoding leptin, and novel genes involved in genetic
deafness and circadian rhythms.

This RFA will establish neuroscience-focused facilities for large-scale,
efficient, whole-genome mutagenesis and phenotyping, in order to promote the
systematic and comprehensive functional analysis of neurobiological and
behavioral phenotypes in the mouse.  Such facilities will create and maintain for
distribution validated protocols for mutagenesis and phenotypic characterization,
a collection of mutant mouse strains and databases containing phenotypic and
genetic data on these strains.  These resources will provide a platform from
which hypothesis-driven research can be developed to gain a more comprehensive
understanding of the molecular and genetic bases underlying nervous system
function and complex behavior in mammals.  Projects supported under this RFA will
complement those supported under RFA HD-99-007, which will focus on genes that
affect murine embryonic and post-embryonic development.

Scope and Objectives

Projects supported under this RFA will conduct genome-wide mutagenesis and high-
throughput phenotyping of genetically altered mice.  These  mutant animals, along
with embryos and/or sperm, will be made available for wide distribution to the
scientific community.  Each of the following areas are of primary importance and
should be explicitly addressed in the application:

o  Utilization of a whole-genome approach to mutagenesis that is phenotype-
driven, genotype-driven, or a combination of the two.  The strategy must enable
identification of both dominant and recessive mutations.

o  Initial, high-throughput characterization of mutant phenotypes relevant to
nervous system function and behavior.

o  Focused phenotypic characterization of mutant mouse strains to screen for
alterations in two or three domains of nervous system function and behavior (see
below).

o  Development and maintenance of a database of all phenotypic data generated
from mutants.

o  Maintenance and provision of animals, embryos, and/or sperm to:(1) one of the
facilities supported under this RFA, which may receive supplemental funds under
competitive peer-review to distribute these biomaterials to the wider scientific
community after projects solicited under this RFA are funded; and/or (2) another
NIH-designated facility (e.g., a National Center for Research Resources (NCRR)-
sponsored Mutant Mouse Regional Resource Center as described in RFA RR-99-001 at
http://grants.nih.gov/grants/guide/rfa-files/RFA-RR-99-001.html).

o  State-of-the-art procedures that will ensure distribution of pathogen-free
mutant mice, embryos, and/or sperm.

o  A proposed sharing plan to insure that mutant mice, sperm, embryos,
phenotyping assays, and phenotypic data for all mutant strains are widely
available to the scientific community.

o  NIH expects to make a Determination of Exceptional Circumstances (DEC) to
eliminate the potential for patents on mutant mice, sperm, and embryos. The
application should include a proposed plan addressing if, or how, the PI and
recipient institution will exercise their intellectual property rights regarding
other patentable research resources not covered under the DEC, such as
phenotyping assays, mutagenesis protocols, and instrumentation produced in
projects funded under this RFA (these issues are addressed below under OTHER
SPECIAL REQUIREMENTS).

o  A proposed plan to permit guest investigators not associated with the facility
to make use of the facility to screen for, and/or to examine, alterations in
nervous system function and behavior not otherwise being studied at the facility. 
Funding for such additional projects would come from other sources.

Applications should utilize pre-existing high-throughput phenotyping assays
and/or newly developed high-throughput assays (e.g., those developed in projects
funded under RFA MH-99-006) to characterize mutant mouse strains.  It is expected
that each facility supported under this RFA will conduct screens of multiple
phenotypic domains of nervous system functions or complex behaviors (see below). 
Each screen should include several assays that collectively measure multiple
components of the phenotypic domain under investigation.  Domains to be screened
may include, but are not limited to, the following:

o  Complex traits related to normal or abnormal nervous system function  and
behavior, including but not limited to the following: emotion, attention,
cognition, perception, concentration, sensation, learning, memory, reproductive
and parenting behaviors, social behavior, circadian rhythms, grooming, impulse
control, appetite, hedonic capacity, weight loss/gain, energy level, and
peripheral sensory and autonomic nervous system function.

o  Neurological symptoms including ataxia, dystonia, seizures, paralysis,
rigidity, tremor, cognitive impairment, motor tics, deficits in sensory, motor,
and cognitive function following ischemic insult, neurotoxic insult, spinal cord
injury, head injury, or nerve trauma.

o  Motor behavior, including measures of strength, motor control and
coordination, and cognitive aspects of motor planning.

o  Acute and chronic sensitivity to neuropathic and inflammatory pain.

o  Visual phenotypes including, but not limited to, the following: retinal
degeneration, cataract, cornea dystrophy, glaucoma, and abnormalities affecting
sensory, plasticity and motor functions in the visual system.

o  Phenotypes that reflect alterations (i.e., impairment, distortion, or
hypersensitivity) in sensory function including, but not limited to, the
following: hearing and susceptibility to noise-induced hearing loss, balance and
vestibular function, olfaction (including assays for neonatal function),
vomeronasal function, and taste.

o  Behavioral traits related to alcohol ingestion, including but not limited to
the following: alcohol drinking preference, alcohol-induced ataxia and locomotor
activation, acute and chronic alcohol withdrawal, alcohol-induced conditioned
place preference and conditioned taste aversion, operant responding for an
alcohol reward, acute behavioral tolerance to alcohol, and alcohol-induced
anxiolysis.

o  Phenotypes that undergo alterations with aging including, but not limited to,
the following: learning, memory and cognition; sensory and motor function; sleep
and circadian rhythms; glial structure and function; blood brain barrier
structure and function; regional brain volume; susceptibility or resistance to
neurodegeneration, neurotoxicity, and oxidative stress; and biochemical and
physiological measures of nervous system function.

o  Behavioral traits related to the taking and seeking of drugs of abuse, which
model aspects of drug addiction and co-morbid behaviors.  These include, but are
not limited to the following: drug preference; conditioned place preference;
acquisition, maintenance, extinction, and reinstatement of drug taking behavior;
narrowing of behavioral repertoires; and drug sensitization, tolerance, and
withdrawal.

o  Behavioral abnormalities that model those found in mental disorders including,
but not limited to, the following: attention-deficit hyperactivity disorder,
autistic disorder, bipolar disorder, depression, eating disorders, obsessive-
compulsive disorder, panic disorder, schizophrenia and other psychotic disorders,
sleep disorders, and Tourette syndrome.

o  Behavioral, neurological, and sensory phenotypes limited to specific stages
of development or to specific stages of the life span, such as neurodegenerative
disorders in early development or aging.

o  High-throughput methods for the following:  structural and functional
characterization of the central and peripheral nervous systems in living animals
through fMRI, PET, and other neuroimaging techniques or through evaluation of
electrophysiological parameters, such as conduction velocity, EEG or long-term
potentiation.

SPECIAL REQUIREMENTS FOR COOPERATIVE AGREEMENTS

I. Definitions

ARBITRATION PANEL: A panel that would be formed to arbitrate scientific or
programmatic disagreement, should any arise, between award recipients and NIH
within the scope of the award.

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

COOPERATIVE AGREEMENT: An assistance mechanism in which there is anticipated
substantial NIH programmatic involvement with the recipient organization during
the performance of the planned activity.

PRINCIPAL INVESTIGATOR (PI): The researcher who assembles the project, submits
an application in response to this RFA, and assumes responsibility for the
overall performance of the project.  The PI will coordinate project activities
scientifically and administratively.

NIH PROGRAM DIRECTOR: A scientist of the NIH program staff who serves on a
rotating basis to represent the 7 NIH Institutes sponsoring this RFA.  The NIH
Program Director has substantial scientific/programming involvement.

NEUROSCIENCE STEERING COMMITTEE (NSC): A committee that is the main governing
board of all of the mutagenesis and phenotyping facilities funded under this RFA,
and the committee through which the NIH interacts and collaborates with the
facilities.  Membership includes the NIH Program Director(s), the PI of each
awarded cooperative agreement, and three scientists with relevant expertise who
are not affiliated with any of the funded projects.

MOUSE GENOMICS & GENETICS SCIENTIFIC PANEL (MSP): A committee that is advisory
to NIH. MSP ensures coordination among projects funded under this RFA and RFA HD-
99-007, and evaluates their progress in relation to the evolving goals for trans-
NIH initiatives on mouse genetics and genomics.

II. Terms and Conditions of Award

The following Terms and Conditions will be incorporated into the award statement. 
The following 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 (Part 92 is applicable when State and local
Governments are eligible to apply), and other HHS, PHS, and NIH grant
administration policies:

1. The administrative and funding instrument used for this program will be the
U01, an "assistance" mechanism (rather than an "acquisition" mechanism), in which
substantial NIH scientific and/or programmatic involvement with the awardees is
anticipated during performance of the activities.  Under the cooperative
agreement, the NIH purpose is to support and/or stimulate the recipients'
activities by involvement in and otherwise working jointly with the award
recipients in a partnership role.  The NIH purpose is not to assume direction,
prime responsibility, or a dominant role in the activities.  Consistent with this
concept, the dominant role and prime responsibility resides with the awardees for
the project as a whole, although specific tasks and activities may be shared
among the awardees and NIH program staff.

2. PI Rights and Responsibilities

The PI will coordinate project activities scientifically and administratively at
the awardee institution.  The PI will have primary responsibility for defining
the details for the projects within the guidelines of this RFA, and for
performing all scientific activities.  The PI will agree to accept the close
coordination, cooperation, and participation of the Program Director(s),
Neuroscience Steering Committee (NSC), and Mouse Genomics & Genetics Scientific
Panel (MSP) in those aspects of scientific and technical management of the
project as described below.  Specifically, the PI will:

o  Determine experimental approaches, design protocols, direct experiments, and
work cooperatively to set project milestones, in consultation with NIH program
staff and NSC.

o  Release data according to plans and publish results, as agreed upon by NIH
program staff and NSC.

o  Submit periodic progress reports in a standard format, as agreed upon by NSC.

o  Accept and implement the common guidelines and procedures approved by NSC and
MSP.

o  Share with other mutagenesis and phenotyping facilities mutants that may be
of interest to those facilities, as directed by NSC and MSP.

o  Be aware of mutants that the other mutagenesis and phenotyping facilities are
producing, and be prepared to accept them for initial screening and/or focused
characterization, as directed by NSC and MSP.

o  Solicit the views of the broad neuroscience and behavioral research
communities for the phenotypes and/or genotypes of interest.

o  Participate in NSC meetings (budget requests should include travel funds for
the PI and other critical staff to attend NSC meetings in the metropolitan
Washington, DC area at least twice per year).

3. NIH Program Staff Responsibilities

The NIH Program Director(s) will have substantial scientific/ programmatic
involvement during the conduct of this activity through technical assistance,
advice, and coordination.  This includes functioning as a peer with the PIs,
facilitating the partnership relationship between NIH and the neuroscience-
focused mutagenesis and phenotyping facilities funded under this RFA, helping to
maintain the overall scientific balance in the program commensurate with new
research and emerging research opportunities, and ensuring that the activities
of the neuroscience-focused mutagenesis and phenotyping facilities are consistent
with the missions of the participating Institutes.

The role of NIH will be to facilitate and not to direct activities.  It is
anticipated that decisions will be reached by consensus of the PIs and that NIH
staff will be given the opportunity to offer input to this process.  One to two
NIH Program Directors shall participate as members of NSC. NIH staff will have
a total of one vote.  In order to separate the functions of the Program
Director(s) from scientific stewardship functions (e.g., review of annual
progress report, decisions about permitting carryover, re-budgeting,
administrative supplements, etc.) for each facility, the Project Officers for the
facilities funded under this RFA will not serve on NSC as Program Director(s).

Specifically, the NIH Program Director(s) will:

o  Provide relevant scientific expertise and overall knowledge.

o  Participate with other NSC members in the group process of setting research
priorities and milestones, deciding optimal research approaches and protocol
designs, and contributing to the adjustment of research protocols or approaches
as warranted.  The Program Director(s) will assist and facilitate the group
process and not direct it.

o  Serve as administrative liaison to MSP, attending MSP meetings as a non-voting
member, to help coordinate activities of facilities funded under this RFA with
those funded under RFA HD-99-007 and other NIH mouse genomics and genetics
initiatives.  The Program Director(s) will also coordinate the activities of
facilities funded under this RFA with other US and international efforts.

o  Provide information about ongoing NIH-supported research and resource
collections.

o  Appoint the NSC Chair based on a recommendation from NSC committee members.

o  Attend NSC meetings as one voting member, and assist to develop operating
guidelines, quality control procedures, and consistent policies for dealing with
recurrent situations that require coordinated action.  The Program Director(s)
must be informed of all major interactions of members of NSC.  The Program
Director(s) will be responsible for preparing within 30 days a concise summary
of each NSC meeting.

o  Serve as scientific liaison between the awardees and other NIH program staff.

o  Assist in promoting the mutagenesis facilities to the scientific community at
large.

o  Assist in developing timetables for the wide distribution of biomaterials and
data to the scientific community.

o  Coordinate the activities of facilities to ensure the efficient long-term
storage and timely release of biomaterials and data to the wider scientific
community.

o  Help determine the most appropriate mechanisms for storage and distribution
of biomaterials and data to the scientific community, i.e., storage and
distribution by one of the facilities funded under this RFA and/or by another
NIH-funded facility.

o  Retain the option to recommend re-allocating NIH support among awardees, as
scientific goals evolve.

o  Participate in data analyses and, where warranted, co-authorship of papers
resulting from projects funded under this RFA.

4. Collaborative Responsibilities - NSC Functions

All collaborative activities of awardees and NIH staff will occur through the
activities of NSC, which will serve as the governing board of all the
neuroscience-focused mutagenesis and phenotyping facilities funded under this
RFA. NIH will interact and collaborate with the facilities through the NSC, which 
will include the PIs, the NIH Program Director(s), and three scientists
(advisors) with relevant scientific expertise who are not affiliated with any of
the facilities.  These advisors will be appointed by the directors of the 7 NIH
Institutes supporting this RFA, and may include PIs on projects funded under RFA
MH-99-006.  One of the advisors will be appointed to be the committee's chair by
the Program Director(s), after consideration of recommendations made by NSC.
After appointment by the Program Director(s), the Chair of NSC will schedule the
first NSC meeting.  The Chair will be responsible for developing meeting agendas
and chairing meetings. NSC will meet at least twice per year.  Additional NSC
members may be added by action of NSC. Other NIH staff may attend NSC meetings,
when their expertise is required for specific discussions.  The Program
Director(s), each PI, and each advisor will have one vote each.

NSC will coordinate the activities of the mutagenesis and phenotyping facilities
and the exchange of information and biomaterials with the wider scientific
community.  While mutagenesis of multiple regions of varying size across the
whole mouse genome will be conducted, it is expected that priorities for genomic
regions and phenotypes of particular interest will be established by NSC.

NSC will discuss scientific progress, make recommendations regarding how
mutations should be obtained, analyzed, and collected, in order to be maximally
valuable to all interested investigators.  MSP recommendations will be addressed
by NSC.

5. Mouse Genomics & Genetics Scientific Panel (MSP)

MSP will coordinate activities among the facilities and resources participating
in NIH's mouse mutagenesis and phenotyping initiative, including this RFA and RFA
HD-99-007.  MSP will use its knowledge of the activities of all of the
participating facilities to ensure adequate investigation, communication and
sharing, and to avoid redundant activities.  It will advise NIH with respect to
the coordination of all activities that involve the mutagenesis, phenotyping,
maintenance, and distribution of mutant mouse strains.  MSP will evaluate and
make recommendations regarding the coordination of the activities of the
facilities that are funded by the mutagenesis and phenotyping initiatives, and
other related activities that may be developed in the future.

It will be the responsibility of MSP to make recommendations that will lead to
exchanging mutants between facilities, sharing assay strategies, adopting common
policies on data sharing, creating compatible databases, and other activities
that will make these facilities of maximal utility to the scientific community. 
MSP will also set standards for data format and nomenclature, as well as develop
common guidelines and procedures for deposition of the primary phenotypic data
and for the preservation of mutant mouse strains.

The committee will consist of about 10 scientists (advisors) who are not
affiliated with any of the mutagenesis and phenotyping facilities, and are not
members of the advisory committees of those facilities.  They will be appointed
by NIH.  These advisors will be selected for their broad expertise in relevant
topics such as, developmental biology, aging, neurobiology, behavior,
mutagenesis, phenotyping, mouse genetics, husbandry, genomics, and database
issues.  MSP will meet at least once each year.  A schedule for subsequent
meetings will be prepared at the first meeting.

NIH will select one member to be the committee chair, after considering MSP's
recommendations.  The chair will schedule the first meeting, will be responsible
for developing meeting agendas and chairing the meetings. Additional MSP members
may be added by an action of the original MSP members.  Program Director(s) will
attend MSP as non-voting members and will act as a representative of NSC.  Other
NIH staff and NSC members may attend MSP meetings, when their expertise is
required for specific discussions.

6. Milestones and Evaluations

Applicants should define yearly milestones in their applications, and the
selected awardees will have the opportunity to modify these milestones at the
time of their awards. The awardees' milestones will be provided to NSC and MSP. 
It is expected that the milestones should 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 NSC and MSP
recommendations.  Following the evaluation of milestones, NIH program staff may
recommend augmenting any project or reducing or withholding funds for any project
that substantially fails to meet its milestones or to remain state-of-the-art.

7. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters within the
scope of the award between recipients and the NIH may be brought to arbitration. 
This special arbitration procedure in no way affects the awardee's right to
appeal an adverse action that is otherwise appealable in accordance with PHS
regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16.  An
Arbitration Panel will help resolve both scientific and programmatic issues that
develop during the course of work that restrict progress.  The Arbitration Panel
will be composed of three members: a designee of NSC chosen without the NIH staff
voting, one NIH designee, and a third designee with expertise in the relevant
area who is chosen by the other two (in the case of an individual disagreement,
the first member is not chosen by NSC rather by the individual awardee).

OTHER SPECIAL REQUIREMENTS

Restricted availability of unique research resources, upon which further studies
are dependent, can impede the advancement of research and delivery of medical
care.  The sharing of biomaterials, data, and software in a timely manner, on the
other hand, has been an essential element in the rapid progress that has been
made in the genetic analysis of mammalian genomes.  PHS policy requires that
investigators make unique research resources readily available for research
purposes to qualified individuals within the scientific community when they have
been published (PHS Grants Policy Statement in the July 12, 1996 issue of the NIH
Guide to Grants and Contracts).  Biomaterials (pathogen-free mutant animals,
preserved sperm and embryos) and other patentable research resources (e.g.,
phenotyping assays, mutagenesis protocols, instrumentation) produced in projects
funded by this RFA will be made available and distributed to the broader
scientific community.

For applications submitted in response to this RFA, three special requirements
exist regarding research resources produced in the proposed project: (1)
applicants are required to include a specific plan by which they will share
research resources with the wider scientific community; (2) NIH expects to make
a Determination of Exceptional Circumstances (DEC) to eliminate the potential for
patents on mutant mice, sperm, and embryos; and (3) applicants are required to
include a plan addressing if, or how, they will exercise their intellectual
property rights while making available to the broader scientific community other
patentable research resources (e.g., phenotyping assays, protocols,
instrumentation, and methodologies) not covered under the DEC.  Each is discussed
in detail below.

Plan to Share Research Resources

To address the joint interests of the government in the availability of, and
access to, the results of publicly funded research NIH requires applicants who
respond to this RFA to propose detailed plans for sharing the research resources
generated through the grant.  It is expected that the resources to be shared
include all materials developed in projects funded under the RFA, including but
not limited to, the following: mutant animals, preserved embryos and sperm,
phenotypic and genetic data, phenotyping assays, instrumentation, and mutagenesis
protocols. For this purpose, it is NIHs opinion that dissemination of such data
and materials via individual laboratories and Web sites is not sufficient, as it
would force interested investigators to search several different data collections
to make use of the results of this initiative.  It is preferable that data,
protocols, technologies, and biomaterials generated in grants funded under this
RFA should be placed in common, public repositories and databases that are widely
accessible by investigators in the scientific community.

It is expected that the investigator's data and biomaterials sharing plan will
include the following elements: (1) establishment of and access to a
comprehensive database containing detailed results from phenotyping screens; (2)
access to mutants identified through high-throughput phenotyping; (3) access to
preserved embryos and sperm for these mutants; (4) access to phenotyping assays
not currently available to the wider scientific community that are used to
characterize mutants; (5) access to mutants which have been screened but not
found to have a phenotype of interest to investigators associated with this
facility.  This means that, before discarding rejected mice, the facility will
specifically advertise their availability to the facility supported under RFA HD-
99-007, and other investigators in the wider scientific research community
wishing to conduct screens of their own but who do not otherwise have access to
mutagenesis facilities.  If demand for these mice is great enough, the facility
may have to develop priorities and rules for distribution; (6) elaboration of
mechanisms and protocols to be followed to promote the wide distribution of
resources to investigators in the scientific community; and (7) a distribution
timeline.

The initial review group will make an administrative comment on the adequacy of
the proposed plan for sharing and data access.  The adequacy of the plan will be
considered by NIH program staff 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.  Evaluation of renewal applications
will include assessment of the effectiveness of research resource release.

It is expected that this plan includes all elements of the guidelines developed
by the 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/Grant_info/Funding/Statements/data_release.html.
Adherence with this time frame is highly desirable. More rapid sharing is
encouraged.  Requests for exemptions or extensions will require compelling
justification and will be fully evaluated through peer review and by NIH program
staff.

Where appropriate, awardees may work with the private sector to make unique
resources available to the wider biomedical research community at a reasonable
cost.  Applicants may request funds to defray the costs of sharing resources,
with adequate justification.

Intellectual Property Rights

NIH is interested in ensuring that the research resources developed through this
RFA become readily available to the research community.  To ensure unrestricted
availability of mutant mice developed under this RFA, NIH expects to make a
Determination of Exceptional Circumstances (DEC) pursuant to 37 CFR 401.3(a)(2)
which will cover mutant animals, embryos, and sperm.  The purpose of the DEC is
to eliminate the potential for patents on mutant mice, embryos, and sperm to
undermine the development of a widely available national resource that is the
fundamental purpose of this RFA.

With regard to other patentable research results, such as phenotyping assays,
mutagenesis protocols, instrumentation, and methodologies, NIH requires
applicants who respond to this RFA to develop and propose a plan addressing if,
or how, they will exercise their intellectual property rights while making
available to the broader scientific community research resources produced in
projects funded under this RFA.  This is expected to include an elaboration of
the awardee's anticipated plans to generate, or not generate, patents and/or
exclusive or non-exclusive licensing of biomaterials and other patentable subject
matter created in projects funded 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 may be generated.  Note that this plan will NOT include mutant
animals, embryos and sperm (for which the potential for patents will be
eliminated pursuant to the DEC described above).  This plan also is in addition
to the plan for sharing and disseminating research resources described in the
previous section.

The initial review group will make an administrative comment on the proposed
plan.  The plan will be considered by NIH program staff in determining whether
the grant shall be awarded. The plan as approved, after negotiation with the
applicant when necessary, will be a condition of the award.  Evaluation of
renewal applications will include assessment of the awardee's adherence to the
proposed plan.

Applicants are also 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 awardee institution personnel responsible for patent matters.  The
awarding Institute reserves the right to monitor awardee activity in this area
to ascertain if patents or patent applications on phenotyping assays, protocols,
instrumentation, methodologies or other patentable subject matter are adversely
affecting the goals of this RFA.

LETTER OF INTENT

Prospective applicants are asked to submit by August 2, 1999 a letter of intent
that includes a descriptive title of the proposed research, the name, address,
and telephone and facsimile numbers of the PI, 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 and is not binding, it is highly
encouraged.  The information it contains will allow NIH program staff to estimate
the workload and also to avoid potential conflicts of interest in the review.

The letter of intent is to be sent to:

Dr. Hemin R. Chin
Division of Neuroscience & Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7190, MSC 9643
Bethesda, MD 20892-9643
Telephone: (301) 443-1706
FAX: (301) 443-9890
Email: hemin@nih.gov

PUBLIC BRIEFING

Prospective applicants are invited to attend a briefing on this RFA and on RFA
HD-99-007 on June 21, 1999 at the NIH Campus in Bethesda, MD.  Interested
scientists should contact the NIH program staff contact listed under LETTER OF
INTENT to obtain further information.  At the public briefing NIH program staff
will explain the purpose of these RFAs, provide detailed instructions about the
application process, and answer questions. Potential applicant institutions are
urged to send a representative to this briefing, both to gather information and
to exchange ideas with other potential applicants.  Anyone who cannot attend this
briefing will be provided with any distributed materials and with a summary of
the discussion.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) 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) 435-0714, Email: GrantsInfo@nih.gov. It
is also available at http://grants.nih.gov/grants/funding/phs398/phs398.html.

Because the application is expected to be more complex than applications for
regular research projects, it may be up to forty (40) pages in length.  Within
this page limitation, the application should include separate sections on 1)
overall strategy, purpose and plans, 2) mutagenesis (including breeding
strategy), 3) phenotyping, 4) database/bioinformatics, and 5) procedures for
distribution and sharing of pathogen-free biomaterials and data.

The RFA label available in the PHS 398 (rev. 4/98) 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, "Mouse Mutagenesis and Phenotyping: Nervous System and Behavior - MH-99-
007," 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 four 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, send one additional copy to:

Dr. Hemin R. Chin
Division of Neuroscience & Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7190, MSC 9643
Bethesda, MD 20892-9643
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 443-1706
FAX: (301) 443-9890
Email: hemin@nih.gov

Applications must be received by October 14, 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.  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.  The applicants should also ensure that their revised
applications respond to the review criteria by which applications in response to
this RFA will be evaluated.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and for
responsiveness by NIH program staff.  Incomplete and/or unresponsive applications
will be returned to the applicant without review.

Those applications that are complete and responsive to this RFA will be evaluated
for scientific and technical merit in accordance with the criteria stated below
by an appropriate peer review group.  There will be no site visits.  As part of
the initial merit review, all applications will receive a written critique and
may undergo a process in which only those applications deemed to have the highest
scientific merit will be discussed and assigned a priority score.  All
applications will receive a second level of review by the appropriate NIH
National Advisory Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In their
written comments reviewers will be asked to discuss the following aspects of the
application 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 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 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.

o  Significance: What will be the expected impact of mutant mice produced by the
facility on our understanding of the genetic bases of nervous system functions
and complex behaviors?  Will the facility have the capacity to serve as a
resource for the wider scientific community?

o  Approach: Does this study specify methodologies for rapid and efficient
genome-wide mutagenesis and high-throughput phenotypic characterization?  Is the
conceptual framework for efficiently conducting large-scale mutagenesis across
the mouse genome and comprehensive high-throughput phenotyping, adequately
developed, well- integrated, and appropriate to the aims of the project?  Does
the proposed strategy enable identification of both dominant and recessive
mutations? Does the applicant acknowledge potential problem areas and consider
alternative tactics?

o  Innovation:  Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

o  Investigator:  Is the investigator 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 (if any)?

o  Integration with other resources: Are the plans adequate to integrate the
mutants and phenotypic data with those collected in other comparable projects? 
Does the applicant have a plan to share with other mutagenesis and phenotyping
facilities mutants that may be of interest to those facilities?  Does the
application reflect awareness that the proposed facility be prepared to accept
mutants produced by other mutagenesis and phenotyping facilities for initial
screening and/or focused characterization?  Likewise, does the application
reflect awareness that some of the mutants produced by the proposed facility may
be sent to other mutagenesis and phenotyping facilities?

o  Exportability and accessibility: What is the likelihood that the mutants and
phenotypic information generated in the project will be made widely available in
a timely fashion to the scientific community?  Are state-of-the-art procedures
employed to ensure the distribution of pathogen-free mutant strains, embryos,
and/or sperm?  What is the likelihood that other patentable research results will
be widely available for the scientific community, given the proposed plan to
exercise (or to not exercise) intellectual property rights regarding phenotyping
assays, mutagenesis protocols, instrumentation, and methodologies?  Does the
project specify creation of a highly efficient and organized bioinformatics
database?  Do the investigator's quality control plans assure that databases
provided to the wider scientific community are accurate and highly efficient?

o  Environment:  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?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o  The reasonableness of the proposed budget and duration in relation to the
proposed research.

o  The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project proposed
in the application.

Applicants will be evaluated in the review process for their response to the
Research Objectives described above and for their ability to establish an
infrastructure that will permit rapid and efficient achievement of the project
aims.  This will include evaluation of the proposed project's ability to serve
as a resource to the broader scientific community.  In addition, the plan to
share research resources and the plan to exercise (or not exercise) intellectual
property rights regarding patentable research resources not covered under the DEC
will be judged for appropriateness.  The initial review group will also examine
the safety of the research environment.

AWARD CRITERIA

The earliest anticipated date of award is August 1, 2000.  Subject to the
availability of funds, and consonant with the priorities of this RFA, the
participating Institutes will provide funds for a project period not to exceed
five years.  Factors that will be used to make award decisions are as follows:
o  Quality of the proposed project as determined by rigorous scientific peer
review;

o  Cost effectiveness of the proposed strategy;

o  Promise of the proposed project to accomplish the goals of this RFA, by which
rapid, cost-effective high-throughput mutagenesis and phenotyping will be
accomplished;

o  Promise of the facility to serve as a resource for the broader scientific
community;

o  Adequacy of plans to make widely available to the research community all
research resources developed during the project;

o  Adequacy of plans to exercise (or not exercise) intellectual property rights
while permitting wide availability to the research community of patentable
research resources (e.g., phenotyping assays, mutagenesis protocols,
instrumentation, and methodologies) developed during the project that are not
covered under the DEC;

o  Adequacy of plans for participation by guest investigators;

o  Availability of funds.

SCHEDULE

Public Briefing:                June 21, 1999
Letter of Intent Receipt Date:  August 2, 1999
Application Receipt Date:       October 14, 1999
Scientific Review Date:         February/March 2000
Advisory Council Date:          May/June 2000
Anticipated Award Date:         August 1, 2000

INQUIRIES

Inquiries concerning this RFA are strongly encouraged, and NIH staff welcomes the
opportunity to clarify issues or questions from potential applicants.  Direct
inquiries regarding programmatic issues to:

Dr. Hemin R. Chin
Division of Neuroscience & Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7190, MSC 9643
Bethesda, MD 20892-9643
Telephone: (301) 443-1706
FAX: (301) 443-9890
Email: hemin@nih.gov

Dr. Jonathan D. Pollock
Division of Basic Research
National Institute on Drug Abuse
6001 Executive Boulevard, Room 4274, MSC 9555
Bethesda, MD 20892-9555
Telephone: (301) 435-1309
FAX: (301) 594-6043
Email: jp183r@nih.gov

Dr. Robert W. Karp
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402 þ MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 443-4223
FAX: (301) 594-0673
Email: rkarp@willco.niaaa.nih.gov

Dr. Bradley C. Wise
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C307, MSC 9205
Bethesda, MD  20892-9205
Telephone: (301) 496-9350
FAX: (301) 496-1494
Email: bw86y@nih.gov

Dr. Maria Y. Giovanni
Fundamental Retinal Processes
National Eye Institute
6120 Executive Boulevard, Suite 350 - MSC 7164
Bethesda, MD  20892-7164
Telephone: (301) 496-0484
FAX:  (301) 402-0528
Email:  myg@nei.nih.gov

Dr. Gabrielle Leblanc
Division of Fundamental Neuroscience and Developmental Disorders
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2139, MSC 9170
Bethesda, MD  20892-9170
Telephone: (301) 496-5745
FAX: (301) 402-1501
Email: gl54h@nih.gov

Dr. Rochelle Small
Division of Human Communication
National Institute on Deafness and Other Communication Disorders
6120 Executive Blvd. þ MSC 7180, Room 400C
Bethesda, MD 20892-7180
Telephone: (301) 402-3464
FAX: (301) 402-6251
Email: rochelle_small@nih.gov

Direct inquiries regarding fiscal matters to:

Mr. Bruce L. Ringler
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6122, MSC 9605
Bethesda, MD  20892-9605
Telephone: (301) 443-2811
FAX:  (301) 443-6885
Email:  bringler@mail.nih.gov

Mr. Gary Fleming
Grants Management
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3131, MSC 9541
Bethesda, MD 20892-9541
Telephone: (301) 443-6710
FAX: (301) 594-6847
Email: gf6s@nih.gov

Ms. Linda Hilley
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 504 þ MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 443-4703
FAX: (301) 443-3891
Email: lhilley@willco.niaaa.nih.gov

Mr. Joseph Ellis
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231
Bethesda, MD 20892-9205
Telephone: (301) 496-1472
FAX: (301) 402-3672
Email: ellisj@exmur.nia.nih.gov

Ms. Carolyn E. Grimes
Grants Management Branch
National Eye Institute
Executive Plaza South þ MSC 7164, Suite 350
Bethesda, MD 20892-7164
Telephone: 301-496-5884
FAX: 301-496-9997
Email: cegrimes@nei.nih.gov

Ms. Tina Carlisle
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3261, MSC 9190
Bethesda, MD  20892-9190
Telephone: (301) 496-9231
FAX: (301) 402-0219
Email: carlislt@ninds.nih.gov

Ms. Sharon Hunt
Division of Extramural Activities
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard þ MSC 7180, Room 400B
Bethesda, MD  20892-7170
Telephone:  (301) 402-0909
FAX:  (301) 402-1757
Email:  sh79f@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.242 (NIMH), 93.279 (NIDA), 93.273 (NIAAA), 93.866 (NIA), 93.853 (NINDS),
93.173 (NIDCD), and 93.867 (NEI).  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. Awards will be administered under PHS grants policy
as stated in the NIH Grants Policy Statement (October 1, 1998).

The PHS strongly encourages all grant 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.


Return to Volume Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.