Subject: RFA HD-9l-0l 2/l/9l NIH Guide
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Wed, 06 Feb 91 07:54 EST

Hi Paul,
   #4 in the revised string.  Please post as: RFAHD-91-01.910201.
Thanks.    Dottie
 ---------------------------- Text of forwarded message -----------------------
 
REQUEST FOR COOPERATIVE AGREEMENT APPLICATIONS
 
RFA:  HD-91-01
 
MULTICENTER COOPERATIVE AGREEMENT FOR STUDYING NEURAL TUBE
DEFECTS IN MUTANT MICE
 
P.T. 34; K.W. 0710030, 1002004, 1002019, 1002059, 0755030
 
National Institute of Child Health and Human Development
 
Application Receipt Date:  April 22, 1991
 
OVERVIEW
 
The National Institute of Child Health and Human Development
(NICHD) invites applications from investigators willing to
participate with NICHD assistance under cooperative agreements
in a multicenter cooperative study designed to investigate the
etiology of neural tube defects.  The objective of this study
is to bring together a multidisciplinary group of
investigators to characterize mammalian neurulation in a mouse
genetic model for spina bifida, the curly tail mouse.  The
benefit of such a cooperative venture will be to better define
the mechanisms by which normal neurulation occurs and to
characterize the processes leading to neural tube defects (NTDs) in a
well-defined mammalian model with potential applicability to
the human condition.
 
The Institute Staff Research Coordinator will cooperate with
the Principal Investigators in identifying research topics of
high priority, designing appropriate experimental protocols,
and integrating information and probes obtained from
individual projects among the group.  Awards will be for five
years.
 
BACKGROUND
 
Malformations of the central nervous system (CNS) are among
the most devastating developmental defects of man.  Among the
CNS malformations, NTDs are the most
frequent and most severe and pose a significant burden on the
individual and society, occurring in 1-2/1000 live births.
Attempts at prevention have been consistently blocked by an
inability to identify the major responsible factors.  Little
is known about the epidemiology of NTDs, nor are their
etiology and pathogenesis understood.  Neural tube defects are
thought to have multifactorial genetic and environmental
origins and are thought to result from interactions between
a number of inherited genes and generally unidentified
environmental factors.  Indeed, the current state of our
understanding of mammalian neural tube formation is still very
elementary.
 
Neurulation involves a series of tightly orchestrated events
involving changes in cell behaviors, cell structures, and
molecular determinants that occur both in the neural plate and
in adjoining tissues.  Research to date has demonstrated that
a perturbation in any of these complex processes may cause a
neural tube defect.  Fundamental cell and
molecular biological research is needed to understand the
critical events of normal development in order to identify the
mechanisms by which NTDs occur.
 
The Genetics and Teratology Branch issued two contracts for
the development, analysis, and distribution of genetic mouse
models for NTDs to identify the processes that cause spina
bifida.  One of these, the curly tailed mutant, has
provided a particularly suitable model for the study of human
neural tube defects.  The ct/ct mutation is incompletely
penetrant and is responsive to the same classes of
environmental factors as those affecting the human.  The NTDs
resemble human spina bifida morphologically with the majority
of the lesions located in the lumbo-sacral region.  Initial
characterization of ct/ct embryos has demonstrated that spina
bifida is due to a delay in closure of the posterior neuropore
and mice destined to have spina bifida exhibit a reduction in
the proliferative rate of gut endoderm and notochord cells.
In these mice NTDs are also associated with a reduction in
the basement membrane-associated hyaluronate accumulation in
the posterior neuropore region.
 
Other models, such as those identified at the Brachyury locus
(TCu/tct), delayed splotch and a number of transgenic mice,
also exhibit phenotypes in which neural tube formation is
abnormal.  Such mutant mice provide particularly suitable
models for characterizing the mechanisms by which the neural
tube is formed because, as in mammalian models, neurulation in mice
is similar to that which occurs in humans, the murine genome
is well characterized and embryos can be cultured in vitro
during neural tube formation.  These techniques allow
experimental manipulation of the embryo and permit the
assessment of both genetic and environmental factors on the
formation of NTDs.
 
This Request for Applications (RFA) aims to initiate cooperative
agreements in which the NICHD would participate with
investigators in a multidisciplinary study designed to identify
the mechanisms by which NTDs occur in mice destined to produce
spina bifida, focusing on the curly tail mouse.  The workscope
should include experimental protocols using genetic, cell
biological, and morphological approaches.  Analyses of various
aspects of neural tube formation will be coordinated among the
investigators and molecular probes that are developed will be
disseminated within the group.  Additionally, both the
NICHD-supported Human DNA Probe Repository and Monoclonal
Antibody Bank for Developmental Studies will be utilized for the
appropriate reagents.
 
RESEARCH SCOPE
 
This cooperative program will include four research groups
each of which will focus on different aspects of neural tube
formation using the curly tail mouse model for spina bifida.
The Principal Investigators will design experiments to address
several specific aspects of the process of neurulation using
the mouse model.  Investigators are expected to work in close
association with each other and with assistance of the NICHD
Staff Research Coordinator.  The Principal Investigators will
meet at the commencement of the cooperative program and then
yearly to evaluate the latest results and coordinate further
research.  In order to ensure a multidisciplinary approach,
individual Centers should emphasize research designs that
address the study of different aspects of neurulation.  The
scope of the entire cooperative program should include, but
not be limited to, the following research areas; and individual
investigators should focus on several, but not all, of these
questions in their proposal:
 
 o   development of markers to identify animals at risk for
     forming neural tube defects
 
 o   identification and characterization of those genes whose
     misexpression results in neural tube defects
 
 o   identification of tissue, cellular, and molecular changes
     in embryos destined to produce spina bifida, including
     adjacent cells and tissues involved in neural plate
     formation
 
 o   identification of the repertoire of behaviors that cells
     in the neural plate undergo during neurulation such as
     programmed cell death, changes in cell shape, cell
     interactions, position, and migratory behavior
 
 o   identification of the physical forces and molecular
     mechanisms involved in joining the neural folds including
     cell surface specialization and cell protrusions, cell
     recognition, and site specificity along the neural tube
 
 o   identification of environmental factors that modify the
     phenotypic expression of mutant genes affecting the
     developing nervous system.
 
 o   characterization of critical developmental periods during
     which the neural tube is primarily vulnerable to
     environmental perturbations and, if identified, the
     extent to which these perturbations are reversible
 
STUDY ORGANIZATION
 
A.  Requirements for individual applicants:
 
1.  Participants must be based in institutions where
    appropriate laboratory space and animal facilities are
    available.
 
2.  Applicants must have demonstrated expertise in an area of
    research associated with the problem and have committed
    adequate time for the proposed study and participation in
    the cooperative program.
 
3.  Applicants must be interested in interacting as a group
    with other laboratories, sharing information and reagents,
    and reevaluating research protocols.
 
B.  Guidance and Management:
 
Planning and implementation of studies will be supervised by a
Steering Committee consisting of Principal Investigators and
the NICHD Staff Research Coordinator for Genetics and
Teratology.  The chairperson will be selected on a rotating
basis from among the Principal Investigators.  The steering
committee will review the progress of the individual projects
annually, evaluate new perspectives on underlying biological
mechanisms, and determine the design of the future
experiments.
 
The responsibilities of the NICHD Staff Research Coordinator
for Genetics and Teratology include:
 
Assisting in the development of optimal approaches to
protocols where there are areas requiring interaction among
the Centers.
 
Assisting and reviewing all phases of the study, improving and
strengthening cooperation among the Centers, and helping to
redirect efforts if necessary.
 
Assisting in determining jointly with awardees, the need to
add additional Centers or to phase out a Center when
performance requirements are not met or research aims are
fulfilled.
 
C.  Content of the Application
 
Responses to this RFA must use the
research project application (Form PHS 398, rev. 10/88) that
include a description of the research protocols and the
participant's perceived role in this cooperative venture.  The
scope of each proposal should focus on 2-3 areas of research
on neural tube formation in this model in order to ensure that
the cooperative program will have adequate breadth.  Proposals
will be selected both on scientific merit and on their
contribution to the balance of the scope of the program.  All
essential information should be entered into the body of the
application.
 
MECHANISM OF SUPPORT
 
The funding mechanism to be used to assist the scientific
community in undertaking this program of research into the
etiology of neural tube defects will be a cooperative
agreement (UO1) between each participant and the NICHD.  The major
difference between a cooperative agreement and a research
grant is that there will be substantial programmatic
involvement of NICHD staff above and beyond the levels
required for traditional program management of grants.
Specifically, the awardees will develop the research protocols
to meet overall needs of the study with assistance from the
NICHD Staff Research Coordinator, who will aid the awardees
and the Steering Committee in the following ways:
 
 o   Assistance in the identification of important areas of
     study.
 o   Assistance in the development of research protocols.
 o   Assistance in the review and evaluation of the programs
     at yearly intervals.
 o   Assistance in reporting results to the community of
     investigators.
 
The responsibilities of the awardees will be as follows:
 
 o   Identification of priority issues for research.
 o   Development and implementation of research aims.
 o   Collection and transmission of data to the steering
     committee.
 o   Analysis of data and publication of the results of the
     study.
 
All parties will agree to accept the coordinating role of the
group and the participatory and cooperative nature of the
group process.  Awardees will retain custody of and rights to
their data developed under these awards.
 
The support of awards pursuant to this RFA is contingent upon
ultimate receipt of appropriated funds for this purpose.  The
number of awards will be influenced by the overall merit of the
applying Centers and by the amount of funds available to the
Institute.  $800,000 (for direct costs) has been set aside for
the first year of these Cooperative Agreements and it is
anticipated that four meritorious applications will be funded.
 
Arbitration procedures will be instituted in addition to the
customary programmatic and financial negotiations that occur
in the administration of grants only when agreement cannot be
reached between the awardee and the NICHD Staff Research
Coordinator on programmatic issues that may arise after the
award has been made.  These procedures will be invoked if
actions of the awardee inhibit the exchange of information and
reagents among the members of the cooperative program.  In
that event, an arbitration panel will be formed consisting of
one person selected by the Principal Investigator, one person
selected by the Staff Research Coordinator, and a third person
selected by these two members.  The decision of the
arbitration panel will be binding.
 
These program-related terms and conditions will be
incorporated into the Notice of Grant Award.  The special
Terms of Award of cooperative agreements are in addition to,
and not in lieu of, otherwise applicable OMB administrative
guidelines, DHHS grant administration regulations at 45 CFR
Part 74, and other DHHS, PHS, and NIH grant administration
policies.  The NICHD arbitration procedure in no way affects
the right of a recipient of a Cooperative Agreement to appeal
an adverse determination in accordance with PHS regulations at
42 CFR Part 50, Subpart D, and DHHS regulations at 45 CFR Part
16.  Business management aspects of these awards will be
administered in the NICHD Grants Management Branch in
accordance with DHHS, PHS, and NIH grant administration
requirements.
 
REVIEW PROCEDURES AND CRITERIA
 
A. Review Procedure
 
Applications will be reviewed by NICHD staff for
responsiveness to the RFA.  Applications judged to be
nonresponsive will be returned to the applicant.  Responsive
applications may be subjected to a triage by a peer-review
group to determine their scientific merit relative to the
other applications received in response to this RFA.  NIH will
withdraw from competition those applications judged to be
noncompetitive for award and notify the applicant investigator
and institutional business official.  Those applications
judged to be competitive will be further evaluated for
scientific/technical merit by a review group convened solely
for this purpose by the Division of Scientific Review, NICHD.
Following review by the Initial Review Group, applications
will be evaluated by the Institute's Advisory Council for
program relevance and policy issues before awards for
meritorious proposals are made.
 
B.  Review Criteria
 
Applications found to be responsive to the RFA and meeting the
minimum requirements will be evaluated on technical merit
according to the criteria listed below.
 
1.  Qualifications, experience, and commitment of key personnel
will be judged on scientific knowledge and abilities in areas
relevant to the conduct of the experiments proposed and an
adequate commitment of time for the proposed study and
participation in the cooperative program.
 
2.  Protocols and procedures will be judged on the scientific
merit of the proposal, the responsiveness to the objectives of
the study as outlined in this RFA, and to the appropriate
balance of experimental approaches among the groups.
 
3.  Facilities and management will be judged by the adequacy
of institutional animal facilities, animal care management,
and administrative and technical capabilities.
 
4.  Overall program balance will be assessed relative to the
research design of each individual application to ensure a
wide diversity of approaches to the neural tube studies.
 
APPLICATION PROCEDURE
 
Applications must be submitted on form PHS 398 (rev.  10/88),
available in business or grants offices at most academic research
institutions and from the Division of Research Grants, NIH.  The
phrase PREPARED IN RESPONSE TO RFA HD-91-01 Cooperative
Multicenter Agreement for Studying Neural Tube Defects in Mutant
Mice must appear in item 2 of the face page.  The RFA label,
available in the 10/88 version of Form PHS 398, must be affixed
to the bottom of the face page.  Failure to use this label could
result in delayed processing of your application such that it may
not reach the review committee in time for review.  The original,
and four (4) copies, to be received no later than April 22, 1991,
must be sent to:
 
Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
In addition to the copies sent to the Division of Research
Grants, two (2) copies of the application must be sent to:
 
Laurance Johnston, Ph.D.
Division of Scientific Review
National Institute of Child Health and Human Development
Executive Plaza North, Room 520A
Bethesda, MD  20892
 
TIMETABLE
 
Application Receipt Date:  April 22, 1991
 
Initial Review Date:  June/July 1991
 
Review by Advisory Council:  September 1991
 
Anticipated Award Date:  December 1, 1991
 
Inquiries regarding this announcement may be directed to:
 
Delbert Dayton, M.D.
Genetics and Teratology Branch
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
Executive Plaza North, Room 643
9000 Rockville Pike
Bethesda, MD  20892
Telephone:  (301) 496-5541
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.865, Research for Mothers and Children.
Awards will be made under the authority of the Public Health
Service Act, Section 301 (42 USC241), and administered under
PHS grant policies and Federal Regulations 42 CFR Part 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.