EXPIRED
MUTAGENESIS SCREENS/PHENOTYPING TOOLS FOR ZEBRAFISH
Release Date: February 16, 2000
RFA: HD-00-004
Trans-NIH Zebrafish Coordinating Committee
National Institute of Child Health and Human Development
National Cancer Institute
National Center for Research Resources
National Eye Institute
National Heart, Lung, and Blood Institute
National Human Genome Research Institute
National Institute on Alcohol Abuse and Alcoholism
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute on Deafness and Other Communication Disorders
National Institute of Dental and Craniofacial Research
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute on Drug Abuse
National Institute of Environmental Health Sciences
National Institute of General Medical Sciences
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke
Letter of Intent Receipt Date: April 16, 2000
Application Receipt Date: May 19, 2000
THIS RFA USES THE MODULAR GRANT AND JUST-IN-TIME CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.
PURPOSE
The purpose of this Request for Applications (RFA) is to encourage research
designed to exploit the power of mutagenesis screening in zebrafish in order
to detect and characterize genes, pathways, and phenotypes of interest in
development, behavior, organ formation, disease processes. Applications that
propose to advance the technologies associated with such phenotyping also are
welcome.
This RFA is the result of an NIH initiative with participation of the
Institutes listed above, working though the Trans-NIH Zebrafish Coordinating
Committee (ZFCC), under the co-chairmanship of the National Institute of Child
Health and Human Development (NICHD) and the National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK). Since its formation in 1998, the
committee has played an active role as an advocate for the zebrafish as an
important model for development and disease research.
The following components of the National Institutes of Health (NIH) are co-
sponsors of this solicitation: National Institute of Child Health and Human
Development (NICHD), National Cancer Institute (NCI), National Center for
Research Resources (NCRR), National Eye Institute (NEI), National Heart, Lung
and Blood Institute (NHLBI), National Human Genome Research Institute (NHGRI),
National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute
of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute
on Deafness and Other Communication Disorders (NIDCD), National Institute of
Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK), National Institute on Drug Abuse
(NIDA), National Institute of Environmental Health Sciences (NIEHS), National
Institute of General Medical Sciences (NIGMS), National Institute of Mental
Health (NIMH), and the National Institute of Neurological Disorders and Stroke
(NINDS).
HEALTHY PEOPLE 2010
The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2010," a PHS-led national
activity for setting priority areas. This RFA is related to one or more of
the priority areas. Potential applicants may obtain "Healthy People 2010" at
http://odphp.osophs.dhhs.gov/pubs/hp2000.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign for-profit and non-
profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and eligible
agencies of the Federal government. Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as Principal
Investigators (PI).
MECHANISM OF SUPPORT
This RFA will use the NIH research project grant (R01) award mechanism.
Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant. The total project period for an
application submitted in response to this RFA may not exceed five years. The
anticipated award date is April 1, 2001.
This RFA is a one-time solicitation. Future new or competing continuation
applications will compete with all investigator-initiated applications and be
referred and reviewed according to the customary peer review procedures.
Although this RFA is the result of a trans-NIH initiative, awards will be made
through the Institute whose mission is most closely related to the proposed
work. Through the Trans-NIH Zebrafish Coordinating Committee, each
Institute/Center (IC) will share with the other participating ICs, findings of
any research supported as a result of this RFA. All investigators funded under
this initiative will be expected to work together cooperatively so that the
information learned and the models developed will be of maximum usefulness to
the community.
FUNDS AVAILABLE
The participating ICs intend to commit approximately $4.5 million in total
costs (direct plus Facilities and Administrative [F & A] costs) in FY 2001 to
fund 8 to 10 new grants in response to this RFA. An applicant may request a
project period of up to five years and a budget for direct costs of up to
$250,000 per year, including F & A costs on consortium arrangements. Because
the nature and scope of the research proposed may vary, it is anticipated that
the size of awards also will vary. Although the financial plans of the
participating ICs provide support for this program, awards pursuant to this
RFA are contingent upon the availability of funds and the receipt of a
sufficient number of meritorious applications.
RESEARCH OBJECTIVES
Background
The trans-NIH Zebrafish Coordinating Committee (ZFCC) continues to play an
active role as an advocate for the zebrafish model. The committee’s initial
efforts resulted in RFA DK-98-006, entitled Genomic Resources for the
Zebrafish, and continued with a Program Announcement PA-98-074, entitled The
Zebrafish as an Animal Model for Development and Disease Research. On May
10-11, 1999, the ZFCC sponsored a workshop entitled Genomic and Genetic Tools
for the Zebrafish. At this workshop, which expanded upon the Non-mammalian
Models Workshop held on February 16-17, 1999, zebrafish researchers were
asked to help prioritize the short- and long-term needs of the community. One
result of the workshop was the recommendation that more genetic screens in the
zebrafish need to be supported by the NIH. The current RFA addresses, in
part, this and some of the other recommendations made by workshop
participants. This RFA is designed to complement and continue NIH efforts to
support the zebrafish as an important and timely animal model for research.
In the past decade, mutational analyses in the non-vertebrate genetic models
of the worm (Caenorhabditis elegans) and the fruitfly (Drosophila
melanogaster) have contributed significantly to our understanding of early
developmental pathways. For example, these studies have led to the discovery
of genes encoding signals, components of signaling systems, enzymes, and
transcriptional regulators that act during embryonic development. These genes
often operate in complex cascades to regulate pattern formation, cell fate,
and specification, as well as later events such as development of the eye,
heart, and other organs. While these invertebrate systems have revealed much
information and shown that numerous aspects of development are highly
conserved among invertebrates and vertebrates, many features of patterning and
morphogenesis of the vertebrate embryo are distinct and thus cannot be studied
in invertebrates. The vertebrate embryo has many characteristics not found in
invertebrates, including a substantially different body plan and greater
complexity of the nervous system, as well the presence of organs that have no
clear counterparts in simple invertebrates. Thus, a complete understanding of
human development will require experimentation in vertebrate model organisms.
The study of mutations that affect development has been possible in the
mouse, but the mouse embryo is not accessible in utero throughout much of its
development. Consequently, mutational studies in this species have been
limited largely to defects in postnatal maturation. While reverse genetics
(e.g., gene knockouts) have been useful in the mouse model, the substantial
cost of maintaining large mouse colonies has limited the applicability of
forward genetic approaches on a large scale. These limitations will have a
profound impact on the rapid discovery of genes important in vertebrate
development, and relevant to human disease.
As a vertebrate, the zebrafish, Danio rerio, is more closely related to humans
than are yeast, worms or flies. It has a number of advantageous features as a
model organism for study of vertebrate development, disease, and biological
pathways. Many features of zebrafish development have been characterized,
including early embryonic patterning, early development of the nervous system,
and aspects of cell fate and lineage determination. The embryos are easily
obtainable in large numbers and accessible throughout development, they are
transparent, and undergo rapid organogenesis, making them very amenable for
developing phenotypic screens. In live embryos, the same specific cell or
even cellular processes can, in many cases, be identified from individual to
individual, affording a high level of precision in characterizing the effect
of a developmental, environmental or genetic perturbation. The use of
zebrafish to study vertebrate development, disease, and pathways of interest
has been validated further by the demonstration that many of its genes show a
high degree of structural and functional similarity to their human homologues.
The most powerful and unique feature of the zebrafish is that it is a
vertebrate model organism that has proven that large-scale forward mutagenesis
screens can be performed with relative ease.
The purpose of this initiative is to provide support for zebrafish mutagenesis
and phenotypic screening efforts. To date, screens have focused exclusively
on phenotypes in embryonic development, despite interest in the zebrafish
research community to do so, phenotypic screens in adult fish have not yet
been possible, because of the general difficulty in obtaining funding for
mutagenesis and screening research. Phenotypic screens of post-embryonic fish
will be needed to identify alterations in sensory and motor systems function,
learning and memory, or behavioral responses to environmental toxins and
pharmaceutical agents. Two large-scale screens have been performed, and the
transparent embryos have been screened for defects in overall embryonic
pattern morphogenesis or organ formation.
As reported in the December1996 issue of Development, screens have
identified a substantial number of mutations that affect the formation of
organ systems, including defects in the nervous system, skeletal muscle,
craniofacial region, kidney and endocrine organs, cardiovascular and
gastrointestinal systems, and the sensory cells of lateral line systems that
are important to auditory and vestibular function. In the last three years,
many of the mutations responsible for these phenotypes have been mapped, and
the genes cloned and characterized. Investigators in the zebrafish community
have only begun to exploit the power of mutagenesis screening to detect genes
essential for organogenesis and associated developmental physiology, and they
have yet to attempt screens for mutations affecting nervous system function
(other than its development) and behavior. Saturation mutagenesis of the
zebrafish genome will be an indispensable means of achieving a complete
understanding of the development, physiology, and behavior of this vertebrate.
With the advent of new, promising insertional mutagenesis strategies for the
zebrafish, it is more pressing than ever to develop a strong support base for
creative, intensive mutagenesis screens.
In the past year, significant progress has been made in the characterization
of the zebrafish genome, which will facilitate the identification by
positional cloning of zebrafish genes responsible for specific phenotypes.
The Trans-NIH Initiative on Genomic Resources for the Zebrafish, that was co-
supported by 13 NIH Institutes and Centers and that funded five investigators
beginning in the fall of 1998, has contributed significantly to this progress.
To date, grantees funded under this initiative are increasing the resolution
of zebrafish physical maps using microsatellite markers, CA repeat markers,
and conformational polymorphisms, they have completed and published a new
radiation hybrid map that covers at least 88 percent of the zebrafish genome
[an invaluable tool for mapping expressed sequence tags (ESTs), cloned genes,
and candidate genes for specific mutations], they have generated approximately
20 thousand new ESTs, and they have begun to determine a genetic map for the
zebrafish by construction of a complete deletion panel.
Research Scope
The objective of this RFA is to broaden the range, power, and utility of
screens for new mutants of zebrafish. It will, therefore, support proposals
for development of improved or novel methods for mutagenesis screens, as well
as proposals for the actual execution of such screens. Methodology developed
and data and mutants generated as a result of this RFA are expected to be made
widely available to the research community. Applicants must include as part
of their application a plan for disseminating these resources, adequacy of
this plan will be considered in the review of applications responding to this
RFA (see below).
Objectives to be addressed in applications submitted in response to this RFA
include, but are not limited, to the following:
o Development and/or application of novel phenotypic screens for mutants.
These screens may be based on observation of alterations in morphology,
physiology, or behavior.
o Development and/or application of novel methods of mutagenesis (e.g.,
insertional).
o Genetic screens focusing on identifying mutations that affect the structure
and function of specific tissue/organ systems.
o Screens focusing on identifying novel developmental genes and pathways,
including those mediating sensitivity or resistance to environmental
teratogens.
o Screens to analyze the genetic basis of adult phenotypes including behavior,
aging, organ disease, cancer, and responses to environmental toxins and drugs.
o Screens to detect altered gene expression patterns, as a tool to identify
components of genetic pathways or those altered by environmental agents.
o Sensitized screens, using strains carrying a known mutation, in order to
identify extragenic suppressors or enhancers of that mutation.
In addition, all applications are expected to address the following:
o A proposed sharing plan to insure that mutant zebrafish, sperm, embryos,
genetic and phenotypic screens, mutagenesis protocols, and genetic and
phenotypic data for all mutant strains are widely available to the scientific
community.
o A proposed plan addressing if, or how, the PI and grantee institution will
exercise their intellectual property rights regarding patentable research
resources, such as mutant fish, sperm, embryos, genetic and phenotypic
screens, mutagenesis protocols, and genetic and phenotypic data for all mutant
strains produced in projects funded under this RFA (see SPECIAL REQUIREMENTS,
below).
Interests of Participating Institutes and Centers
The participating NIH ICs have provided a brief outline of their interests as
they relate to the goals of this RFA. These brief mission statements are
intended to give some understanding of the breadth of the biomedical areas of
interest in development of this model.
NCI: Generation and study of zebrafish models to identify and place genes in
functional pathways that affect growth and development, in particular,
genes/pathways that, when altered, result in uncontrolled or cancerous growth.
Identification of key sites within these pathways that could be exploited for
cancer therapeutic discovery purposes.
NCRR: The NCRR supports research projects that broaden the utility of the
zebrafish model for cross-cutting biomedical research that is not encompassed
within a single NIH Institute or Center. Interests include, but are not
limited to, development of new methods for mutagenesis and/or phenotypic
characterization that would be of use in research on a wide range of diseases
or organs, particularly if these methods could be applied to other animal
models as well as the zebrafish.
NEI: Fundamental mechanisms underlying all aspects of eye development,
function and disease, including development of the retina and lens, optic
nerve axon guidance and the neural circuitry producing eye movements and
oculomotor behaviors.
NHGRI: Proposals for the development of high throughput, widely applicable
technologies or methodologies to examine gene function on a genomic scale.
This could include initial development of high throughput or large-scale
methods for examining gene expression, development of tools for comprehensive
mutational analysis, or genome-scale identification of regulatory regions.
NHLBI: Cellular and molecular functions of the mutant genes in development as
models for human cardiovascular, blood, and pulmonary disorders, and circadian
mechanisms regulating rest/activity cycles. Genetic basis of disorders of
cardiovascular development and function, developmental aspects of endothelial
dysfunction as the basis for systemic and pulmonary vascular disorders,
developmental defects in hematopoiesis and relationship to disorders of the
hematopoietic system, genetic basis of angiogenesis and vasculogenesis, effect
of mutations on subsequent organ development leading to such disorders as
arrhythmia, cardiac hypertrophy, dilated cardiomyopathy, heart failure, lung
hypoplasia and bronchopulmonary dysplasia, the genetic basis, regulation, and
role of biological clock mechanisms in development and circadian behavior.
NIAAA: Mechanistic studies of ethanol-induced teratogenesis, behavioral
impairments, and organ damage.
NIAMS: Mutations that have the potential to illuminate the development and
function of the vertebrate musculoskeletal system and skin. The
musculoskeletal system includes muscle, bone, articulated joints, cartilage,
tendon, and ligament. Priority will be given to the establishment of
collaborations between investigators with expertise in the zebrafish and
investigators with expertise in the musculoskeletal systems and skin of
mammals and humans.
NICHD: Identification, cloning, and characterization of the genes important
in normal development as well as those mutant genes that cause developmental
defects. Elucidation of the cellular, biochemical, molecular, and genetic
mechanisms underlying normal and defective development. This includes, but is
not limited to, the study of general mechanisms of pattern formation and cell
lineage, neural crest development, cell specification, differentiation,
migration, and fate in early development of many organs/systems such as limb,
nervous system, immune system, and heart.
NIDA: Identification of mechanisms underlying tolerance, sensitization, and
addiction to drugs of abuse such as nicotine, amphetamine, cocaine, opiates,
barbiturates, and hallucinogens. Identification of genetic suppressors and
enhancers of the teratological effects of drugs of abuse on behavior and the
nervous system. Processes involved in the development of brain regions
mediating the hedonic properties of drugs of abuse.
NIDCD: Identification and cloning of genes involved in the normal and
disordered development of hearing, balance, smell, and taste sensory systems.
Elucidation of the cellular, molecular, and biochemical mechanisms governing
the proliferative, plastic, and regenerative capacities of these sensory cells
and tissues.
NIDDK: Research on diabetes, particularly studies on pancreatic beta cell
function and development, obesity and mechanisms underlying satiety, other
endocrine, and metabolic diseases, hematologic disorders, and diseases of the
digestive system, liver, kidney, and urinary tract. Studies aiming to clarify
the cellular and molecular events that dictate tissue and organ formation in
all these systems are considered of relevance. These studies could include,
but need not be limited to, studies to develop cell lines from any of the
tissues or organs of interest, studies to characterize normal or abnormal
function of tissues or organs of interest, methods to screen and identify
additional mutations in these systems, studies to define the molecular
mechanisms that dictate cell-specific gene expression in relevant cell types.
NIDCR: All aspects of normal and abnormal craniofacial development, including
genetics, complex origins of craniofacial disorders, cell lineages and
differentiation, cell signaling and gene regulation, embryonic patterning,
imaging, biomimetics, and new technologies for high-throughput genetic and
protein screens.
NIEHS: Studies to examine the mechanism whereby environmental factors/agents
alter any aspect of development. This includes the screening for mutants that
ameliorate the toxicity of environmental agents, and the subsequent
identification and characterization of the genes and pathways involved in
their action. Characterization of the interactions among genetics,
environmental agents, and time during development that lead to structural or
functional abnormalities. Development of a mechanistically based model for
testing environmental agents for developmental toxicity.
NIGMS: Basic biomedical research that addresses fundamental biological
mechanisms such as those that underlie gene regulation, chromosome
organization and mechanics, cell growth and differentiation, pattern
formation, sex determination, morphogenesis, cell cycle control, behavior, the
genetics of complex traits, and the application of mathematical models to
complex biological systems.
NIMH: Investigations that examine molecular, cellular, and biochemical bases
of genetic mutations affecting neurogenesis, biological rhythms, learning,
memory, and other cognitive functions and behaviors of the nervous system.
These studies include, but are not limited to, development of screening
methods for such mutations, identification, isolation, mapping, and functional
analyses of the genes underlying mutations.
NINDS: Research on the development, normal function, and diseases of the
nervous system. This research might include the use of mutants to understand
the mechanisms controlling the following processes: neurogenesis, nervous
system patterning, cell lineage, cell migration, programmed cell death, axon
pathfinding and regeneration, myelination, and motor and sensory function.
The areas of interest listed above are not presented in any order of priority,
they are only examples of areas of research to consider. Applications
representing areas of interest to more than one Institute or Center will be
assigned to multiple Institutes or Centers for funding consideration.
Applicants are encouraged to propose work in other areas that are related to
the objectives and scope of this RFA.
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. NIH 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 [NIH Grants Policy Statement
(http://grants.nih.gov/grants/policy/nihgps, Principles and Guidelines for
Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating
Biomedical Research Resources: Final Notice, December 1999
(http://www.ott.nih.gov/policy/rt_guide_final.html)]. Biomaterials (pathogen-free
mutant animals, preserved sperm and embryos) and other patentable research
resources (e.g., genetic and phenotypic screens, mutagenesis protocols, and
genetic and phenotypic data for all mutant strains) produced in projects
funded by this RFA are expected to be made available and distributed to the
broader scientific community.
The NIH is interested in ensuring that the research resources developed
through this RFA become readily available to the research community for
further research, development, and application, in the expectation that this
will lead to products and knowledge of benefit to the public. For this reason,
NIH is concerned that patents on mutant fish, embryos, and sperm, genetic and
phenotypic screens, mutagenesis protocols, and genetic and phenotypic data for
all mutant strains and other research resources might have a chilling effect
on the future development of products and information that may improve the
public health. At the same time, NIH recognizes the rights of grantees to
elect and retain title to subject inventions developed under Federal funding
under the provision of the Bayh-Dole Act.
For applications submitted in response to this RFA, there are two special
requirements regarding research resources produced in the proposed project:
(1) Applicants are required to include in their applications a specific plan by
which they will
share research resources with the wider scientific community.
(2) 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 patentable research resources (e.g., mutant fish, embryos and sperm,
genetic and phenotypic screens, mutagenesis protocols, and genetic and
phenotypic data for all mutant strains).
Applicants are encouraged to discuss their proposed plans for addressing these
requirements with their institutional offices of technology transfer. Each of
the two requirements are 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 fish, embryos and sperm,
genetic and phenotypic screens, mutagenesis protocols, and genetic and
phenotypic data for all mutant strains. For this purpose, it is NIH’s 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.
The National Resource for Zebrafish at the University of Oregon is being
established as a focal point for sharing of resources among investigators
using zebrafish. Currently, the Resource is capable of accepting frozen sperm
and some live fish stocks. It is expected to be fully operational, with
expanded capacity to accept live fish stocks, by mid-2000. In addition to
serving as a stock center, the Resource operates a comprehensive database,
ZFIN. Plans to share materials generated by projects under this RFA through
the National Resource for Zebrafish should include evidence/documentation of
coordination with investigators at the Resource. Plans to deposit fish at the
Resource should state whether this will be done as frozen sperm or live fish
stocks. For frozen sperm, adequate personnel and funding must be requested to
produce, cryopreserve, and ship the sperm according to Resource specifications
and using appropriate shipping containers available from the Resource. For
live fish stocks, it must be clear that the Resource is prepared to accept the
numbers of stocks to be generated or agrees to handle the demands of producing
and freezing sperm from live stocks deposited. Plans to deposit reagents
should likewise be coordinated. Plans for informatics should be coordinated
with the Resource to ensure that necessary hardware/software requirements can
be accommodated for automatic deposit of data finalized by individual
laboratories to ZFIN on a periodic basis. A reasonable time frame for
periodic deposition of mutants, sperm, reagents and data should be specified
in the application and will be considered during the review of the plan for
sharing.
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 genetic and phenotypic screens, mutagenesis protocols,
and genetic and phenotypic data for all mutant strains, (2) access to mutants
identified through genetic and phenotypic screens, for example, through the
National Resource for Zebrafish, (3) access to mutant fish, embryos, oocytes
and sperm for these mutants, for example, through the National Resource for
Zebrafish, (4) access to methods for genetic and phenotypic screens and
mutagenesis protocols, not currently available to the wider scientific
community, and (5) access to mutants with unusual phenotypes, not of interest
to investigators associated with this grant.
The scientific review group will evaluate the adequacy of the proposed plan
for sharing and data access. Comments on the plan and any concerns will be
presented in an administrative note in the summary statement. The adequacy of
the plan will be considered by NIH program staff on the Trans-NIH Zebrafish
Coordinating Committee and will be important 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
non-competing continuation applications will include assessment of the
effectiveness of research resource release.
Intellectual Property Rights
NIH is interested in ensuring that the research resources developed through
this RFA become readily available to the research community.
With regard to patentable research results, such as mutants identified through
genetic and phenotypic screens, embryos, oocytes and sperm for these mutants,
genetic and phenotypic screens, mutagenesis protocols, and genetic and
phenotypic data for all mutant strains and methodologies, the 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 applicant’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 agreements involving
intellectual property rights, including options to for-profit research
sponsors that are associated with biomaterials and data that may be generated.
The requirement for this plan is in addition to the requirement for the plan
for sharing and disseminating research resources described in the previous
section.
The scientific review group will evaluate the adequacy of the proposed plan
for handling intellectual property rights. Comments on the plan and any
concerns will be presented in an administrative note in the summary statement.
The adequacy of the proposed plan will be considered by NIH program staff on
the Trans-NIH Zebrafish Coordinating Committee 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
non-competing continuation applications will include assessment of the
awardee’s adherence to the proposed plan.
Applicants also are reminded that the grantee institution is required to
disclose each subject invention to NIH within two months after the inventor
discloses it in writing to grantee institutional 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
mutants identified through genetic and phenotypic screens, embryos and sperm
for these mutants, genetic and phenotypic screens, mutagenesis protocols, and
genetic and phenotypic data for all mutant strains or other patentable subject
matter are adversely affecting the goals of this RFA.
Principles and guidelines for recipients of NIH research grants on obtaining
and disseminating biomedical research resources can be found at:
http://www.ott.nih.gov/policy/rt_guide_final.html.
Post-Award Management
During the course of the award period, the Principal Investigators may be
invited to meet with NIH staff to review and share scientific progress. Other
scientists external to and knowledgeable about these studies also may be
invited to participate. Application budget requests should include travel
funds for the Principal Investigator to attend annual meetings in the
metropolitan Washington, D.C. area.
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the overall proposed research, the name, address and
telephone number of the Principal Investigator, the identities of other key
personnel and participating institutions, and the number and title of this
RFA. Although the letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information that it
contains allows NIH staff to estimate the potential review workload and to
avoid conflict of interest in the review.
The letter of intent is to be sent to Dr. Deborah Henken at the address listed
under INQUIRIES by April 16, 2000.
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, on the Internet at
http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the Division
of Extramural Outreach and Information Resources, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301-710-0267, E-mail: [email protected].
Application Instructions
Specific application instructions have been modified to reflect MODULAR
GRANT and JUST-IN-TIME streamlining efforts being examined by the NIH.
Complete and detailed instructions and information on Modular Grant
applications can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm.
The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The
just-in-time concept allows applicants to submit certain information only when
there is a possibility for an award. It is anticipated that these changes
will reduce the administrative burden for the applicants, reviewers and
Institute staff.
Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year. (Applications that request
more than $250,000 direct costs in any year must follow the traditional PHS
398 application instructions.) The total direct costs must be requested in
accordance with the program guidelines and the modifications made to the
standard PHS 398 application instructions described below:
o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (F&A) costs] for the initial budget
period. Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.
o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the
application.
o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required
and will not be accepted with the application.
o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample
pages.) At the top of the page, enter the total direct costs requested for
each year. This is not a Form Page.
Under Personnel, list key project personnel, including their names, percent of
effort, and roles on the project. No individual salary information should be
provided. However, the applicant should use the NIH appropriation language
salary cap and the NIH policy for graduate student compensation in developing
the budget request.
For Consortium/Contractual costs, provide an estimate of total costs (direct
plus F & A) for each year, each rounded to the nearest $1,000. List the
individuals/organizations with whom consortium or contractual arrangements
have been made, the percent effort of key personnel, and the role on the
project. Indicate whether the collaborating institution is foreign or
domestic. The total cost for a consortium/contractual arrangement is included
in the overall requested modular direct cost amount. Include the Letter of
Intent to establish a consortium.
Provide an additional narrative budget justification for any variation in the
number of modules requested.
o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by
reviewers in the assessment of each individual"s qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for
all key personnel, following the instructions below. No more than three pages
may be used for each person. A sample biographical sketch may be viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm.
- Complete the educational block at the top of the form page,
- List position(s) and any honors,
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years,
- List selected peer-reviewed publications, with full citations.
o CHECKLIST: This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the
type of agreement and the date. All appropriate exclusions must be applied in
the calculation of the F&A costs for the initial budget period and all future
budget years.
o The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.
Submission Instructions
The RFA label available in the PHS 398 (rev. 4/98) application form must be
stapled to the bottom of the face page of the application and must display the
RFA number HD-00-004. A sample RFA label is available at
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this is
in the pdf format. Failure to use this label could result in delayed
processing of the application such that it may not reach the review committee
in time for review. In addition, the RFA title and number must be typed on
line 2 of the face page of the application form and the YES box must be
marked.
Submit a signed, typewritten original of the application, including the
Checklist, and five 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)
Applications must be received by May 19, 2000. If an application is received
after that date, it will be returned to the applicant without review.
The CSR will not accept any application in response to this RFA that is
essentially the same as one currently pending initial review, unless the
applicant withdraws the pending application. The CSR will not accept any
application that is essentially the same as one already reviewed. This does
not preclude the submission of substantial revisions of applications already
reviewed, but such applications must include an introduction addressing the
previous critique.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness and adherence to
the Application Instructions above by CSR and for responsiveness by the Trans-
NIH Zebrafish Coordinating Committee. Incomplete and/or non-responsive
applications will be returned to the applicant without further consideration.
Applications that are complete and responsive to the RFA will be evaluated
for scientific and technical merit by an appropriate peer review group
convened by the CSR in accordance with the review criteria stated below. As
part of the initial merit review, all applications will receive a written
critique and undergo a process in which only those applications deemed to have
the highest scientific merit, generally the top half of the applications under
review, will be discussed, assigned a priority score, and receive a second
level review by the appropriate National Advisory Council or Board.
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 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.
1. Significance: Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be advanced?
What will be the effect of these studies on the concepts or methods that drive
this field?
2. Approach: Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics?
3. 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?
4. 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)?
5. 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, applications responding to this RFA will be assessed with respect
to the following criteria. This evaluation will be presented in an
administrative note in the summary statement, and will not factor into the
numerical score:
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 not to exercise) intellectual property
rights regarding mutants identified through genetic and phenotypic screens,
embryos and sperm for these mutants, genetic and phenotypic screens,
mutagenesis protocols, and genetic and phenotypic data for all mutant strains
and methodologies?
o In addition, the plan to share research resources and the plan to exercise
(or not exercise) intellectual property rights regarding patentable research
resources will be judged for appropriateness.
In addition to the above criteria, in accordance with NIH policy, all
applications also will 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 of human, animals, or the
environment, to the extent they may be adversely affected by the project
proposed in the application.
SCHEDULE
Letter of Intent Receipt Date: April 16, 2000
Application Receipt Date: May 19, 2000
Peer Review Date: October 2000
Advisory Council Review: January 2001
Earliest Anticipated Start Date: April 2001
AWARD CRITERIA
Factors that will be used to make award decisions are as follows:
o Scientific and technical merit of the proposed project as determined by peer
review,
o Cost effectiveness of the proposed strategy,
o Adequacy of plans to make widely available to the research community all
research resources developed during this 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 (mutants identified through genetic and phenotypic screens,
embryos and sperm for these mutants, genetic and phenotypic screens,
mutagenesis protocols, and genetic and phenotypic data for all mutant strains
and methodologies) developed during this project,
o Program priorities and program balance,
o Availability of funds.
INQUIRIES
Potential applicants are strongly encouraged to contact program staff with any
questions regarding the responsiveness of their proposed project to the goals
of this RFA.
Written and telephone inquiries concerning this RFA are encouraged. The
opportunity to clarify any issues or questions from potential applicants is
welcome.
A complete listing of contacts for both programmatic and fiscal/administrative
inquiries may be found at:
http://www.nichd.nih.gov/rfa/hd-00-004/hd-00-004.htm.
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance Nos.
93.865, 93.396, 93.306, 93.867, 93.839, 93.172, 93.273, 93.846, 93.173,
93.121, 93.847, 93.848, 93.849, 93.279, 93.113, 93.862, 93.242, 93.853.
Awards are made under authorization of Sections 301 and 405 of the Public
Health Service Act, as amended (42 USC 241 and 284) and administered under NIH
grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.
This program is not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency review.
The PHS strongly encourages all grant and contract recipients to provide a
smoke-free workplace and promote the non-use of 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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NIH Funding Opportunities and Notices
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