This Program Announcement expires on March 1, 2004, unless reissued.

DEVELOPMENT OF ZEBRAFISH MUTAGENESIS AND SCREENING TOOLS

Release Date:  March 19, 2001

PA NUMBER:  PA-01-070

Trans-NIH Zebrafish Coordinating Committee
 (http://www.nih.gov/science/models/zebrafish/)
National Institute of Child Health and Human Development
 (NICHD, http://www.nichd.nih.gov/)
National Cancer Institute
 (NCI, http://www.nci.nih.gov/)
National Center for Research Resources
 (NCRR, http://www.ncrr.nih.gov/)
National Eye Institute
 (NEI, http://www.nei.nih.gov/)
National Human Genome Research Institute
 (NHGRI: http://www.nhgri.nih.gov/)
National Institute on Aging
 (NIA, http://www.nih.gov/nia/)
National Institute on Alcohol Abuse and Alcoholism
 (NIAAA: http://www.niaaa.nih.gov/)
National Institute of Arthritis and Musculoskeletal and Skin Diseases
 (NIAMS, http://www.nih.gov/niams/)
National Institute on Deafness and Other Communication Disorders
 (NIDCD, http://www.nidcd.nih.gov/)
National Institute of Dental and Craniofacial Research
 (NIDCR, http://www.nidr.nih.gov/)
National Institute of Diabetes and Digestive and Kidney Diseases
 (NIDDK, http://www.niddk.nih.gov/)
National Institute on Drug Abuse
 (NIDA, http://www.nida.nih.gov/)
National Institute of Environmental Health Sciences
 (NIEHS, http://www.niehs.nih.gov/)
National Institute of General Medical Sciences
 (NIGMS, http://www.nigms.nih.gov/)
National Institute of Mental Health
 (NIMH, http://www.nimh.nih.gov/)
National Institute of Neurological Disorders and Stroke
 (NINDS, http://www.ninds.nih.gov/)

THIS PA 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 PA.

PURPOSE

This Program Announcement (PA) is to encourage investigator-initiated 
applications for 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 and aging, organ formation, 
behavior, and disease processes.  Applications that propose to advance the 
technologies associated with such phenotyping also are welcome.  This PA is a 
continuation of the program initiated by RFA HD-00-004, “Mutagenesis 
Screens/Phenotyping Tools for Zebrafish” 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-HD-00-004.html).  This 
effort stems from an NIH initiative with participation of the Institutes and 
Centers listed above, working though the Trans-NIH Zebrafish Coordinating 
Committee (TZCC, http://www.nih.gov/science/models/zebrafish/) under the co-
chairmanship of NICHD and NIDDK.  Since its formation in 1997, the committee 
has played an active role as an advocate for the zebrafish as an important 
model for development and disease research. 

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 PA is related to one or more of the 
priority areas.  Potential applicants may obtain  "Healthy People 2010" at 
http://www.health.gov/healthypeople/.  

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.  Applications from new investigators are 
particularly encouraged.  Racial/ethnic minority individuals, women, and 
persons with disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) individual research 
project grant (R01) award mechanism.  Because the nature and scope of the 
research proposed in response to this PA may vary, it is anticipated that the 
size of awards will also vary.  Responsibility for the planning, direction, 
and execution of the proposed project will be solely that of the applicant.

Although this PA is the result of a trans-NIH initiative, awards will be made 
through the Institute or Center whose mission is most closely related to the 
proposed work.  Through TZCC, each funding component will share with the other 
committee members findings of any research supported as a result of this PA.  
All investigators funded under this initiative will be expected to work 
together cooperatively so that the information learned, and the mutants and 
tools developed will be of maximum usefulness to the community.

For all competing applications requesting up to $250,000 direct costs per 
year, specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by NIH.  
Complete and detailed instructions and information on Modular Grant 
applications can be found at: 
http://grants.nih.gov/grants/funding/modular/modular.htm.  Applications that 
request more than $250,000 in any year must use the standard PHS 398 (rev. 
4/98) application instructions.
 
RESEARCH OBJECTIVES

Background

The TZCC 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 TZCC 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.  RFA-HD-00-004, entitled “Mutagenesis 
Screens/Phenotyping Tools for Zebrafish,” addressed, in part, this and some of 
the other recommendations made by workshop participants.  Due to the response 
of the community to this most recent RFA, this PA is being released to provide 
an umbrella under which to continue NIH efforts to support mutagenesis 
screening and development of phenotyping tools for zebrafish.

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 they 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 with a proven track record of easily executed, 
large-scale forward mutagenesis screens. 

As reported in the December 1996 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.  While this large-scale 
screen focused primarily on developmental defects, it is clear that saturation 
mutagenesis of the zebrafish genome will be an indispensable means of 
achieving a complete understanding not only of development, but also of the 
physiology, behavior, aging, and disease processes of this vertebrate.  RFA-
HD-00-004 has boosted efforts for zebrafish mutagenesis screening, including 
screening of adult fish, and the current initiative is intended to further 
this effort.   

Research Scope 

The objective of this PA is to continue 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 PA 
are expected to be made widely available to the research community.  
Applicants must include as part of their applications a plan for disseminating 
these resources, adequacy of this plan will be considered in making funding 
decisions for applications responding to this PA (see AWARD CRITERIA, below).  
Objectives to be addressed in applications submitted in response to this PA 
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, alcohol, 
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 Principal Investigator 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 PA (see SPECIAL 
REQUIREMENTS, below). 

Interests of Participating Institutes and Centers 

The participating NIH Institutes and Centers have provided a brief outline of 
their interests as they relate to the goals of this PA.  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. 

NIA:  Basic research on the genetic and molecular basis of aging and 
longevity.  Generation and analysis of late-age onset or long-lived mutants 
that can be used to identify, clone, and characterize genes involved in normal 
and pathological aging.  Cellular and molecular function of genes expressed, 
for example, in the aging nervous system, cardiovascular, immune, and 
musculoskeletal systems.  Such genes include, but are not limited to, those 
involved in neurodegenerative disorders, neuroplasticity, cell death, damage 
and repair of DNA and proteins, and oxidative metabolism, and maintenance of 
differentiated cell function. 

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. 

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. 

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. 

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, and studies to define the molecular 
mechanisms that dictate cell-specific gene expression in relevant cell types. 

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. 

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.  Studies to examine the mechanistic pathways 
involved in developmental exposure to environmental agents and subsequent 
increased susceptibility to adult onset disease (developmental imprinting).  
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 PA.

SPECIAL REQUIREMENTS 

Restricted availability of unique research resources, upon which further 
studies are dependent, can impede the advancement of research.  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 as well as other research areas such as 
developmental biology.   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_2001/index.htm), 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) and 
(http://ott.od.nih.gov/pdfs/64FR72090.pdf)].  Biomaterials (e.g., 
pathogen-free mutant animals, preserved sperm and embryos, etc.) and other 
patentable research resources (e.g., genetic and phenotypic screens, 
mutagenesis protocols, and genetic and phenotypic data for all mutant strains, 
etc.) developed in projects funded as a result of this PA 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 PA become readily available to the research community in a timely 
manner for further research, development, and application, in the expectation 
that this will lead to products and knowledge of benefit to the public health.  
Accordingly, for applications submitted in response to this PA, 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, etc.). 

Each of the two requirements are discussed in detail below. 

Both the sharing and intellectual property plans should, at a minimum, address 
the elements discussed in detail below in a clear and concise manner.  
Applicants are encouraged to inform and/or confer with their institutional 
offices of technology transfer to develop plans for addressing these 
requirements.
 
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 PA to propose detailed plans for sharing the research 
resources generated through the grant.  It is expected that the resources to 
be shared include, for example, all materials developed in projects funded 
under the PA, 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. 

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 Spring 2001.  In addition to 
serving as a stock center, the Resource operates a comprehensive database, the 
Zebrafish Information Network (ZFIN).  Plans to share materials generated by 
projects under this PA 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. 

The adequacy of the plan will be considered by NIH program staff on the TZCC 
and will be important in determining whether the grant shall be awarded.  The 
sharing plan, as approved, 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 PA become readily available to the research community. With regard to 
patentable research results, for example, 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 PA to develop and propose a plan addressing how they will make 
available to the broader scientific community research resources produced in 
projects funded under this PA.

The requirement for this intellectual property rights plan is in addition to 
the requirement for the research resources sharing plan described above.   The 
adequacy of the proposed plan will be considered by NIH program staff on the 
TZCC in determining whether the grant shall be awarded. The plan, as approved, 
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 
technology arising out of this funded research (e.g., 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) are adversely affecting the goals of 
this PA and the overall mission of benefiting the public health. 

Points to Consider When Proposing the Sharing and Intellectual Property Plans

Applicants should consider the following points when developing their 
proposals for sharing and intellectual property plans:

o  Do the plans fully adhere to the NIH Grants Policy on Sharing of Unique 
Research Resources including the Sharing of Biomedical Research Resources 
Principles and Guidelines for Recipient of NIH Grants and Contracts 
(http://www.ott.nih.gov/policy/rt_guide_final.html)?

o  Will material transfers be made with no more restrictive terms than in the 
Simple Letter MTA or the UBMTA and without reach through requirements? 

o  Should any intellectual property arise which requires a patent, will the 
technology (e.g., materials, data, etc.) remain widely available to the 
research community?

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.  Overall application budget requests should include 
travel funds for the Principal Investigator to attend biennial meetings in the 
metropolitan Washington, D.C. area scheduled to alternate with the Zebrafish 
Development and Genetics Meetings. 

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, Internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 
(revised 4/98) and will be accepted at the standard application deadlines as 
indicated in the application kit.  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 
301-435-0714, E-mail: grantsinfo@nih.gov. 

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended/revised 
version of the preceding grant application types requesting $500,000 or more 
in direct costs for any year are advised that they must contact the Institute 
program staff before submitting the application, i.e., as plans for the study 
are being developed.  Furthermore, applicants must obtain agreement from 
program staff that the Institute will accept the application for consideration 
for award.  Finally, applicants must identify, in a cover letter sent with the 
application, the program staff member and Institute who agreed to accept 
assignment of the application.  

This policy requires an applicant to obtain agreement for acceptance of both 
any such application and any such subsequent amendment.  Additional 
information about this policy may be found in the NIH Guide for Grants and 
Contracts, March 20, 1998 at:  
http://grants.nih.gov/grants/guide/notice-files/not98-030.html. 
  
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

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 PHS398 
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 ALL 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 all 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 telephone number of the individual 
to contact concerning fiscal and administrative issues if additional 
information is necessary following the initial review. 

Submission Instructions

The title and number of the program announcement 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral 
guidelines and will be reviewed for completeness by the Center for Scientific 
Review.  Applications will be evaluated for scientific and technical merit by 
an appropriate scientific review group convened in accordance with the 
standard NIH peer review procedures.  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 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 
the 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.

(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 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 animals or the environment, to 
the extent they may be adversely affected by the project proposed in the 
application. 

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 in a 
timely manner 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 PA. 

Written and telephone inquiries concerning this PA 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/PA/Zebrafish_Mutagenesis.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, 93.866, 93.273, 93.855, 
93.846, 93.173, 93.837, 93.849, 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, and portion of a facility) in which 
regular or routine education, library, day care, health care or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.



Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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


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