FUNCTIONAL ATLAS OF ORPHAN NUCLEAR RECEPTORS

Release Date:  June 7, 2001

RFA:  RFA-DK-01-026 (Reissued as RFA-DK-06-503)

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute on Aging

Letter of intent:          October 17, 2001
Application Receipt Date:  November 19, 2001

PURPOSE

The purpose of this initiative is to develop a Functional Atlas of 
Orphan Nuclear Receptors emphasizing understanding and cataloging of 
structure, tissue distribution, specificity, and function. 

Nuclear hormone receptors, their ligands, and relevant accessory 
proteins play important roles in development and aging, metabolism, and 
disease, and comprise a large superfamily of receptors for a multitude 
of hormones, xenobiotics, lipids, and other known and unknown ligands.  
Knowledge of the function, structure, and specificities of these 
receptors can serve as the basis for the development of therapeutics to 
treat diseases, including diabetes, obesity, osteoporosis, heart 
disease, and prostate and breast cancer.  While a great amount of 
information has already been uncovered, recent advances continue to 
provide a wealth of new data that must be collated and analyzed.  Thus, 
further understanding of receptor specificity, ligand selectivity, 
interaction with cytoplasmic and/or nuclear accessory proteins, 
chromatin, and the transcriptional machinery, will require development 
of a unique database to collect and integrate this information. It is 
anticipated that this initiative will enhance coordination with 
emerging genetic information from the human (and other) genome 
effort(s).  This initiative will focus specifically on one sub-group of 
the superfamily, the orphan nuclear receptors (ONR).

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, 
(Functional Atlas of Orphan Nuclear Receptors), is related to the 
priority area of: Chronic Diseases.  Potential applicants may obtain a 
copy of "Healthy People 2010" at http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit 
organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and 
eligible agencies of the Federal Government.  Racial/ethnic minority 
individuals, women, and persons with disabilities are encouraged to 
apply as principal investigators.  In addition, collaborators from 
foreign institutions are permitted.

MECHANISM OF SUPPORT

The funding instrument to be used for this program will be a Research 
Program-Cooperative Agreement (U19), an assistance mechanism (rather 
than an acquisition mechanism), in which substantial NIH scientific 
and/or programmatic involvement with the awardee is anticipated during 
performance of the activity.  The U19 allows for support of a series of 
components designed to explore a cohesive theme.  Under the cooperative 
agreement approach, the NIH purpose is to support and/or stimulate the 
recipient's activity by involvement in and otherwise working jointly 
with the award recipient in a partner role, but it is not to assume 
direction, prime responsibility, or a dominant role in the activity.  
Details of the responsibilities, relationships and governance of the 
study to be funded under cooperative agreement(s) are discussed later 
in this document under the sections "TERMS AND CONDITIONS OF AWARD", 
“OBJECTIVES AND SCOPE", and "SPECIAL REQUIREMENTS."  Except as 
otherwise stated in this announcement, awards will be administered 
under NIH grants policy as stated in the NIH Grants Policy Statement 
(http://grants.nih.gov/grants/policy/nihgps/).  Funding is anticipated 
before the end of FY 2002.

The total project period for applications submitted in response to the 
present RFA may not exceed 5 years.  The anticipated award date is 
September 30, 2002. Awards and level of support depend on receipt of a 
sufficient number of applications of high scientific merit.  

FUNDS AVAILABLE  

For Fiscal year 2002 $2.5 Million (Total Costs = Direct + Facilities 
and Administrative Costs) will be committed by NIDDK to fund one 
application in response to this RFA.  In addition, the National 
Institute on Aging has committed $0.5 Million (Total Costs) in support 
of this initiative, for a total of $3.0 Million (Total Costs). Although 
this program is provided for in the financial plans of the NIDDK and 
NIA, the awards pursuant to this RFA are contingent upon the 
availability of funds and receipt of a sufficient number of 
applications of outstanding scientific and technical merit.  

RESEARCH OBJECTIVES

Background  

Nuclear receptors comprise a large family of hormone-dependent and -
independent transcription factors responsible for reproduction, growth, 
differentiation, and homeostasis.  The nuclear receptors are part of a 
large superfamily consisting of receptors for steroid hormones 
(estrogen, androgen, adrenal glucocorticoid, aldosterone, and 
progesterone; ER, AR, GR, MR, and PR, respectively), nuclear hormones 
(vitamin D, retinoids, thyroid hormone; VDR, RAR/RXR, TR, 
respectively), and orphan nuclear receptors (peroxisome proliferator 
activated receptor or PPAR, lipid receptors, COUP-TFI/II, SF-1, etc.).  
The latter have functions in cells, during development and in the 
adult, but with no, or only poorly, defined ligand(s).  While some 
orphan receptors have recently been classified as responding to defined 
ligands (e.g. PPAR?), the identity of true natural ligands in most 
instances remains to be elucidated.

Studies in model organisms have suggested that members of this 
superfamily have a long evolutionary history, are well conserved in 
lower organisms, and constitute a significant portion of known genomes 
(Tsai and O'Malley, Ann. Rev. Biochem. 63:451-486, 1994; McKenna et al. 
J. Steroid Biochem Mol Biol 69:3-12, 1999).  With the rapid onset of 
knowledge of the human genome, it is clear that nuclear receptors are 
present in abundance in humans, as well (Lander et al., Nature 409:860, 
2001), with both known and unknown functions.  Moreover, it is 
anticipated that with further annotation of the human genome other 
orphan nuclear receptors will be discovered.  While some of these 
receptors will prove to have redundancies (e.g. Brown, et al. JCI 
106:73-79, 2000), many will be found to be unique with specific 
localizations and/or functional implications as well as implications 
for disease (Lazar, J. Investig. Med. 47:364-368, 1999).  Others may 
have temporal specificities associated with developmental roles (Zhou 
et al., Neuron 24:847-859, 1999).  As additional genomic information 
emerges, expression studies utilizing proteomics tools become an 
important component of discovery.

Although primarily functioning as transcription factors, it has become 
clear that the biology of these receptors is complex:  they are often 
bound to chaperone proteins in the cytoplasm, and/or to DNA in the 
nucleus; they may bind to DNA as monomers, dimers, or heterodimers---
with or without ligand; they may interact with any of a number of 
different classes of nuclear accessory and/or chromatin remodeling 
proteins; the presence or absence of ligand can define interactions 
with other proteins which foster the ability of the receptor to 
activate or repress gene expression; and alterations in the receptor, 
the ligand, or various of the accessory proteins, such as co-activators 
and co-repressors, can have profound effects on development, and 
protein/lipid/carbohydrate metabolism, and in diseases such as prostate 
and breast cancer, and diabetes, obesity, heart disease, and 
osteoporosis, as well as processes associated with aging.  The 
receptor, the ligand, and relevant accessory proteins can also serve as 
the basis for the development of therapeutics to treat disease.  To do 
so, further research is required to fully understand the molecular 
mechanism of action of these receptors, the underlying basis for tissue 
specificity of action, the nature of cellular co-activator or co-
repressor usage, and the role(s) these may play in the development, 
progression, and treatment of disease.

With this in mind, it has become clear that the vast amount of 
information already available, coupled with the new information 
emerging from model organisms and from the human genome project, calls 
for a large-scale, collaborative effort designed to develop, categorize 
and integrate knowledge of orphan nuclear receptors.  To this end, the 
U19 encompasses research projects and shared resources designed as part 
of a collaborative effort to address the objectives of the program.  

Objectives and Scope  

Two overriding objectives govern this initiative: 1) collation and 
characterization of information already in hand, and 2) new research to 
more fully understand the role(s) of orphan nuclear receptors in 
health, disease, and aging. In developing a Functional Atlas of Orphan 
Nuclear Receptors, the long-term goal is to focus on orphan receptors 
(e.g. PPAR, FXR, LXR, SXR, SF-1, CAR, COUP TFI/II, etc.), as well as 
the cofactors and the ligands with which many interact to complete a 
functional loop.  Among these cofactors are those present in the 
nuclear compartment (coactivators, corepressors, chromatin modifying 
proteins and RNA transcripts, linkers, methylases, histone modifying 
enzymes, etc.), as well as those in the cytoplasmic compartment 
(chaperones, binding proteins, kinases/phosphatases).  Beyond the scope 
of this present initiative, but certainly relevant in functional 
contexts, is consideration of the nuclear (VDR, RAR, RXR, TR), and 
steroid  (ER, AR, GR, MR, PR) receptors, as they intersect with ONRs.

Insights into the structures of several receptors both bound and 
unbound to ligand and/or cofactor(s) have been revealed by x-ray 
crystallographic and NMR studies.  Discovery of natural and artificial 
ligands has added much to our understanding of function. For some 
Orphan Nuclear Receptors, role(s) in disease has preceded knowledge of 
putative ligand(s), as for PPAR? and its role in adipogenesis and 
insulin resistance in Type 2 diabetes mellitus.  Indeed, based on less 
than complete knowledge, several ligands directed at PPAR?  have already 
been developed for use as insulin sensitizing agents in the treatment 
of Type 2 diabetes (e.g. thiazoladinediones;TZDs).  The general concept 
of Selective Receptor Modulators (SRMs) has evolved rapidly to include 
clinical use of drugs with selective actions on nuclear receptor 
function, such as TZDs for Type 2 diabetes and tamoxifen for estrogen-
dependent breast cancer.  With greater knowledge of nuclear receptor 
structure, tissue specificity, and function, in general, it will be 
possible to develop more powerful and effective SRMs, many of which 
will be relevant to ONRs. 

Finally, while much is known about the expression and function of many 
of the members of this family, studies exploiting gene knock-outs in 
mouse transgenic models have revealed redundancies and levels of 
compensation that confound our full understanding of the physiology of 
many of the integral components of the hormone action loop.  

Although it is desirable to create a unified Functional Atlas for the 
entire Nuclear Receptor Superfamily, limited resources initially 
available for this initiative do not at this time allow for development 
of such a comprehensive program.  While considerable information exists 
regarding the structure and function of the steroid receptors and the 
nuclear receptors, less information is currently available for the 
orphan nuclear receptors (ONR).  The ONRs have developed a central 
importance as a consequence of their role(s) in development 
(organogenesis) and metabolism (e.g. lipid and carbohydrate; see Chawla 
et al., Cell 103:1-4, 2000), as well as aging.  With this in mind, the 
immediate focus of this initiative will be with development of a 
Functional Atlas of Orphan Nuclear Receptors.  To do so it is 
envisioned that the final program will include research and development 
in the following areas:

o Determination of tissue specificity: understanding and 
cataloging levels and extent of expression in different 
cells/tissues.

o Preference in cofactor usage: tissue specificity and context 
of coactivator and/or corepressor usage; role of putative 
ligand(s) in cofactor recruitment (binding/dissociation) and 
function.

o Receptor domain structure and function: DNA and/or ligand 
binding, transactivation, cofactor association.

o Receptor/DNA interaction:  roles in and effects of chromatin 
remodeling cofactors on regulation of transcription; roles of 
receptor dimerization and (homo-, hetero-) dimer partner usage 
(e.g. with nuclear receptors such as RXR).

o Regulation of expression: role(s) in development and aging; 
signaling cross-talk; ligand feedback; receptor subtype 
expression.

o Physiology/pathophysiology: issues of redundancy and/or 
compensation; mutations and polymorphisms which affect 
metabolic function and/or disease.

o Target for therapeutics: putative ligands, partial agonists, 
antagonists, subtype specific factors (e.g. Selective Receptor 
Modulators or SRMs).

o Orphan receptors in lower and model organisms: functional 
correlations with mouse and/or human.

o New gene discovery based on data mining through genome 
databases.

o Use of appropriate proteomics tools to determine the function 
of orphan nuclear receptors, associated cofactors, or gene 
targets.

While some of these objectives represent efforts to collect and catalog 
what is already known, others require research efforts that may involve 
novel and innovative approaches to develop needed information. In order 
to maximize the resources available in a rich and diverse research 
community, it is anticipated that a defined structure must be 
developed, which will allow for development of a series of components, 
defined as research projects and shared resources.  The latter will 
include Administrative, Bioinformatics (required elements), and other 
shared resources as proposed by the applicant. The former (collectively 
called Research Components) include bridging and pilot projects (at the 
host institution or through appropriate subcontracts to other sites) 
directed at delineation of specific components of the overall program 
(see SPECIAL REQUIREMENTS).  Since the primary objective of this large-
scale collaborative effort will be data integration, each contributing 
project will include a plan that addresses data integration and an 
interface with the Bioinformatics Resource.  Full integration of data 
with the Bioinformatics Resource will facilitate rapid dissemination of 
new information, development of new hypotheses, and allow for data 
mining via a web-based interface.  Given the breadth of the task, a 
large-scale collaborative effort (i.e., the U19 mechanism) is best 
suited for development of a Functional Atlas of Orphan Nuclear 
Receptors. 

The objectives listed above suggest a scope for this initiative, and 
they do not preclude additional objectives proposed in applications 
responsive to this RFA.

To develop a Bioinformatics Resource for the Functional Atlas of Orphan 
Nuclear Receptors it will also be necessary to include research and 
development of the following objectives:

o Development of a functioning relational database as the basis 
of a Bioinformatics Resource for the Functional Atlas of 
Orphan Nuclear Receptors.

o Development of (and/or use of existing) software to enable 
collection and analysis of data from many different sources 
and formats, including cDNA and protein sequences, 
microarrays, histopathological analysis, structural biological 
analyses (e.g. NMR, X-ray crystallography), and other 
databases and analytical tools.

o Regular curation of existing and emerging information, 
including evaluation and annotation of data and incorporation 
into appropriate databases; integration of information from 
many different sources; database and interface design and 
implementation.

o Development of appropriate algorithms to allow for rapid data 
mining and in silico analyses of structural and functional 
relatedness and/or gene discovery.

o Development of algorithms to facilitate interactive and 
integrated analyses of function (e.g. metabolic flow charts).

o Providing for the maximal interoperability to facilitate the 
ability to rapidly search other databases for related 
information relevant to nuclear receptors, including 
functional databases, lower (model) organisms databases (e.g. 
Flybase (http://www.fruitfly.org/), and the human genome 
project (e.g. National Center for Biotechnology Information).

o Development and maintenance of web tools and a web site for 
the Functional Atlas which facilitates use on any platform. 

o Provision of capability, by investigators of the Functional 
Atlas program, to readily enter and access data.

Since the mechanism for this program is a cooperative agreement in the 
form of a Research Program (U19), an overall collaborative protocol 
will be developed at the time of initiation of funding by a Steering 
Committee (see TERMS AND CONDITIONS OF AWARD), composed of the 
awardee(s), individual project principal investigators, and the NIDDK 
Program Scientist.  

It is anticipated that intense and meaningful interactions between and 
among the collaborating investigators involved in the U19 will result 
in achievement of progress at a rate and in a fashion not possible for 
the individual.  While some of the information to be developed is 
anticipated to be of a descriptive, but necessary, nature, other work 
will involve new approaches and conceptual leaps that will be driven by 
the collaborative nature of the interactions.  In the application a 
detailed explanation of the rationale should be provided, along with 
definitive and progressive landmarks, with a timeline for the 
achievement of the goals (see below and APPLICATION PROCEDURES).  
Research Components, together with Shared Resources, should be 
integrated to produce a collaborative effort that maximizes the 
individual efforts and facilitates fulfillment of the overall 
objectives of the Functional Atlas.

The expertise appropriate for this research program includes knowledge 
of the molecular endocrinology, pharmacology, histology, and 
pathophysiology of Orphan Nuclear Receptors.  In addition, expertise in 
development and use of transgenic models and of mouse genetics is 
essential.  Expertise in computational biology, bioinformatics, 
genomics, proteomics, and phenotypic analysis is also highly 
recommended.

SPECIAL REQUIREMENTS

GENERAL ORGANIZATION OF THE FUNCTIONAL ATLAS OF ORPHAN NUCLEAR 
RECEPTORS RESEARCH PROGRAM (U19)

Development of a Functional Atlas of Orphan Nuclear Receptors requires 
considerable effort to organize.  A U19 application should be headed by 
a Principal Investigator (PI), who is an expert in the field.  As a 
cooperative agreement, the primary governing body for the program will 
be a Steering Committee, which will have responsibility for overall 
study design and policy decisions (described in more detail under 
“TERMS AND CONDITIONS OF AWARD”).  Members of the Steering Committee 
will include the PIs of research components and shared resources, and 
key independently supported collaborators, as well as representative(s) 
of the NIH.  

Since the overall purpose of this initiative is to develop a Functional 
Atlas of Orphan Nuclear Receptors, a Bioinformatics Resource will serve 
as the focal point for the collaborative efforts, and will be a 
required Shared Resource.  This Bioinformatics Resource will be the 
focal point for data collection and analysis, and serve as the primary 
interface with the general research communit(ies)y.  Research in the 
form of individual projects (bridging and pilot) will be used to 
acquire new information and fill in gaps, where needed.

In order to give structure to the collaborative arrangements inherent 
in a U19, it is anticipated that at least two meetings/year of the 
Steering Committee (study investigators and the NIDDK) will take place.  
These meetings will commence once the Steering Committee has had an 
initial organizational meeting at or near the time funding is 
initiated.  Applicants should formally state their willingness to 
participate in such activities and plans for these meetings should be 
included in the budget requests of the individual applications (see 
below in TERMS AND CONDITIONS).  The purpose of these meetings will be 
to provide periodic updates on progress, resolve issues related to 
sharing of resources and data, and modification (if necessary) of study 
design and/or timetable, develop needs for additional expertise and 
coverage through subcontracts, as well as development and entry of data 
with the Bioinformatics Resource.

To promote the development of a collaborative program among the award 
recipients, a number of issues need to be addressed in the application, 
as discussed below.  Applicants should discuss the rationale for their 
individual and collaborative approaches, how they will interact 
effectively with the Steering Committee and the Bioinformatics 
Resource, and state their willingness to follow the common protocol 
that will be agreed upon by the Steering Committee and that would apply 
to all participants in the U19.

The U19 application should include elements of the following 
categories:

RESEARCH COMPONENTS:

1. Bridging projects (e.g. Gene Expression, Tissue Specificity, 
Physiology, Structure/Function) may be requested for 
collaborative activities that would function as supplements to 
the ongoing, funded, independent work in the laboratories of 
participating investigators. These bridging projects to the 
laboratories of participating investigators are to add to or 
bridge the intellectual and technological approaches of the 
collaborative program.  They are not meant to be stand-alone 
research efforts but are to be subprojects that tie (or enhance 
the contribution of) the independent work of the participating 
investigator to the large-scale collaborative program. These 
bridging projects may be from 2-5 years in duration, as needed.

2. Pilot projects (e.g. Imaging, Ligand Discovery, Data Mining) may 
be requested for investigators in an area deemed important to the 
collaborative project, to add elements where gaps exist, or to 
add investigators with critical knowledge or expertise.  These 
need not be from individuals having a research background in the 
area of the collaborative program.  These projects may not exceed 
$75,000 in annual direct costs and must be limited to no more 
than three such projects. Each project should be of sufficient 
scope to qualify as an independent research effort.  It is 
primarily intended to allow the collaborative program to address 
gaps in the overall scope, or to add investigators outside the 
scientific mainstream of the project area in a mode that will 
allow them to develop independent research in the area of the 
collaborative program. While funding for an individual pilot may 
run for three (3) years, at the discretion of the steering 
committee, it is expected that the principal investigator of a 
project will seek R01 funding during the period of the 
collaborative project, based on the results obtained from the 
project.  Such R01 funding should include plans for further 
interaction with other components of the Functional Atlas.

SHARED RESOURCES:  The organizational structure of the collaborative 
project may assume a variety of different forms, all focused on 
addressing the scope described above.  In addition to required 
Bioinformatics and Administrative Resources, other Shared Resources may 
be included, as needed (e.g., Transgenic Animals, Microarray, 
Proteomics) to speed progress on the scientific goals of the project, 
add additional capability to the collaborative project by bringing in 
new or improved technology and/or by standardizing data among different 
research teams among the collaborating or participating laboratories.  
This might include such technologies as high-throughput gene chip 
microarrays, imaging or transgenic methodologies. Other types of 
resources might be for instrumentation, genomics, proteomics, high-
throughput assays, or computational/bioinformatics/modeling 
capabilities not already provided by a Bioinformatics Resource.  Any 
such requests should be strongly justified in terms of contributions to 
achieving the long-term goals of the Functional Atlas of Orphan Nuclear 
Receptors, to increasing the synergy of the collaborative project, or 
to enhancing overall cost effectiveness.  The major focal point for 
shared resources should be a Bioinformatics Resource, which will be 
devoted to data collection, coordination, analysis, and to 
dissemination of information developed by the various components of the 
collaborative program.  Each of the sub- and/or participating projects 
should have plans for interfacing with this Bioinformatics Resource.

TERMS AND CONDITIONS OF AWARD

These special Terms of Award are in addition to and not in lieu of 
otherwise applicable OMB administrative guidelines, HHS Grant 
Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, 
PHS, and NIH Grant Administration policy statements. 

1. Collaborative Responsibilities 

The administrative and funding instrument used for this program is a 
cooperative agreement (U19-Research Project), an "assistance" mechanism 
(rather than an "acquisition" mechanism) in which substantial NIH 
scientific and/or programmatic involvement with the awardee is 
anticipated during performance of the activity.  Under the cooperative 
agreement, the NIDDK purpose is to support and/or stimulate the 
recipient's activity by involvement in and otherwise working jointly 
with the award recipient in a partnership role, but it is not to assume 
direction, prime responsibility, or a dominant role in the activity.  
Consistent with this concept, the dominant role and prime 
responsibility for the activity resides with the awardee(s) for the 
project as a whole, although specific tasks and activities in carrying 
out the studies will be shared among the awardees and the NIDDK Program 
Scientist.

2. Participating investigator: 

A research project (U19) application will include a team of 
investigators who will contribute to and benefit from participation 
(collaboration) in the program.  The members of the collaborative 
project will be referred to collectively as participating 
investigators, although one will be the Principal Investigator.  It is 
expected that each of the participating investigators will hold an 
externally peer reviewed and funded research grant in the area of the 
project, with the majority funded through regular research grants 
supported by NIDDK, other NIH institutes and centers, and other 
governmental and private agencies.  Exceptions to the rule of external 
funding may include participating investigators from industry, foreign 
institutions or allied fields not traditionally supported by the NIH 
(e.g., physics, computational biology, mathematics). Each participating 
investigator must provide evidence of their commitment to the project 
and a listing of organizational resources that will be committed to the 
project.  

Participating investigators will work together via the Steering 
Committee to develop workable guidelines for achieving the objectives 
of the collaborative program.  Participating investigators must agree 
to abide by the policies and rules set up for the collaborative program 
and to the terms and conditions described in this document to be 
eligible to participate.  During the period of the award, a 
participating investigator whose independent research support 
terminates may continue as a participating investigator at the 
discretion of the Steering Committee and with the approval of the NIDDK 
Program Scientist.  Funds from this award are not to be used to support 
the independent project of such an investigator.  It is expected that 
new participating investigators will be added to the collaborative 
project over the period of the award as deemed appropriate by the 
principal investigator and steering committee and with the approval of 
the NIDDK Program Scientist; these additions will be reported in the 
annual progress report.

3. Awardee Rights and Responsibilities:

The PI, and participating investigators, will have primary authority 
and responsibility to define objectives and approaches, and to plan, 
conduct, analyze, and publish results, interpretations, and conclusions 
of studies conducted under the terms and conditions of the cooperative 
agreement award.

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

The PI and one participating investigator from each participating 
project of the program will participate as permanent, voting members of 
the Steering Committee (see below), will attend the initial Planning 
Meeting and any subsequent Steering Committee meetings in the first and 
subsequent years, as needed. 

The PI will be responsible for contributing to and implementing the 
goals, priorities, procedures, and policies agreed upon by the Steering 
Committee, and will be responsible for close coordination and 
cooperation with other of the Functional Atlas of Orphan Nuclear 
Receptors program and NIDDK staff.

Awardees will retain custody of, and have primary rights to, the data 
developed under these awards, subject to Government rights of access 
consistent with current HHS, PHS, and NIH policies.  Investigators 
conducting biomedical research frequently develop unique research 
resources.  The policy of the PHS is to make available to the public 
the results and accomplishments of the activities that it funds.  
Principles and guidelines for recipients of NIH research grants on 
obtaining and disseminating biomedical research resources can be found 
at: http://www.nih.gov/od/ott/RTguide.

The NIDDK reserves the right to require the transfer of animals, 
reagents, and pertinent data that are generated as the result of 
participation in research supported under these awards to an eligible 
third party, in order to preserve the continuity of the research 
project.  Third parties supported under these awards must be informed 
of this right.

The Functional Atlas group will be expected to provide the NIDDK and 
the NIA with data in a uniform, usable platform throughout the course 
of the studies and after the termination of the studies supported by 
this RFA.

Effective conduct of Functional Atlas goals, as defined in this RFA and 
following Steering Committee action, will require considerable 
electronic communication of data and other information among the 
Functional Atlas and between the various constituent components and the 
NIDDK. The Functional Atlas members will be required to demonstrate 
that they have the ability to transfer data accurately and effectively.

4. NIDDK Staff Responsibilities 

The NIDDK Program Scientist will have substantial scientific-
programmatic involvement during conduct of this activity, through 
technical assistance, advice and coordination above and beyond normal 
program stewardship for grants, as described below. The dominant role 
and prime responsibility for the activity resides with the awardees for 
the project as a whole, although specific tasks and activities in 
carrying out the studies will be shared among the awardees and the 
NIDDK Program Scientist.

The NIDDK Program Scientist will have voting membership on the Steering 
Committee and, as determined by that committee, its subcommittees; will 
coordinate and facilitate the Functional Atlas programs, attend and 
participate as a voting member in all meetings of the Functional Atlas 
Steering Committee, and provide liaison between the Steering Committee, 
the Functional Atlas investigators, and the NIDDK.

The NIDDK Program Scientist and the NIDDK will ensure that there is an 
effective, Internet-based mechanism to enable electronic communication 
among the Functional Atlas, and with the NIH.

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

Since the NIDDK Program Scientist will be a participating member of the 
Steering Committee, to avoid any conflicts of interest, a separate 
NIDDK Project Officer will have responsibility for the analysis, 
review, and approval of all budgetary actions.  This Project Officer 
will be separate and distinct from the NIDDK Program Scientist, and 
will not be a member of the steering committee.  

NIDDK and NIH extramural staff with relevant scientific expertise, or 
who manage research grant programs that relate scientifically to the 
goals of the Functional Atlas program, will form a separate NIDDK 
Functional Atlas Working Group. The Group will meet regularly to review 
the progress of the Functional Atlas, and to advise the NIDDK Program 
Scientist of scientific developments and opportunities that may enhance 
the achievement of the goals.

The NIDDK Functional Atlas Working Group will collaborate with the 
NIDDK Program Scientist to organize and implement the workshops and 
symposia recommended by the Functional Atlas Steering Committee, and to 
provide a liaison between the appropriate research communit(ies)y and 
the members of the Functional Atlas, as well as the External Scientific 
Working Group.

The NIDDK reserves the right to terminate or curtail the study (or an 
individual award) in the event of a major breach in the protocol or 
substantial changes in the agreed-upon protocol with which the 
Institute does not agree.

5. Governance

A Steering Committee, composed of the Project PI, the participating 
project principal investigator(s), and the NIDDK Program Scientist will 
be the main governing board of the study and will have primary 
responsibility for developing common research designs, protocols and 
manuals, facilitating the conduct and monitoring of studies, reporting 
study results, and resolving issues that may arise.  The principal 
investigators from the participating projects, any relevant subcontract 
projects, and the Bioinformatics Resource, and the NIDDK Program 
Scientist will each have one vote.  The chairperson, who will be 
someone other than an NIDDK staff member, will be selected by the 
Steering Committee.  Subcommittees will be established by the Steering 
Committee, as appropriate; the Program Scientist will serve on 
subcommittees, as he/she deems appropriate. The collaborative protocols 
will be developed by the Steering Committee.  Data will be reviewed and 
submitted centrally to the Bioinformatics Resource.  Protocols will 
define rules regarding access to data and publications, as well as 
ensuring rapid dissemination of data to the general research community. 
It is anticipated that awardees will have lead responsibilities in all 
joint tasks and activities, as assisted by the NIDDK Program Scientist, 
where appropriate.  Awardees will be required to accept and implement 
the common protocol and procedures approved by the Steering Committee.

6.	Arbitration 

Any disagreement that may arise on scientific/programmatic matters 
(within the scope of the award), between award recipients and the 
Institute may be brought to arbitration.  An arbitration panel will be 
composed of three members: one selected by the Steering Committee (with 
the NIDDK member not voting) or by the individual awardee in the event 
of an individual disagreement, a second member selected by NIDDK, and 
the third member selected by the two prior selected members.  This 
special arbitration procedure in no way affects the awardee's right to 
appeal an adverse action that is otherwise appealable in accordance 
with the PHS regulations at 42 CFR Part 50, Subpart D and HHS 
regulation at 45 CFR Part 16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups 
and their sub- populations must be included in all NIH-supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification is provided 
indicating that inclusion is inappropriate with respect to the health 
of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 
1993 (Section 492B of Public Law 103-43). 

All investigators proposing research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html.  

A completed copy of the updated Guidelines is available at: 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm.

The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to provide a 
description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups, if applicable; and b) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age 
of 21) must be included in all human subjects research conducted or 
supported by the NIH, unless there are scientific and ethical reasons 
not to include them.  This policy applies to all initial (Type 1) 
applications submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines" on the Inclusion of Children as 
Participants in Research Involving Human Subjects that was published in 
the NIH Guide for Grants and Contracts, March 6, 1998, and is available 
at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators also may obtain copies of these policies from the program 
staff listed under INQUIRIES.  Program staff may also provide 
additional relevant information concerning the policy.

REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS

All investigators proposing research involving human subjects should 
read the policy that was published in the NIH Guide for Grants an 
Contracts, June 5, 2000 (Revised August 25, 2000), and is available at 
the following URL address 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

GUIDELINES FOR RESEARCH USING HUMAN PLURIPOTENT STEM CELLS

At the present time, the NIH cannot fund research involving the use of 
stem cells derived from human embryos.. This restriction does not apply 
to: human adult stem cell research; derivation or use of pluripotent 
stem cells from human fetal tissue; or animal stem cell research.   For 
the most current information on policies related to research using 
human pluripotent stem cells, investigators should access the National 
Institutes of Health Stem Cell Information site at: 
http://stemcells.nih.gov/index.asp
Details on the approval process and the procedures for submitting the 
required documentation of compliance are at the following URL address:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-050.html

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.

LETTER OF INTENT  

Prospective applicants are asked to submit, by October 17, 2001 a 
letter of intent that includes a descriptive title of the proposed 
research; name, address, and telephone number of the Principal 
Investigator; identities of other key personnel and participating 
institutions; and the number and title of the RFA in response to which 
the application may be submitted.

Although a letter of intent is not required, is not binding, and does 
not enter into the review of subsequent applications, the information 
allows NIDDK staff to estimate the potential review workload and to 
plan the review.

The Letter of Intent is to be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes
  and Digestive and Kidney Diseases
6707 Democracy Blvd
Room 752, MSC 5452
Bethesda, MD 20892
(For Fed Ex and UPS use 20817)
301-594-8897
301-480-3505 fax
FC15Y@NIH.GOV

APPLICATION PROCEDURES

U19 application should demonstrate essential elements of unity and 
interdependence that, through the collaborative effort, result in a 
greater contribution to program goals, as defined in the objectives for 
the Functional Atlas, than would occur if each project were pursued 
individually. Specifically, the relationship and contributions of each 
Research Component and Shared Resource to the goals of the Functional 
Atlas of Orphan Nuclear Receptors should be discussed.  These programs 
provide support for research projects as well as shared resources and 
facilities, which are available to individual projects comprising the 
program. Shared Resources must provide essential functions, services, 
techniques, determinations or instrumentation that will enhance at 
least 2 individual research projects.  A Bioinformatics Resource is 
required. In this component, details as to how data that are generated 
from individual projects will be stored, organized, analyzed, or 
visualized should be described. An Administrative Resource is required 
to assist in allocation of resources, coordination of projects, provide 
logistical support for meetings and workshops, and coordination with 
subcontracts. Subcontract budgets should be listed on a separate page, 
and the subcontract Facilities and Administrative (F&A) costs should be 
calculated and listed in the usual place as part of the direct costs of 
the budget (see “TABLE OF CONTENTS”).  

Preparation of Application

Applications are to be submitted on the standard research grant 
application form PHS 398 (rev. 4/98).  Application kits are available 
at most institutional offices of sponsored research and may be obtained 
from the Division of Extramural Outreach and Information Resources, 
National Institutes of Health, 6701 Rockledge Drive, MSC 7910, 
Bethesda, MD 20892-7910, telephone (301) 435-0714, email: 
grantinfo@nih.gov and on the Internet at:  
http://grants.nih.gov/grants/funding/phs398/phs398.html.

A response to this RFA should consist of an application that, in 
addition to or in lieu of part of the items requested in the PHS 398 
(http://grants.nih.gov/grants/funding/phs398/phs398.html), includes:

Description, Performance Site(s), and Key Personnel:  On page 2, 
describe briefly the proposed large scale-collaborative research 
project (Abstract).  List all key personnel involved in the 
collaborative project; use a continuation page if needed.

Table of Contents.  Prepare a Table of Contents for the overall project 
that includes the items listed below. Page limitations are given in the 
specific descriptions for each section.

SAMPLE TABLE OF CONTENTS

SECTION I

Face Page
Table of Contents (Overall program)
Detailed Budget for First 12-Month Period 
Budget Estimate for Each Year of Project 
Summary of All Other Sources of Support 
Biographical Sketches (PI and all participating investigators, key 
personnel and collaborators)

SECTION II

Overall Program
        Goals        
        Research Plan 
	Program Summary
	Administrative Management Plan
	Project Management Plan
	Preliminary Studies
        Plan for Data Sharing and Intellectual Property
        Institutional Environment and Resources
        Organization and Administrative Structure 

SECTION III

Shared Resources

Shared Resource A 
        Title Page (Title, Resource Director)
        Description of Resource
        Budget for the First 12-Month Period 
        Budget Estimate for Each Year of Requested Support 
        Role and Justification for the Shared Resource 
	Plan of operation
	Integration with the program  
         Gender and Minority Inclusion
	 Children Inclusion
         Human Subjects
         Vertebrate Animals
         Consortium/Contractual Arrangements
         Consultants/Collaborators

Shared Resource B, etc 
        Title Page (Title, Resource Director)
        Description of Resource
        Etc.

SECTION IV.

Research Components

Bridging Project 1 
        Title Page (Title, Project Leader)
        Description of Research Plan/List of Key Personnel 
        Detailed Budget for First 12-Month Period 
        Budget Estimate for Each Year of Requested Support
        Resources and Environment
        Research Plan 
        Plan for integration with overall program        
        Gender and Minority Inclusion
        Children Inclusion
	Human Subjects
        Vertebrate Animals
        Consortium/Contractual Arrangements
        Consultants/Collaborators
        
Bridging Project 2, etc.
         Title Page (Title, Project Leader)
         Etc.

Pilot Projects (up to 3)
        Title Page (Project 1, 2, etc)
        Detailed Budget for First 12-Month Period 
        Budget Estimate for Each Year of Requested Support
        Resources and Environment
        Research Plan 
        Plan for integration with overall program        
        Gender and Minority Inclusion
        Children Inclusion
	 Human Subjects
        Vertebrate Animals
        Consortium/Contractual Arrangements
        Consultants/Collaborators

Literature Cited with complete titles and authors for the entire 
program.

Checklist

The major areas to be listed in the Table of Contents above, appear 
below in capital letters.                      

BUDGET ESTIMATES: Specific examples of allowable costs that may be 
requested include:

In addition to the overall budget for the entire Functional Atlas 
program, include a separate budget for each bridging project, the (up 
to 3) pilot projects and the Shared Resources.  Applications for U19-
Research Project awards may not request more than $3.0 million in 
annual total costs (exclusive of subcontract F&A costs requested as a 
direct cost by the applicant organization) for any year of the award. 
Salaries for support personnel required for coordination and 
maintenance of the program, such as secretaries or administrative 
assistants, may also be included, as necessary, in the Administrative 
Resource.

Specific Items that may be included:
1. Salaries for the principal investigator, members of the steering 
committee, participating investigators, technical, and support 
personnel commensurate with their level of effort in the large-scale 
collaborative program.

2. Pilot projects to investigators relevant to the Functional Atlas can 
be without current independent research support in the area.  Pilots 
must not exceed $75,000 in annual direct costs and must be limited to 
no more than three such projects per application. They may include 
travel of personnel (e.g. predoctoral students, postdoctoral trainees, 
and investigators) to different laboratories to gain specialized 
expertise.  These grants may be for no more than 3 years each, and may 
be replaced by such new projects as the Steering Committee deems 
appropriate to achieve the goals of the overall program (see Project 
Management Plan).  The Pilot and Feasibility projects should be listed 
with a common budget, each project not to exceed the individual cap of 
$75,000.

3. Travel to and conduct of regular meetings of the steering committee 
and regular meetings of the participating investigators.

4. Shared Resource facilities (examples: instrumentation, genomics, 
proteomics, model organism, high-throughput assay, or 
computational/bioinformatics). 

5. Electronic media resources to allow participation of off-site 
laboratories and/or the means necessary to establish collaboratory 
capabilities and for information dissemination.  Travel to and conduct 
of regular meetings of an external advisory working group.

Composite budget.  Use Form Page 4, "DETAILED BUDGET FOR INITIAL BUDGET 
PERIOD," of Form PHS-398 to present the total budget for all requested 
support for the first year.  For each category such as "Personnel," 
Equipment," etc., give the amount requested for each Resource unit and 
each component project, with subtotals. For consortium arrangements 
involving other institutions or organizations, include total (direct 
and facilities and administration) costs
associated with such third-party participation in the 
"Consortium/Contractual Costs" category.  Note that consortium costs 
will count against the $3.0 Million Total Costs cap. Costs for 
purchased services should be itemized under "Other Expenses."

Use Form Page 5, "BUDGET FOR ENTIRE PROPOSED PROJECT PERIOD," of Form 
PHS-398 to prepare a budget, by category, that provides totals for each 
year of requested support.  The costs for the Pilot and Feasibility 
studies should be reported as one total figure for the (up to) three 
such projects. Requests for any increases in succeeding years must be 
justified in the individual component subprojects (bridging projects 
and pilot projects) and Resource budgets.

Individual budgets for shared resource and research components: For the 
first year budgets of each of the shared resource and research 
projects, use Form Page 4 of the PHS-398.  Use Form Page 5 of the PHS-
398 to report the budgets of each of the projects and shared resources 
for total project period (years 02-05).

Budget justifications and explanations:  Describe the specific 
functions of all key personnel, including consultants, collaborators, 
and technical staff.  Provide justifications for requested equipment.  
For years 02-05 of the application, justify any significant increases 
or decreases in any category over the first year budget.  Applicants 
must budget for travel and per diem that will allow the Principal 
Investigator, and designated participating or senior investigator to 
participate in at least two steering committee meetings each year.  
Applicants should plan to attend a workshop or symposium every year in 
years 2-5.  

BIOGRAPHICAL SKETCHES AND LETTERS OF COMMITMENT: Biographical sketches 
and letters of commitment must be included from all participating 
investigators indicating their willingness to follow guidelines and 
procedures established for the large-scale collaborative project.  The 
format described in the PHS398 application for modular applications 
should be followed for this information.

RESOURCES AND ENVIRONMENT:  Complete the "Resources" page of PHS-398 
for the overall large-scale collaborative project, including both the 
host institution and any participating institutions.  Briefly describe 
the features of the institutional environment(s) that are relevant to 
the effective implementation of the proposed program.  As appropriate, 
describe available resources, such as clinical and laboratory 
facilities, participating and affiliated units, patient populations, 
geographical distribution of space and personnel, and consultative 
resources.

RESEARCH PLAN

In the PHS398 application kit a 25 page limit for the Research Plan is 
described.  In lieu of that limitation, for the Functional Atlas, a 
forty (40) page limit is in effect for the following four sections 
(PROGRAM SUMMARY, ADMINISTRATIVE MANAGEMENT PLAN, PROJECT MANAGEMENT 
PLAN, and PRELIMINARY STUDIES). Investigators should endeavor to be 
concise. For other sections please follow the instructions for each 
individual part of the application, as below.
  
PROGRAM SUMMARY: A summary describing the goals and operation of the 
program.  Explain how the scope of this initiative will be addressed 
and how the approach of using a large-scale collaborative agreement is 
critical to its solution.  Discuss the range of scientific expertise to 
be brought to bear on the research problem.  Explain the interactions 
that will occur between investigators at the host site and at the 
participating sites.  Explain how each element of the large-scale 
collaborative project will contribute to successful attainment of its 
goals. Explain the programmatic value of the Shared Resources, and the 
Research Components (bridging and pilot projects). Explain how the 
information resulting from the collaborative efforts of the entire 
program, to include the laboratories of the participating 
investigators, will be integrated into the Bioinformatics Resource and 
with comprehensive program, as a whole.  Discuss how information 
generated by the collaborative program will be disseminated to the 
scientific community, in general.

ADMINISTRATIVE MANAGEMENT PLAN: Describe the structure, organization, 
and operation of the program. Describe the organizational framework and 
provide an organizational chart detailing the flow of information 
within the collaborative program. Discuss arrangements between the 
collaborating institutions that are important to effective operation of 
the U19.  Detail the usage of the Shared Resources by the participating 
investigators.  Include any outreach efforts to provide access to the 
Shared Resource to investigators outside the collaborative program.  
Discuss how the views of the scientific community impacted by the 
collaborative program will be considered.

PROJECT MANAGEMENT PLAN: Provide a timeline for the program, as a 
whole, and for each component, defining yearly landmarks to be used to 
assess progress. Explain how progress in the bridging and pilot 
projects and efficiency of the Shared Resources will be tracked.  
Include an evaluation plan to determine how the collaborative program 
is progressing.  Discuss the plan for evolving landmarks. Explain how 
the External Scientific Working Group will be used in updating the 
project management plan.  Explain how decisions will be made to 
add/delete participating investigators and to respond to changes in 
short term goals that research findings will make necessary.  Provide a 
plan for assessment of the bridging and pilot studies with emphasis on 
how it will be decided what duration they should have and whether and 
how they should be replaced.

PRELIMINARY STUDIES:  Provide any preliminary studies/data that may be 
relevant to the overall program.  Data should be in a readily 
interpretable form, with legends and appropriate identification of 
figures/tables in the text. 

Specific page limitations have been established for the following 
sections:

PLAN FOR DATA SHARING AND INTELLECTUAL PROPERTY (two page limit): The 
principal investigator and steering committee should (1) propose a plan 
for providing access to the data and information generated by the 
large-scale collaborative project to the members of the project and the 
scientific public; (2) address if or how intellectual property rights 
will be exercised; (3) discuss guidelines for licensing of joint 
inventions; (4) discuss procedures for settling of intellectual 
property disputes; (5) discuss the existence of any pre-existing 
intellectual property rights, including options to for-profit research 
sponsors; and (6) propose a plan for disseminating the technologies, 
assays, and associated reagents developed under this RFA

INSTITUTIONAL ENVIRONMENT AND RESOURCES (two page limit):  The 
environment and resources at the host institution that will be 
available to this program should be described.  The environment and 
resources available at collaborating institutions should be provided in 
the descriptions of those specific projects. 

SHARED RESOURCES

SHARED RESOURCE A.  BIOINFORMATICS RESOURCE (required; ten page limit):  
This Resource will be required for data accumulation, analysis, 
coordination and dissemination. Dissemination of information on 
techniques, scientific findings, and methodologies is a vital component 
of the large-scale collaborative program.  Effective use of computer 
technology, print media, and telecommunications are relevant.  Describe 
the staffing (including a Resource Director, as well as any 
professional or technical personnel and their duties), facilities, and 
resources that will be devoted to this goal.  Indicate plans to make 
results of research or other unique features of the collaborative 
project available for as wide an audience as possible.  Describe how 
data generated by the Shared Resource and Research Components will be 
processed into the information to be disseminated.  Discuss how data 
will be reviewed prior to inclusion in the bioinformatics database. 
Discuss plans for dissemination of published and unpublished data.

SHARED RESOURCE  B.  ADMINISTRATIVE RESOURCE (required; five page 
limit): This Resource must be directed by the principal investigator.  
Include the objectives of the Resource, a description of its staffing 
and services to be provided to other resources and to the participating 
investigators.  Communicating the objectives of the collaborative 
program and fostering opportunities for collaboration are encouraged.  
Expenses associated with the operation of the steering committee, 
meetings of all or subgroups of the participating investigators, and 
meetings and operation of the External Scientific Working Group would 
fall under the Administrative Resource.

SHARED RESOURCE C (and others):  There is a 10 page limit per Resource.  
Provide specific titles for any proposed scientific Shared Resources 
(e.g., instrumentation; genomics; proteomics; model organism; high-
throughput assay; or computational, modeling, or bioinformatics), along 
with a designated Resource Director who possesses expertise in the area 
of each Resource.  Describe the professional and technical staff to be 
involved in the Resource(s), and their duties.  Include plans to 
utilize the Resource(s), including services that will be provided, and 
to whom, and their bearing on productivity and quality of the 
collaborative research effort.

RESEARCH COMPONENTS

BRIDGING PROJECTS (ten page limit for each bridging project):  A 
bridging project should be designed to support work in the laboratory 
of a participating investigator relevant to the objectives of the 
overall program. For all proposed projects, the underlying rationale 
and potential impact of the studies should be specifically addressed. 
The need for the bridging project to tie (or enhance) the independent 
work of the participating investigator to the goals of the 
collaborative program must be described.  Essential information for the 
research plan should include specific aims, background and 
significance, preliminary studies, and research design and methods, and 
may be presented as a combined summary of these sections emphasizing 
the following:

Describe the new research proposed in the bridging project and explain 
how this work more fully integrates the participating investigator’s 
independently supported work into the overall theme and objectives of 
this collaborative Research Program.  A bridging project should extend 
the participating investigator’s independent work in a direction(s) 
relevant to goals of the Functional Atlas program.  A bridging project 
to do more of what the investigator is already doing should be 
considered only if there are extraordinary circumstances that make it 
essential for the effective functioning of the large-scale project.  If 
the participating investigator’s work is already closely tied to the 
large-scale project, a bridging project should not be needed.  
Substantial new research projects should not be submitted for bridging 
projects; these should be submitted as regular R01 applications, even 
if they add value to the large-scale project.

Projects must be described in sufficient detail to permit evaluation 
through the competitive peer-review process.  For each bridging project 
undertaken as part of the collaborative program, also to be included 
are sections (where appropriate) that address:  Gender and Minority 
Inclusion for Research Involving Human Subjects, Inclusion of Children 
as Participants in Research Involving Human Subjects, Human Subjects, 
Vertebrate Animals, Consortium/Contractual Arrangements, Consultants. 
Literature Cited should be included in the citations for the entire 
program, at the end of the application.

PILOT PROJECTS (five page limit for each pilot project for the research 
plan: specific aims, background and significance, preliminary studies, 
and research design and methods; maximum of three pilot projects per 
large scale collaborative program): Pilot projects may support the work 
of investigators not already supported in the area of the collaborative 
program but who have unique skills or expertise that add to the 
collaborative effort.  For all proposed projects, the underlying 
rationale and potential impact of the studies should be specifically 
addressed. How the pilot project will add new elements essential to 
achieving the goals of the collaborative program must be described.  
Projects must be described in sufficient detail to permit evaluation 
through the competitive peer-review process.  For each pilot project 
undertaken as part of the collaborative project, include the following 
sections: Abstract (one paragraph), Specific Aims, Background and 
Significance, Preliminary Studies, Research Design and Methods, as well 
as Gender and Minority Inclusion for Research Involving Human Subjects, 
Inclusion of Children as Participants in Research Involving Human 
Subjects, Human Subjects, Vertebrate Animals, Consortium/Contractual 
Arrangements, Consultants. Literature Cited should be included in the 
citations for the entire program, at the end of the application.

INSTITUTIONAL COMMITMENTS: Letters signed by authorized business 
officials of each of the participating investigators' institutions 
committing support to the large-scale collaborative project must be 
included.  Applicants for proposals that include consortium 
arrangements should refer to the NIH Grants Policy Statement appendix 
on consortium arrangements at: 
http://grants.nih.gov/archive/grants/policy/nihgps/part_iii_5.htm#Consortium.  

OTHER SUPPORT OF PARTICIPATING INVESTIGATORS:  For the principal 
investigator, steering committee members, participating investigators, 
and heads of Resource resources, provide a listing of all other support 
for each participant in the usual NIH format for non-modular 
applications 
(see http://grants.nih.gov/grants/funding/phs398/phs398.html); support 
for other investigators such as postdoctoral students should not be 
listed.  For the relevant grant support that allows participating 
investigators to be part of the large-scale collaborative project, 
provide the specific aims of the project and describe in sufficient 
detail for evaluation the relationship of the funded grant to the goals 
of the proposed collaborative Research Program (U19).

METHOD OF APPLYING

The RFA label available in the PHS 398 (rev. 4/98) application form 
must be affixed to the bottom of the face page of applications.  
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. Enter the RFA number on the label.  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.

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

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, exact photocopies, in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive
Room 1040 - MSC 7710
Bethesda, MD  20892-7710

BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application and 
all five sets of any appendix material must be sent to:

Francisco O. Calvo, Ph.D. 
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Room 752
Bethesda, MD  20892-5452

Applications must be received by November 19, 2001.  If an application 
is received after the due date, it will be returned to the applicant 
without review.  The Center for Scientific Review (CSR) will not accept 
any application in response to this RFA that is essentially the same as 
one currently pending initial review, unless the applicant withdraws 
the pending application.  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 by CSR and 
responsiveness by the NIDDK.  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 NIDDK in accordance with the review 
criteria stated below.

As part of the initial merit review, a process may be used by the 
initial review group in which applications receive a written critique 
and undergo a process in which only those applications deemed to have 
the highest scientific merit, generally the top half of the 
applications under review, will be discussed, assigned a priority 
score, and receive a second level review by the National Diabetes and 
Digestive and Kidney Diseases Advisory Council.

NIH Review Criteria for Investigator-initiated projects:

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, reviewer 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.

In addition to the criteria below, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following (where 
relevant):

o Adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals 
of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. 
o The reasonableness of the proposed budget and duration to the 
proposed research.

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

o For applications with foreign components: Availability of special 
opportunities for furthering research programs through the use of 
unusual talent resources, populations, or environmental 
conditions in other countries which are not readily available in 
the United States or which provide augmentation of existing U.S. 
resources.

REVIEW CRITERIA FOR THE RESEARCH PROJECT-COOPERATIVE AGREEMENT (U19)  

Overall Project

1.  Significance.  Does this collaborative Research Program adequately 
address the central question of this initiative, i.e. development of a 
Functional Atlas of Orphan Nuclear Receptors, in a way that would be 
difficult to address by separate grants?  Do the arrangements for data 
sharing maximize the impact of the collaborative program?

2.  Approach.  Are the conceptual framework, design, methods, and 
analyses adequately developed, well integrated, and appropriate to the 
scientific aims of the collaborative program?  Is the project 
management plan adequate and comprehensive?  Is the administrative 
framework appropriate and designed to integrate the various components?  
Do landmarks articulate key indicators set for appropriate times that 
will demonstrate significant forward progress for the collaborative 
program?  Are the plans to monitor and evaluate progress of the 
collaborative program adequate? Will the Bioinformatics Resource 
support the objectives of the Functional Atlas?  Are the plans to share 
the data and findings with the larger community adequate? How will the 
group take the views of the scientific community impacted by the large-
scale collaborative program into consideration?

3.  Innovation.  Will the collaborative program challenge existing 
paradigms or develop new methodologies or technologies?  Will the 
collaborative program attack the problem in a significantly new way?  
What will be the value added over individual grants?

4.  Investigators.  Is the principal investigator's major research 
activity within the research area of the collaborative program?  Is the 
principal investigator well suited to the scientific and administrative 
leadership required to carry out this work?  Is the level of effort 
proposed for the principal investigator and the members of the steering 
committee appropriate?  Is the work proposed appropriate to the 
experience level of the collaborative program's research and technical 
staff?  Are the research grants of the participating investigators 
within the area of the collaborative program?  Are the participating 
investigators well chosen for their roles in the collaborative program?  
Is the plan to add and delete participating investigators to and from 
the collaborative program satisfactory?

5.  Environment.  Will the proposed collaborative program take 
advantage of unique features of the scientific environments of the 
component projects?  Is the level of institutional support adequate?  
Are the requested Shared Resource facilities critical to achieving the 
scientific goals of the collaborative program; are they cost effective?  
Is access to the Shared Resource facilities appropriate?

In addition, the following criteria will be considered for merit 
review: The commitment to the program by the principal investigator and 
the members of the steering committee will be a consideration.  For 
applications that are multi-institutional or that involve industry, the 
adequacy of plans to resolve intellectual property issues will be a 
consideration.  The commitment of the host and participating 
universities to supporting the large scale collaborative program will 
also be considered: this would be reflected in efforts to work out 
ahead of time potential intellectual property issues and to remove any 
institutional barriers to the establishment and healthy maintenance of 
the collaborative program.

Review Criteria for Research Components (Bridging and Pilot Projects)

1. Significance.  Does this project address an important problem 
relevant to the overall scope of the Functional Atlas? If the aims of 
the application are achieved, how will scientific knowledge be 
advanced? What will be the effect of these studies on the achieving the 
goals of the collaborative program?  Will the bridging project tie or 
enhance the independent work of the participating investigator to the 
collaborative program, or will the pilot project add an essential 
missing aspect to the collaborative program?

2. Approach.  Are the conceptual framework, design, methods, and 
analyses adequately developed, well-integrated, and appropriate to the 
aims of the program?  

3. Innovation.  Does the collaborative nature of the project enhance 
potential innovation? 

4. Investigator.  Is the participating investigator appropriately 
trained and well suited to carry out a collaborative project?  Is the 
work proposed appropriate to the experience level of the participating 
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?

Review Criteria for Shared Resources.

1. Facilities within the Shared Resource compared to the state of the 
art; the contributions of the Shared Resources to fulfilling the goals 
of collaborative program.

2. The extent to which Shared Resource units promote greater 
collaboration and cohesiveness among the participating investigators.  
Does this resource promote an economy of scale?  Are there unique 
aspects of the resource that contribute to achieving the overall goals 
of the program?

3. Qualifications, experience, and commitment to the large-scale 
collaborative program mission of the investigators responsible for the 
Shared Resources and their abilities to devote the required time and 
effort to the program.

4. Appropriateness of the budgetary requests.

AWARD CRITERIA

Award criteria that will be used to make funding decisions include:

o scientific merit (as determined by peer review)
o program priorities
o program balance
o availability of funds

SCHEDULE

Application Receipt Date:         November 19, 2001
Peer Review Date:                 Feb.-March 2002
Advisory Council Date:            May 2002
Earliest Anticipated Award Date:  September 30, 2002

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.  
The opportunity to clarify any issues or questions from potential 
applicants is welcome.

Direct inquiries regarding programmatic issues relevant to NIDDK to:

Ronald Margolis, Ph.D.
Senior Advisor, Molecular Endocrinology
Division of Diabetes, Endocrinology, and Metabolism
National Institute of Diabetes and Digestive and Kidney Diseases 
6707 Democracy Boulevard, Rm. 6107 MSC 5460
Bethesda, MD 20892-5460
Telephone:  (301) 594-8819
FAX:  301-435-6047
E-mail:  rm76f@nih.gov

Direct inquiries regarding fiscal matters to:

Cheryl Chick
Division of Extramural Activities 
NIDDK
6707 Democracy Boulevard, Rm. 714 MSC 5460
Bethesda, MD 20892-5460
Telephone:  (301) 594-8825
FAX:  301-480-3504
E-mail:  cc149o@nih.gov
 
Direct inquiries regarding programmatic issues relevant to NIA to:

Frank Bellino, Ph.D.
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231 MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  FB12A@nih.gov

Direct inquiries regarding fiscal matters to:

Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  lw17m@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.847 for DEM (NIDDK), and No. 93.866 (NIA).  Awards are made 
under authorization of the Public Health Service Act, Title IV, Part A 
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 
285) and administered under 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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