NIDDK PROGENITOR CELL GENOME ANATOMY PROJECTS

Release Date:  October 9, 2001

RFA:  RFA-DK-02-027

National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov)

Letter of Intent Receipt Date:  February 15, 2002
Application Receipt Date:       March 15, 2002

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) invites Cooperative Agreement Applications for Progenitor Cell 
Genome Anatomy Projects (GAPS) that will participate in the discovery 
of the processes necessary for development of tissue specific cells and 
organs from stem cells and the processes by which progenitor cells 
maintain and regenerate tissues and organs in health and disease.  The 
specific goals of the projects will be to develop the necessary 
biological procedures and reagents for characterization of tissue 
specific progenitor cells and to characterize gene expression patterns 
in these cells using advanced technologies and bioinformatic 
techniques.  The focus of the projects will be on progenitor cells of 
the gastrointestinal tract, liver, pancreas, kidney and genitourinary 
tract in both human and murine systems.   Because of the nature of the 
research questions, it is expected that potential applicants will 
include both investigators with expertise in the biology of progenitor 
cells and investigators having substantial expertise in bioinformatics.  
The components of the GAPS will work together as a consortium   It is 
expected that the consortium will serve as a resource to provide 
reagents and databases that will be made available to the research 
community.

The Human Genome Project and similar work in other species have made it 
possible to address in new ways the important biological problems of 
how different tissues and organs develop from small founder populations 
of stem cells, how organs continue to be maintained and sometimes 
regenerate during adult life, and the effects of age and disease on 
this capacity.  While less is known about development of endodermal 
organs, such as the liver and pancreas, than about ectodermal and 
mesodermal tissues, such as skin and blood, recent advances have 
demonstrated two important principles.  First, work in model 
experimental organisms suggests that some critical molecules that 
regulate organ development are evolutionarily conserved.  Second, there 
is emerging evidence that progenitor cells of different tissues may 
share some common basic molecular mechanisms that allow them to self-
renew in the presence of appropriate environmental cues.  The 
elucidation of these mechanisms offers the promise of providing a 
complete understanding of the factors that maintain normal tissues in 
health and the promise for novel approaches to the study of 
pathogenesis and treatment of human diseases.  Therefore, the aim of 
these projects will be to accelerate progress toward identification and 
characterization of progenitor cells and factors that regulate 
development and differentiation of the gastrointestinal epithelium, 
liver, exocrine pancreas and kidney and urologic tissues, including 
prostate and bladder.  As a related NIDDK initiative already is 
directed at the endocrine pancreas and hematopoietic stem cells 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-02-018.html), 
these cell types are specifically excluded from this initiative.

This grant award mechanism will support characterization of appropriate 
stem cell lines that are broadly relevant to study of the target organ 
at multiple stages of target organ development and differentiation, 
determination of gene expression patterns in those cell lines, and 
development of appropriate functional genomics tools to characterize 
the genes expressed.  In addition, this resource will provide 
bioinformatics links to existing NIH-supported genomics databases and 
make relevant biomarkers and genomics tools available to be used by 
researchers investigating both normal and diseased tissue.

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 Request for 
Applications (RFA), NIDDK PROGENITOR CELL GENOME ANATOMY PROJECTS, is 
related to one or more of the priority areas.  Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted from either domestic or foreign 
institutions, 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.

All current policies and requirements that govern the research grant 
programs of the National Institutes of Health (NIH) will apply to 
grants awarded under this RFA.  Among the disciplines and expertise 
that may be appropriate for this program are gastroenterology, 
nephrology, urology, hematology, internal medicine, pediatrics, 
genetics, bioinformatics, pathology and related scientific disciplines. 
 
MECHANISM OF SUPPORT

This RFA will use the NIH cooperative research (U01) award mechanism of 
support, 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 NIH purpose is to 
support and stimulate the recipients’ activity by involvement in the 
activity and otherwise working jointly with the award recipients 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 agreements are discussed below under “Terms and Conditions 
of Award.”

The total requested project period for an application submitted in 
response to this RFA may not exceed 3 years.  The maximum dollar 
request is limited to $1,500,000 in direct costs for the initial budget 
period and $4.5 million in direct costs for the entire project period.  
Projects of varying budget and size are encouraged.  This is a one time 
solicitation. The anticipated award date is September 30, 2002.

FUNDS AVAILABLE

For FY 2002, $4M in total costs will be committed to fund applications 
submitted in response to this RFA.  Since applications for projects of 
various sizes are encouraged, it is anticipated that –two to four 
awards will be made.  Proposed funding levels are subject to change due 
to budgetary, administrative and/or scientific considerations, and are 
dependent upon the receipt of a sufficient number of applications of 
high scientific merit.  It is expected that major equipment costs will 
be incorporated in the first year budget, and that subsequent year 
budgets should be related to the anticipated level of library 
production and sequencing.  Although this program is provided for in 
the financial plans of the NIDDK, the award of grants pursuant to this 
RFA is also contingent upon the availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

On September 19, 2000, the NIDDK convened a Working Group of its 
National Advisory Council to develop strategic plans for several cross-
cutting areas of research, including Stem Cells and Developmental 
Biology.  The primary recommendation of this group was that NIDDK 
should catalyze a nation-wide effort to characterize the molecular and 
cellular features of stem cells during and following development of the 
pancreas, liver, stomach and intestine, kidney and GU tract, bone, and 
hematopoietic tissues.  The goal is to provide entirely new strategies 
for repairing or replacing damaged organs in individuals of all ages, 
and new insights about pathologic processes underlying disordered 
development, disordered maintenance, and neoplastic transformation of 
these organs.

Genome Anatomy Projects (GAPs) have been established by the National 
Cancer Institute and NIDDK to accelerate the pace of discovery of genes 
expressed in specific tissues, such as tumors or the endocrine 
pancreas, and to exploit the sequence data emanating from the Human 
Genome Project.  The GAPs foster the development of national networks 
of laboratories that characterize tissue-specific gene expression and 
identify novel transcripts.  In addition, GAP researchers elucidate 
patterns of gene expression that lend insight into developmental 
programs and disease progression, and that may eventually be useful in 
diagnosis and treatment of disease.  The bioinformatics systems 
associated with each GAP ensure that all of the data produced are 
available to researchers worldwide soon after it is generated in the 
laboratories.  

Given the importance of developing new in vivo models for studying and 
assaying stem cell function, the need for improved isolation and 
recovery of stem cells, and the need for methods to maintain ex vivo 
cell populations that retain their pluripotency, it is essential to 
characterize genomic features of stem cells and their committed 
daughters.  The status of research on stem cells or progenitor cells in 
different organ and tissues varies widely.  For example, hematopoiesis 
is among the best-understood biological systems in mammals.  
Purification of adult hematopoietic stem cells (HSCs) through the use 
of monoclonal antibodies such as CD34 has been accomplished, however 
imperfectly, and lineage-specific progenitors have also been purified 
recently.  HSCs are also used for liver repopulation, but the factors 
that permit the conversion of HSCs to hepatocytes remain to be 
discovered.  In addition, there is some evidence for liver stem cells.  
In the gut, epithelial renewal in the stomach, small intestine, and 
colon is sustained by populations of multipotent stem cells that reside 
in distinct anatomic units.  However, the properties of these stem 
cells remain to be more fully defined.  Finally, the stem cell biology 
of the prostate, bladder and kidney is largely unknown, with the 
features and location of these stem cells mostly undefined.  For these 
tissues, there is a need for the establishment of reproducible 
conditions and protocols for the identification, retrieval, and 
maintenance of stem or progenitor cells.

The current RFA is designed to stimulate GAPs that will catalogue the 
gene expression in recovered stem cell or progenitor cell populations 
in developing and adult normal tissues and provide that information and 
material, along with relevant functional genomics tools, to the entire 
research community.

Since the databases for the GAPs will perform similar functions, it 
should not be necessary for multiple sites to invent similar database 
methods in parallel.   Therefore, researchers from the GAPs will 
develop robust and generic modules to perform particular tasks, so that 
all databases share a common architecture, regardless of the underlying 
database platform.   Although developing a module in a robust and 
generic manner so that it is usable by other projects takes more effort 
than developing it to work within just a single GAP, the modular 
structure will make it easier for the general research community to 
search among the data collected by the various GAPs, and will 
facilitate sharing among the GAPs, comparisons, and data mining.

Objectives and Scope

This RFA is intended to support the cost-effective determination of the 
gene expression profiles in the targeted stem or progenitor cell 
populations of human or murine origin and to develop functional 
genomics tools to characterize the genes expressed.  The relevant 
tissues for this initiative are: developing and adult exocrine pancreas 
(the endocrine pancreas is excluded from this initiative), liver, 
stomach/intestine, kidney/bladder, bone and fat.  Thus, all 
applications must include separate sections describing each of the 
listed aspects of the project.  Since stem cell research is at 
different stages of development for each of the targeted tissues or 
organ systems, it is anticipated that each project will allocate 
resources differently to the various parts of the GAP.  Nevertheless, 
each application must include: 

o Characterization and Definition of Cell Populations – Define and/or 
develop specific biomarkers, such as high-specificity antibodies or 
reporter gene constructs, for detection, classification, and isolation 
of stem cells and progenitors at multiple stages of development and 
differentiation, as well as those specific to particular lineages.  
This will include, where appropriate, development of reliable and 
convenient clonogenic assays for stem cell populations in developing 
and adult tissues so that these cells can be purified and 
characterized.  In addition, this part of the GAP may include 
development of methods to maintain ex vivo cell populations that retain 
their pluripotency.

o mRNA Expression Profile – Profile mRNA expression in the relevant 
cell populations and identify novel genes and transcript splice forms 
specifically expressed in the targeted cell population using in silico 
methods, production and sequencing of cDNA libraries, as well as arrays 
and other methods.  Since many of these factors may be expressed at 
very low levels at key stages in development, strategies should be 
proposed to increase the representation of low abundance transcripts in 
the cDNA libraries and to decrease the redundant sequencing of over-
represented or known genes.  In addition, the application should 
describe the development of custom clone sets for use in microarrays or 
other high-throughput gene expression assays, and the use of those 
arrays to characterize changes in gene expression patterns in the 
target cell population during development, differentiation, or disease 
progression.  Finally, this phase of the project may also include 
efforts to develop and apply single-cell gene expression methodologies.

o Histology and Functional Genomics - Develop rapid, sensitive methods 
for in vivo confirmation of patterns of gene expression.  This phase of 
the project may also include the development of one or more gene-
specific tools, such as reporter gene (e.g. with Green Fluorescent 
Protein, beta-galactosidase) and antisense constructs, conditional or 
nonconditional knockout mutations, and morpholinos or other inhibitors 
of expression, for characterizing the cell lineage under study and for 
analyzing the role of particular genes.

o Database – Although each GAP will develop its own database to store, 
organize, analyze, or visualize data, this database will be based on 
common modules developed by all the funded GAPs.  A module will be 
included that allows for Internet-based comparisons of progenitor cell 
gene expression data to similar data obtained from normal and diseased 
tissues from model organisms and humans.  The overall goal is that GAP 
databases should be easy to search and clearly illustrated.  Applicants 
should discuss how they would participate and contribute to this 
modular approach and summarize their experience in this area.  A 
schedule for rapid disposition of sequences and expression data into 
public databases such as GenBank and the Gene Expression Omnibus (GEO) 
should also be proposed.

o Research Tool Distribution – Develop and distribute to the research 
community well-characterized progenitor cells, cDNA clones, and high-
specificity antibodies.  In addition, the GAP should develop and 
distribute clone sets or long oligonucleotides for printing custom 
microarrays that can be used to identify and characterize the target 
stem cell population during different stages of development and 
differentiation.  Similarly, the project should develop and distribute 
any functional genomics tools developed, including Green Fluorescent 
Protein (GFP) or antisense constructs, knockout cell lines or vectors 
for gene replacement, and other similar reagents that can be used to 
isolate and study the target cells at various stages and/or study the 
role of specific genes.  The selection of sequences for custom arrays 
and reporter constructs should be well-justified and based on their 
utility for research on the relevant stem cell.  The application should 
describe plans to develop and maintain supporting informatics and 
easily accessible Web sites that describe available tools and validated 
methods.  Plans for distributing reagents in a timely and economical 
fashion should be included.

o Outreach - A major objective of this RFA is to disseminate the data 
and research reagents generated through each project to the research 
community as rapidly as possible.  Therefore, the application should 
describe methods for ensuring that the larger research community has 
access to data and available tools generated by the GAP.  In addition, 
applicants are encouraged to describe opportunities for long- and 
short-term training of researchers at all levels to take advantage of 
these data and reagents.

SPECIAL REQUIREMENTS

Applicants must indicate their willingness to be part of a Steering 
Committee consisting of representatives of each GAP funded by NIDDK 
through this RFA and through RFA-DK-02-018 and NIH staff.  The semi-
annual meetings will be held to encourage exchange of information among 
investigators who participate in this program.  A major goal of these 
meetings is to facilitate progress by providing a forum that will lead 
to sharing skills, ideas, technology, data, and biological reagents.  
At the meetings, participants will also discuss quality assurance, 
coordination, sharing, means of informing the research community of 
services offered by the GAPs, and training.  One special focus of the 
meetings will be on bioinformatics and the construction of common 
modules that will be used by all GAP databases.  Applicants must 
include travel funds that will allow the Principal Investigator and the 
key research scientist leading the bioinformatics effort to participate 
each year in two one-day meetings in Bethesda, Maryland.

During the course of the funding period, technologies will improve, and 
the rate of progress and focus of work supported by the cooperative 
agreement may change.  It is expected that the Principal 
Investigator(s), in consultation with NIDDK program staff, the Steering 
Committee, and the External Advisory Board (see below) will make any 
necessary adjustments to accommodate the changing research environment, 
to remain focused on appropriate goals, to maintain excellent 
coordination with the other projects funded by NIDDK, and to 
incorporate new technological advances.

A. Interactions

The GAPs, through the Steering Committee, and other subcommittees will: 

o Share bioinformatics expertise and software tools to develop robust 
database software as modules to perform particular tasks.  Such modules 
will be able to read and write data in certain common formats, but will 
be independent of the underlying database platform.  These modules will 
provide uniformity of data presentation between the GAPs, and 
facilitate distribution of resources between component Units and with 
the broader research community.  The modules developed may include 
modules for storing and presenting microarray data, cell-type-specific 
expression profile, annotation data for expressed genes, and in vivo 
expression data, as well as various queries or views that are generally 
useful.

o Define the best practices and develop controlled vocabularies to 
describe genes, tools and reagents, 

o Identify technological impediments to characterizing gene expression, 
or generating appropriate tools, and select strategies to surmount 
them, 

o Share technological and methodological information both between 
component GAPs and with the broader research community,

o Share molecular tools and constructs between GAPs to avoid 
unnecessary duplication of effort,

At each step, input will be sought from experts both within the GAPs, 
those funded through other NIDDK-sponsored initiatives, such as the 
Functional Genomics of the Developing Endocrine Pancreas (RFA-DK-99-
007), NIDDK Biotechnology Centers (RFA-DK-00-002), and Development of 
the Gut, Liver and Exocrine Pancreas (RFA-DK-01-023), and from the 
broader research community.

B. Genome Anatomy Project Individual Units

Each Unit will be a self-assembled group of investigators from one or 
more institutions who provide a unique mix of complementary research 
experiences.  An applicant team will incorporate an appropriate mix of 
expertise needed to achieve the Unit’s goals and to contribute 
substantially to achieving the overall GAP Consortium goals.  Units 
will be expected to focus on either one or a small number of tissues.  
Each team must contain expertise in stem cell biology, genomic 
analysis, bioinformatics, and pathology

The approaches used to generate the appropriate progenitor cell line or 
lines, and characterize the gene expression profile will reflect the 
blend of experience and creativity of the component investigators. 

It is anticipated that some of these applications will be quite 
speculative, and applications may have limited preliminary data on the 
properties of progenitor cells in some specific organs.  However, 
applications should include sufficient information to indicate that the 
applicant team has sufficient expertise with proposed techniques and 
that the proposed projects are feasible.

C. Data Sharing

Restricted availability of unique research resources, upon which 
further studies are dependent, can impede the advancement of research 
and delivery of medical care.  Sharing biomaterials, data, and software 
in a timely manner has been an essential element in the rapid progress 
that has been made in the genetic analyses of mammalian genomes.  NIH 
policy requires that investigators make unique research resources 
readily available for research purposes to qualified individuals within 
the scientific community after publication [NIH Grants Policy Statement 
(http://grants.nih.gov/grants/policy/nihgps, Principles and Guidelines 
for Recipients of NIH Research Grants and Contracts on Obtaining and 
Disseminating Biomedical Research Resources:  Final Notice, December 
1999 (http://www.ott.nih.gov/policy/rt_guide_final.html)].  
Biomaterials (constructs, cell lines, etc.) and other research 
resources that can be patented (e.g., software tools, expression data) 
produced in projects funded by this RFA are expected to be made 
available and distributed to the broader scientific community.

The NIH is interested in ensuring that the research resources developed 
through this RFA become readily available to the research community for 
further research, development, and application, in the expectation that 
this will lead to products and knowledge of benefit to the public.  At 
the same time, NIH recognizes the rights of grantees to elect and 
retain title to subject inventions developed under federal funding 
under the provision of the Bayh-Dole Act.

This RFA has two special requirements regarding research resources 
produced in proposed projects:

(1)  Applicants are required to include in their application a specific 
plan by which they will share research resources with the wider 
scientific community, as well as copies of all Material Transfer 
Agreements used by all institutions involved in the application. 

(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.  These plans should be consistent with the policies of their 
institutional offices of technology transfer.

The scientific review group will evaluate the adequacy of the proposed 
plans for sharing and data access. Comments on the plan and any 
concerns will be presented in an administrative note in the Summary 
Statement.  The adequacy of the plan will be considered by NIH program 
staff and will be important in determining whether the grant shall be 
awarded. The sharing plan as approved, after negotiation with the 
applicant when necessary, will be a condition of the award.  Evaluation 
of non-competing continuation applications will include assessment of 
the effectiveness of research resource release.

Applicants 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 mice identified through phenotypic screens, 
phenotypic screens, and phenotypic and genotypic data for all mouse 
strains or other patentable subject matter are adversely affecting the 
goals of this RFA.

E. Steering and Other Committees

The Principal Investigator must be willing to be part of a Steering 
Committee that will meet twice each year together with NIH program 
staff to encourage exchange of information among investigators who 
participate in this program.  The Steering Committee may form other 
committees (for example, bioinformatics, technology) that will meet 
once or twice a year either in person or by telephone conference calls.  
A major goal of these meetings is to facilitate progress by providing a 
forum for sharing skills, ideas, technology, data, and biological 
reagents.  At the meetings, participants will also discuss quality 
assurance, bioinformatics, coordination, and training.  If voting is 
necessary for an action item, NIH Project Scientists will share one 
vote.

TERMS AND CONDITIONS OF AWARD
 
The following terms and conditions will be incorporated into the award 
statement and provided to the Principal Investigator(s) and to the 
institutional official at the time 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. Awardee Rights and Responsibilities

o The PI 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.

o 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.

o The PI(s) will serve as voting member[s] of the Steering Committee, 
will attend the Planning Meeting and a Steering Committee meeting in 
the first year, and two Steering Committee meetings a year in 
subsequent years.

o The PI will be responsible for accepting and implementing the goals, 
priorities, procedures, protocols, and policies agreed upon by the 
Steering Committee and subcommittees.

o The PI will be responsible for close coordination and cooperation 
with the other GAPs and with NIH staff.

o The PI will establish an Internal Advisory Committee to provide 
scientific and administrative oversight.  The Internal Advisory 
Committee will be composed of the lead center personnel, and other 
technical or research personnel.  These individuals are not limited to 
GAP faculty.  The committee is expected to meet at least monthly.  
Minutes of these meetings will be made available to NIH staff upon 
request.  The Internal Advisory Committee is charged with both 
prioritizing projects and periodically reviewing GAP activities to 
ensure that the objectives outlined in the application are being met.

o 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 and NIH policies.  However, all awardees 
must adhere to PHS policy for the distribution of unique research 
resources produced with PHS funding as described under Special 
Requirements.  The NIDDK Project Scientists, on behalf of the NIDDK, 
will have the same access, privileges and responsibilities regarding 
the collaborative data as the other members of the Steering Committee.

o NIH reserves the right to require the transfer of appropriate cell 
lines, reagents, tools 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 these materials and data 
about them and/or to continue the research. Third parties supported 
under these awards must be informed of this right.

o Within the first three months of the award period, the PI will be 
responsible for establishing written milestones for the GAP, in 
consultation with NIDDK Project Staff.

o Support or other involvement of industry or any other third party in 
any study performed by the GAPs-- e.g., participation by the third 
party, involvement of project resources or citing the name of the 
project or the NIDDK support, or special access to project results, 
data, findings or resources -- may be advantageous and appropriate.  
However, except for licensing of patents or copyrights, support or 
involvement of any third party will occur only following notification 
to, and concurrence by, NIDDK.

o Upon completion of the project, the GAPs are expected to put all 
study design materials and procedure manuals into the public domain 
and/or make them available to other investigators, according to the 
approved plan for making data and materials available to the scientific 
community and the NIDDK, for the conduct of research at no charge other 
than the costs of reproduction and distribution.

2. NIH Staff Responsibilities

NIDDK Project Scientists 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 project as a whole resides with the 
awardees, although specific tasks and activities in carrying out the 
studies will be shared by awardees and the NIDDK.

o NIDDK will designate a Project Officer and a Grants Management 
Specialist to provide administrative oversight of the cooperative 
agreement.

o NIDDK will form an External Advisory Committee, comprised of NIDDK 
Project Staff and other NIH extramural staff with relevant scientific 
expertise or who manage research grant programs that relate 
scientifically to the goals of the GAPs, and outside advisors picked by 
the NIDDK. The External Advisory Committee will meet regularly to 
review the progress of the GAPs and to advise NIDDK Project Staff of 
scientific developments and opportunities that may enhance the 
achievement of the GAP goals.

o NIDDK Project Scientists will be members of the Steering Committee 
and, as determined by that committee, its subcommittees.

o NIDDK Project Scientists will coordinate and facilitate the GAPs, 
attend and participate as voting members in all meetings of the 
Steering Committee, and provide liaison between the Steering Committee 
and the External Advisory Committee.

o NIDDK Project Scientists will help the Steering Committee develop and 
draft operating policies and policies addressing recurring situations 
that require coordinated action.

o NIDDK Project Scientists will review the scientific progress of the 
individual GAPs, review GAPs for compliance with operating policies 
developed by the Steering Committee, and may recommend to the NIDDK to 
withhold support, suspend, or terminate an award for lack of scientific 
progress or failure to adhere to policies established by the Steering 
Committee.

3. Collaborative Responsibilities
Steering Committee - The NIH Project Scientists and PIs of the GAPs 
funded under this RFA and RFA-DK-02-018 will be responsible for forming 
a Steering Committee as defined below. An arbitration system, as 
detailed below, will be available to resolve disagreements among 
members of the Steering Committee. The Steering Committee will be the 
main governing board of the GAPs.  It will develop collaborative 
protocols, identify technological impediments to success and strategies 
to overcome them, develop shared software tools for disseminating 
information about the GAPs, and identify opportunities for sharing 
techniques and tools developed within each individual GAP.

o The Steering Committee will be composed of the PI from each GAP 
funded through this RFA and RFA-DK-02-018, and NIDDK Project 
Scientists.  The PI from each GAP will have one vote.  The NIDDK 
Project Scientists will share one vote.  The Steering Committee will 
select a chairperson who will be someone other than an NIDDK staff 
member.

o The Steering Committee may, as it deems necessary, invite additional, 
non-voting scientific advisors to meetings at which research priorities 
and opportunities are discussed. The NIDDK reserves the right to 
augment the scientific or consumer expertise of the Steering Committee 
when necessary.

o There will be two Steering Committee meetings annually, both in the 
Washington, DC, area at times agreed upon by the Steering Committee and 
the NIDDK.

o The first meeting of the PIs from GAPs funded under this RFA and RFA 
DK-02-018 will be a Planning Meeting in the Washington, DC, area soon 
after grants are awarded. At the Planning Meeting, the Steering 
Committee will be formed and select a chairperson from among the 
members who represent the awardees. At the Planning Meeting, the 
Steering Committee may: (a) draft a charter to detail policies and 
procedures, a process for monitoring compliance with the policies and 
procedures, and a process for recommending that the NIH Project 
Administrators act on evidence of non-compliance of any Consortium 
component with Steering Committee policies, (b) agree upon the terms of 
the charter, (c) discuss the approaches that were proposed in the 
project applications and any relevant new information, and set initial 
priorities for the projects to be pursued and for new technologies to 
be developed, (d) develop a bioinformatics subcommittee whose 
membership will include the key research scientist from each GAP 
responsible for bioinformatics, NIDDK Project Staff, and outside 
advisors as needed.

o The bioinformatics subcommittee will work together to develop a 
uniform database architecture, deciding on which modules are needed and 
developing those modules for use by all GAPs.

o At their first meeting each year, the Steering Committee will 
formulate plans for any workshops or symposia to be held.

o At the second and subsequent meetings, the Steering Committee will 
refine the GAPs’ scientific objectives and implementation as necessary, 
consistent with progress in the individual GAPs and other laboratories.

o The Steering Committee will plan workshops to which non-GAP 
participants will also be invited to (a) enable the GAPs to explore 
scientific or technologic innovation that occurs during the course of 
the project, (b) inform the research community of the progress made 
toward development of gene expression profiles and progenitor cell 
lines, and (c) inform the research community of any technological 
advances related to implementation of a GAP.  The NIDDK Project 
Scientists, the External Advisory Committee, and other NIH staff will 
provide the Steering Committee with advice on participants for the 
workshops and symposia. 

o The Steering Committee may establish other subcommittees, in addition 
to the bioinformatics subcommittee, as it deems appropriate, NIH 
Project Scientists and other NIH staff who are Steering Committee 
members will serve on subcommittees as they deem appropriate.
 
4.  Arbitration
 
Any disagreement that may arise on scientific and programmatic matters 
within the scope of the cooperative agreement and between award 
recipients and NIDDK may be brought to arbitration.  An arbitration 
panel will be composed of three members: one selected by the GAP 
Principal Investigator, 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 appealable in accordance with 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 are 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 
complete copy of the updated Guidelines are 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 ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS

NIH policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  This policy announcement is found 
in the NIH Guide for Grants and Contracts Announcement dated June 5, 
2000, at the following website: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.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.

NIH POLICY AND GUIDELINES FOR THE USE OF HUMAN FETAL TISSUE 

Applicants must adhere to the current NIH policy and state and federal 
laws governing the use of human fetal tissue in preparing an 
application in response to this RFA.  Information about the use of 
human fetal tissue is available at 
http://grants.nih.gov/grants/guide/notice-files/not93-235.html.  

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT

The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent by 
February 15, 2002.  The letter should include a descriptive title of 
the proposed research, the name, address, and telephone number of the 
Principal Investigator, the identities of other key personnel and 
participating institutions, and the number and title of 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 a subsequent application, the information that it contains 
allows IC staff to estimate the potential review workload and plan the 
review.

The letter of intent is to be sent to:

Chief, Review Branch 
Division of Extramural Activities
National Institute of Diabetes and Digestive Kidney Diseases
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD  20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
E-mail:  fc15y@nih.gov

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 
5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html are 
to be used in applying for these grants. This version of the PHS 398 is 
available in an interactive, searchable PDF format. The NIH will return 
applications that are not submitted on the 5/2001 version.  For further 
assistance contact GrantsInfo, Telephone 301/435-0714, Email: 
GrantsInfo@nih.gov.

SPECIAL INSTRUCTIONS

General Application Format Instructions

The form PHS 398 should be modified as follows. Biosketches and "Other 
Support" pages should be included for all personnel. The number of 
pages allowed for the "Research Plan" is increased from 25 to 40 pages.  
Budget pages, budget justifications, material transfer agreements, and 
letters from collaborators and consultants and their biosketches are 
not included in this limit.

As described in detail above in RESEARCH OBJECTIVES (Objectives and 
Scope), applicants should divide the "Research Plan" into six sections: 
1)Characterization and Definition of Cell Populations, 2) mRNA 
Expression Profile, 3) Histology and Functional Genomics, 4) Database, 
5) Research Tool Distribution, and 6) Outreach.  In all sections, the 
roles and expertise of all key personnel, collaborators, and 
consultants who are associated with this part of the application should 
be well documented.

Applicants must provide methods to maintain GAP records, establish, 
standardize, document, and distribute protocols, and provide for 
quality control and budgetary oversight.  Applicants must also provide 
methods to establish priorities among the proposed projects and to 
oversee the daily operation of Units.

The application should include the description of the internal advisory 
board consisting of the Principal and co-Investigators and other 
important personnel that will oversee the daily operation of the Unit.  
Applicants should describe how the GAP will fit into, augment, and be 
supported by the parent institution and plan for designating an 
alternate or replacement Principal Investigator should it become 
necessary.

In this part of the "Research Plan," applicants must include specific 
plans for responding to the "SPECIAL REQUIREMENTS" section.  Applicants 
should state their willingness to collaborate and share data freely 
with the other GAPs and the wider research community. Applicants must 
include a data sharing plan and copies of all Material Transfer 
Agreements used by all institutions involved in the application. 
Applicants are encouraged to use the NIH Simple Letter of Agreement to 
transfer materials, available at 
http://www.ott.nih.gov/policy/rt_guide_final.html#guide.

Applicants should discuss their willingness to serve on the Steering 
Committee and other Consortium committees and should state their 
willingness to follow the common protocols that will be developed by 
the Steering Committee.  Applicants must state their willingness to 
plan and attend workshops and symposia.  Applicants should also 
describe how they will comply with the involvement of NIH Project 
Scientists and fulfill the responsibilities of Consortium components to 
work together cooperatively. Applicants should describe their 
experience with, and capability for developing modular database tools 
that can be shared.  In addition, applicants should describe their 
experience with Internet-based communication and suggest ideas for 
facilitating electronic communication and other interactions among the 
GAPs, NIH, and the general research community.

Budget Instructions 

Applicants who have additional funds to support (‘leverage’) the 
application should indicate the source of funds (institutional, R01, 
P01, P30, etc.) that permit them to accomplish the project goals. 
Subcontract budgets should be a separate page, and the subcontract 
indirect costs should be calculated and listed in the usual place as 
part of the direct costs of the budget. However, only direct costs 
associated with each subcontract will count toward the direct costs cap 
of $1,500,000 on the budget for the first year.

Applicants must budget for travel and per diem expenses for 
participation in the Steering Committee, subcommittees, workshops, and 
symposia. Applicants should budget for seven trips to the Bethesda, MD, 
area each year.

The RFA label available in the PHS 398 (rev. 5/2001) application form 
must be affixed to the bottom of the face page of the application.  
Type the RFA number(DK-02-027) on the label.  Failure to use this label 
could result in delayed processing of the application such that it may 
not reach the review committee in time for review.  In addition, the 
RFA title and number must be typed on line 2 of the face page of the 
application form and the YES box must be marked. The RFA label is also 
available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

Submit a signed, typewritten original of the application, including the 
Checklist, and three 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)

At the time of submission, two additional copies of the application 
must be sent to:

Dr. Francisco O. Calvo
Chief, Review Branch 
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD  20817)
Telephone:  (301) 594-8897
E-mail:  fc15y@nih.gov

Applications must be received by the application receipt date listed in 
the heading of this RFA.  If an application is received after that 
date, it will be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  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

General Considerations

All applications will be judged on the basis of the scientific merit of 
the proposed project and the documented ability of the investigators to 
meet the RESEARCH OBJECTIVES of the RFA. Although the technical merit 
of the proposed protocol is important, it will not be the sole 
criterion for evaluation of a study. Other factors considered to be 
important for review include demonstrated expertise in progenitor cell 
biology, a multi-disciplinary team of collaborators, substantial 
interactions among collaborating researchers, demonstration of 
appropriate facilities and resources, willingness to share data and 
reagents freely.

Supplemental information of up to three single-sided pages, to include 
figures and photographs will be allowed if received by June 17, 2002 
(this is an approximate date based on a review schedule of July or 
August 2002). Send materials to Chief, Review Branch, at the address 
above.

Review Method

Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIDDK. Incomplete 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, all applications will 
receive a written critique and undergo a process in which only those 
applications deemed to have the highest scientific merit, generally the 
top half of the applications under review, will be discussed, assigned 
a priority score, and receive a second level review by the National 
Diabetes and Digestive and Kidney Diseases Advisory Council.

Review Criteria

Applicants are encouraged to submit and describe their own ideas about 
how best to meet the goals of the cooperative study and their specific 
protocols, and they are expected to address issues identified under 
“SPECIAL REQUIREMENTS,” ”TERMS AND CONDITIONS OF AWARD” and ”SPECIAL 
INSTRUCTIONS” sections of the RFA. The peer review group will assess 
the scientific merit of the applications and related factors using the 
following criteria: 

Significance. The application should address the problem outlined in 
the RFA.  The application should demonstrate how the study would 
advance scientific and/or medical knowledge. Do the cell types chosen 
for expression profiling address important needs of the larger research 
community? What is the immediacy of the research opportunity?

Innovation. Does the project employ novel concepts, approaches or 
method? Is the project original and innovative? Does the project 
challenge existing paradigms or develop new methodologies or 
technologies? Will the approaches advance the field of hematopoietic 
cell development?

Approach. Are the conceptual framework, design, methods, and analyses 
adequately developed and appropriate to the aims of the project? Does 
the applicant acknowledge potential problem areas and consider 
alternative tactics? 

Investigators. Are the principal investigator and his/her collaborators 
appropriately trained and well suited to carry out this work? To what 
extent do these investigators have the necessary complementary skills? 
Have collaborations been established or consultants identified to 
provide the appropriate depth and breadth of scientific expertise 
required for the project? Will this team of investigators contribute 
unique skills to the overall Consortium? There should be evidence of 
prior experience in working collaboratively to carry out a standard 
protocol as well as evidence of willingness to work cooperatively on 
the Steering Committee to develop and follow a unified protocol.

Environment. Are the facilities for gene expression profiling, 
functional genomics, and bioinformatics appropriate to support the 
endeavor? 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 and incorporate the best use of collaborative arrangements? 
Is there evidence of institutional support?

Additional Considerations

Interactions. Are there adequate plans for effective interaction and 
coordination among Consortium components and the NIH? Are the proposed 
plans to share data and tools adequate? Do the investigators state 
their willingness to collaborate extensively and share information 
fully? Are the Material Transfer Agreements straightforward? Do the 
investigators state their willingness to abide by the priorities and 
policies agreed upon by the Steering Committee? Have the applicants 
proposed sound strategies for communication among themselves, with the 
other GAPs and with the NIH?  Have the applicants proposed sound 
strategies and approaches for working collaboratively to develop common 
database modules?

Reasonableness of the proposed budget and duration appropriate in 
relation to the proposed research:  Does it indicate that the 
applicants understand the requirements of managing this sort of high-
throughput genomics enterprise? 

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, protection and retention of human 
subjects also will be evaluated, as will the safety of the research 
environment.  

Schedule

Letter of Intent Receipt Date:    February 15, 2002
Application Receipt Date:         March 15, 2002
Peer Review Date:                 July, 2002
Council Review:                   September 2002
Earliest Anticipated Start Date:  September 30, 2002

AWARD CRITERIA

Applications recommended by the NDDK Advisory Council will be 
considered for award based upon (a) scientific and technical merit as 
determined by peer review, (b) the importance of the proposed cell 
types for research, (c) the degree of originality and innovation, (d) 
the creativity of the approaches and technologies, (e) the likelihood 
for substantial contribution by the applicants to a successful 
collaborative effort, (f) the evidence for willingness to work 
cooperatively, (g) program balance, and (h) the availability of funds.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to 
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Rebekah S. Rasooly, Ph.D.
Genomics Program Director
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
6707 Democracy Blvd, Room 643
Bethesda, MD  20892-5458
Telephone:  (301) 594-6007
FAX:  (301) 480-3510 
E-mail:  rr185i@nih.gov

Direct inquiries regarding fiscal matters to:

Donna Huggins
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
6707 Democracy Boulevard, Rm. 711 MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8848
FAX:  (301) 480-3504
E-mail:  dh48v@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.849.  Awards are 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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