BETA CELL BIOLOGY CONSORTIUM

Release Date:  October 11, 2000

RFA:  DK-01-014

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  March 16, 2001
Application Receipt Date:       April 17, 2001

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) is seeking applications to establish a Beta Cell Biology 
Consortium for the purpose of intensifying investigator-initiated 
research, attracting new investigators into the field, encouraging 
interdisciplinary approaches to research in this area, fostering the 
application of basic research to generate new research tools and 
approaches for the diagnosis, treatment, and cure of diabetes, and 
establishing a comprehensive database for the beta cell.  Through the 
Consortium, individual Beta Cell Biology Programs will have access to 
information, resources, technologies, expertise, and reagents that are 
beyond the scope of any single research effort.  

This RFA is a direct response to recommendations of the 
Congressionally-established Diabetes Research Working Group 
(http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm) that developed a 
strategic plan for research in diabetes.  Two of the extraordinary 
research opportunities recommended by the plan were  “to increase basic 
research on the control and regulation of islet cell differentiation, 
growth and development” and “to create interdisciplinary centers for 
Beta Cell Biology to expand current efforts and bring new investigators 
into the field”.  An NIDDK/Juvenile Diabetes Foundation (JDF) workshop 
entitled, “Imaging the Pancreatic Beta Cell” held in April, 1999, 
further recommended the development of imaging techniques that could be 
used to assess beta cell mass in the pancreas.  A recent RFA entitled, 
“Imaging Pancreatic Beta Cell Mass, Function, or Inflammation” 
addressed recommendations from that workshop, as does this 
solicitation.  In response to the DRWG report, a NIDDK/American 
Diabetes Association (ADA)/JDF sponsored workshop, “Stem Cells and 
Pancreatic Development” was held in April, 2000.  Workshop participants 
recommended the development of specific reagents, assays and animal 
models, and increased collaboration among stem cell biologists, 
developmental biologists, and diabetes investigators to achieve the 
goal of developing a cellular replacement therapy for diabetes. 

Each program will be in the general form of a program project, composed 
of several projects and one or more cores relating to the overall theme 
of the program.  

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. Potential 
applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and 
nonprofit 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.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for these awards 
will be the program project cooperative agreement (U19).  The 
cooperative agreement is an assistance mechanism in which substantial 
NIDDK scientific and programmatic involvement is anticipated during the 
performance of the activity.  Under the cooperative agreement, the 
NIDDK’s purpose is to support and encourage the recipient’s activities 
by working jointly with the awardees in a partnership role, but not to 
assume direction, prime responsibility, or dominance.  Details of the 
responsibilities, relationships, and governance of a study funded under 
a cooperative agreement(s) are discussed later in this document under 
the sections titled “Objectives and Scope”, “Special Requirements”, and 
“Terms and Conditions of Award”.  The total project period for 
applications submitted in response to this RFA may not exceed five 
years.  The anticipated award date is September, 2001.  At this time, 
the NIDDK has not determined whether or how this solicitation will be 
continued beyond the present RFA.

FUNDS AVAILABLE

The NIDDK plans to commit up to $7.25 million in FY 2001 to fund 
approximately five new awards for Beta Cell Biology Programs.  It is 
anticipated that an additional $500,000 in direct costs/year will be 
used to establish the Bioinformatics Coordinating Center in FY 2002.  
An applicant may request a project period of up to five years.  The 
award for each Beta Cell Biology Program will be limited to $1 million 
in direct costs/year.  

The number of awards to be made is dependent on the receipt of a 
sufficient number of applications of high scientific merit and on the 
availability of funds.  Although this program is provided for in the 
financial plans of the NIDDK, awards pursuant to this RFA are 
contingent upon the availability of funds and the receipt of a 
sufficient number of applications of outstanding scientific and 
technical merit.

RESEARCH OBJECTIVES

Background

The beta cell of the endocrine pancreas plays a critical role in the 
pathogenesis of both type 1 and type 2 diabetes. Thus, having a 
comprehensive understanding of the molecular basis of beta cell 
development and function should generate new research tools and provide 
critical insights into the prevention and treatment of diabetes. 

In FY 1999, the NIH initiated a project entitled “Functional Genomics 
of the Developing Pancreas.”  Currently, cooperative agreements support 
the efforts of a consortium of researchers to identify all of the genes 
expressed over the lifespan of the beta cell in mice and humans.  This 
consortium ultimately will identify novel genes that may reveal key 
regulatory mechanisms in controlling the differentiation of beta cells 
and provide information useful in developing strategies in beta cell 
replacement and the modulation of autoimmune beta cell destruction.  
The ongoing program will develop comprehensive microarrays of genes 
expressed in the beta cell allowing investigations of global gene 
expression in islets from mouse models of diabetes and in islets from 
humans.  The Endocrine Pancreas Consortium Database, 
www.cbil.upenn.edu/EPConDB, allows investigators access to these data 
and will promote research on the differentiation and regeneration of 
beta cells.

One of the goals of the current RFA is to build upon the foundation of 
the ongoing Functional Genomics of the Developing Pancreas Consortium 
through the initiation of a series of complementary projects to further 
understand the function of the beta cell, and to generate reagents and 
assays needed for the development of novel cellular therapies for 
diabetes.  In addition to the Functional Genomics of the Developing 
Pancreas Consortium, major scientific advances and technological 
breakthroughs in basic disciplines such as developmental biology, stem 
cell biology, mouse genetics, imaging, bioengineering, and 
bioinformatics demand that a multifaceted, interdisciplinary, and 
coordinated, collaborative approach on several fronts be utilized to 
generate key reagents, assays and new strategies for the diagnosis, 
treatment and prevention of type 1 and type 2 diabetes.

Objectives and Scope

The NIDDK will fund as components of the Beta Cell Biology Consortium 
approximately five Beta Cell Biology Program applications, each 
supporting a multidisciplinary team.  A Beta Cell Biology Program could 
consist of several collaborating investigators representing one or more 
institutions.  Each program, consisting of at least 3 projects and one 
or more cores, must address at least two of the six targeted scientific 
areas described below.  Each program must include a plan that addresses 
the need for data coordination within the Consortium.  

1.  Beta Cell Development

A goal of this RFA is to attract expertise in developmental genetics, 
embryology, stem cell biology, and diabetes and to stimulate 
collaborative interdisciplinary approaches to the study of beta cell 
development.  It is anticipated that scientific advances in these areas 
will ultimately lead to an understanding of the developmental pathways 
required to produce a fully functioning pancreatic islet and insight 
into the mechanisms underlying regeneration of beta cells in the 
pancreas.  Areas of emphasis may include, but are not restricted to:

o Characterization of molecular markers for defining all stages of 
pancreas development, including cell-specific markers that would 
delineate stem/progenitor cells of the pancreas.

o Investigation of islet cell lineage, cell fate determination, and 
differentiation.

o Exploration of the potential use of human or mouse embryonic stem 
cells, fetal or adult human hematopoietic, neural, and other tissue-
specific stem cells in the formation of pancreatic beta cells.

o Identification of key signals, signaling pathway components, and 
transcription factors that regulate beta cell fate determination.

o Elucidation of mechanisms underlying the regeneration of pancreatic 
beta cells.

o Investigation of the role of cell-cell interactions, extracellular 
matrix components, differential cell adhesion, and cell motility in 
morphogenesis of the endocrine pancreas.

2.  Prospective Identification and Purification of Pancreatic 
Stem/Progenitor Cells

Type 1 and type 2 diabetes result from the anatomical or functional 
loss of insulin-producing beta cells of the pancreas.  Replacement of 
these cells through transplantation could offer lifelong treatment for 
diabetes.  A major obstacle in implementing treatment is the lack of 
sufficient islet cell tissue for transplantation.  Tissue-specific stem 
cells potentially could provide a limitless source of islet cells for 
transplantation therapies.

Generating reagents such as antibodies to stem cell surface markers 
would facilitate development of a cellular therapy for diabetes 
involving stem cells. In general, stem cell populations are rare and 
represent only a small fraction of the total number of cells in a 
developing or regenerating tissue, and thus need to be greatly 
enriched.  Methodologies using monoclonal antibodies to cell surface 
markers have been used to enrich and purify hematopoietic and neural 
stem cells.  For example, common myeloid, as well as common lymphoid, 
progenitors from mouse or human have been isolated prospectively, and 
then purified and characterized using antibodies to cell-surface 
markers and flow cytometry. 

Despite recent advances in understanding some of the transcriptional 
regulators important in pancreatic development, major obstacles for 
isolating a stem/progenitor cell population from the pancreas exist, 
including the lack of appropriate cell surface markers and only a 
cursory understanding of the lineage of beta cells during regeneration 
and development.  Overcoming these obstacles would greatly facilitate 
efforts to isolate, purify, and characterize stem/progenitor cells of 
the endocrine pancreas.

One objective of this solicitation is to encourage the development of 
antibodies to cell surface markers specific for stem/progenitor cells 
of the pancreas and the use of these antibodies to isolate and purify 
these cells using flow cytometry.  

Examples of approaches include but are not limited to:

o Isolation of appropriate mouse or human tissue for generating cell 
surface antibodies.  Sources may include:

- Dissected mouse or human fetal tissue (developing foregut or 
pancreatic buds)

- Purified endodermal precursors derived from adult or fetal liver, 
gut, lung, or other endodermal-derived tissue

- Stem/progenitor cells isolated from the regenerating pancreas

- Isolated pancreatic precursor cells from genetically defined mouse 
models (for example, enrichment of cells from transgenic lines in which 
green fluorescent protein (GFP) is driven by a pancreas-specific, 
developmentally regulated promoter)

o Utilization of the database developed by the Functional Genomics of 
the Developing Pancreas Consortium to identify potential cell surface 
markers specific to stem/progenitors of the developing pancreas from 
which antibodies could be generated.

3. Development of Clonogenic Assays for Evaluating Potential Stem Cells

Although there are several existing diabetic animal models that might 
be appropriate for a clonogenic assay, this RFA will support the 
development of new transgenic mouse models, created through genetic 
engineering, in which the complete destruction of pancreatic beta cells 
has been induced in adults.  These animal models then could be used in 
reconstitution assays to determine the differentiation potential of 
pancreatic stem/progenitor cells.

Stem cells are capable of self-renewal and can give rise to multiple 
differentiated lineages.  To characterize stem/multipotential 
progenitor cells, it is necessary to have quantitative assays (both in 
vitro and in vivo) in which to assess the ability of these cells to:  
(1) give rise to multiple lineages, (2) self-renew, and (3) 
reconstitute a cellular compartment.  

This RFA will support the development of in vitro clonogenic assays for 
assessing the potential of stem cells to become functioning beta cells.   
This RFA will also support the development of quantitative clonogenic 
in vivo assays, similar to those used to characterize hematopoietic and 
neural stem cells.  For example, in the hematopoietic system, lethally 
irradiated congenic animals, in which the cells of the bone marrow have 
been eliminated, have been used in reconstitution assays to determine 
the differentiation potential of common lymphoid or myeloid 
progenitors.  In an in vivo clonogenic assay, “true” pancreatic stem 
cells would be transferred or transplanted to a diabetic host and have 
the ability to reconstitute all pancreatic cell lineages.  

4.  Evaluation of Pancreatic Islets for Transplantation

This RFA will support research to develop methods, such as the 
utilization of DNA array technology, for assessing the quality, purity, 
and viability of pancreatic islets isolated for transplantation as 
therapy for type 1 diabetes. Presently there are no accurate predictors 
of which islet preparations will survive upon transplantation.  Such 
assays would be useful for comparison of methods of islet isolation and 
for development of improved approaches to islet isolation. 

Examples of approaches include but are not limited to:

o Expression Arrays

o Metabolic Markers

o Antibodies to Surface Markers

o Imaging Methods

5. Functional Imaging of the Beta Cell

	A number of new therapeutic approaches may hold promise to prevent or 
delay immune destruction of beta cells in people at risk for type 1 
diabetes to foster regeneration or replacement of beta cells or to 
preserve residual beta cell function in patients with new onset type 1 
diabetes.  Studies to validate these proposed therapies would be 
greatly facilitated by the ability to image the pancreatic beta cell in 
patients, and detect changes in cell number, cell mass, function and 
metabolism.  Modern molecular and functional imaging techniques 
potentially allow small populations of cells, like the beta cell, to be 
visualized in vivo.  Most extant techniques, using MRI, PET, 
ultrasound, fluorescence or absorption spectroscopy, rely on knowledge 
of some unique aspect of the target cell such as a specific cell 
surface marker.  In conjunction with information from the Functional 
Genomics of the Developing Pancreas Consortium and objective 2 of this 
solicitation, it will be possible to identify cell surface markers 
differentially expressed in the beta cell during development, 
differentiation, inflammation, or apoptosis.  Taking advantage of this 
new opportunity, this RFA is a limited extension of a previous 
solicitation, Imaging Pancreatic Beta Cell Mass, Function, and/or 
Inflammation (http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-99-018.html) 
to develop (1) tagged antibodies to cell surface markers 
specific to the beta cell, (2) related imaging methodologies for 
imaging the beta cell, and (3) assessing cell mass and function.  
Because of the highly specialized nature of this work, collaborations 
between imaging experts, and beta cells biologists are highly 
encouraged. 

6. Cell Culture Model of the Human Pancreatic Beta Cell

Cell lines derived from insulin-producing tumors (e.g., mouse and rat 
insulinomas), as well as modified neuroendocrine cells (e.g., mouse 
AtT20 cells), have proven useful for studies of insulin secretion, 
however, these culture systems do not accurately reflect all of the 
physiology of a normal beta cell.  In bioengineering approaches to a 
cellular therapy for diabetes, it will be essential to have a 
comprehensive and global understanding, at the molecular level, of the 
human beta cell.  This RFA will support research to develop a cell 
culture model of the human pancreatic beta cell that will have the 
following salient features: (1) stably maintain its physiologic 
responsiveness to glucose and other secretagogues, (2) accurately 
reflect in vivo signaling through cell surface and nuclear receptors 
relevant to the regulation of insulin production and secretion, (3) 
maintain responsiveness to growth factors and cytokines normally active 
in the development and maintenance of the pancreatic beta cell, and (4) 
retain contact growth inhibition as in the in vivo situation.  It is 
anticipated that these human cell lines will be an important resource 
not only because of their clinical implications in the development of 
new therapies, but their creation will allow expression profiling 
studies, and a comprehensive study on cellular signaling/signaling 
networks in the human beta cell.
 
Data Coordination Plan
 
As part of an Administrative Core, each BCB program application should 
submit plans as to the nature of a database that will be used to store, 
organize, analyze, or visualize data that is generated from individual 
projects for the purpose of disseminating information and facilitating 
data sharing within the consortium.  

Bioinformatics Coordinating Center

Within the first year, the Consortium Steering Committee, working in 
conjunction with the Functional Genomics of the Developing Pancreas 
Consortium, will develop a plan for a Bioinformatics Coordinating 
Center that will house and operate a centralized and comprehensive 
public database of the pancreatic beta cell.  Additional funds for a 
subcontract to support the Bioinformatics Coordinating Center will be 
provided.  The Bioinformatics Coordinating Center will be responsible 
for implementing a plan that will include the development of a 
functioning relational database, development of software to enable 
collection and analysis of data from many different formats and other 
databases, curation of existing and emerging information, and the 
development and maintenance of web tools and a web site for the 
Consortium. 

SPECIAL REQUIREMENTS 

To promote the development of a collaborative program among the award 
recipients, principal investigators and designated Co-PIs or Senior 
Investigators are expected to attend the initial planning meeting and 
the Beta Cell Biology (BCB) Steering Committee meetings twice a year.  
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 discuss 
quality assurance, bioinformatics, coordination, sharing, and a means 
of informing the community about progress made by the Consortium.  

During the course of the funding period, technologies will improve and 
the rate of progress and scope of the research may change.  It is 
expected the Principal Investigators, in consultation with NIDDK 
program staff, will make necessary adjustments to accommodate the 
changing research environment, to remain focused on appropriate goals, 
to maintain excellent coordination with the other projects funded under 
this RFA, and to incorporate new technological advances.

TERMS AND CONDITIONS OF THE 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 and 
NIH Grant Administration policy statements.  

The administrative and funding instrument used for this program is a 
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.  Under the cooperative agreement, 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.  Consistent with 
this concept, 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 Coordinator.

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 and one Co-PI or selected senior investigator from each 
program will participate as permanent, voting members of the Steering 
Committee.
 
o The PI will be responsible for contributing to and implementing the 
goals, priorities, procedures, and policies agreed upon by the Steering 
Committee.

o The PI will be responsible for close coordination and cooperation 
with the other components of the BCB Consortium and with the NIDDK 
staff.

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.  Investigators conducting 
biomedical research frequently develop unique research resources.  The 
policy of the NIH 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.ott.nih.gov/policy/rt_guide_final.html. 

2.   NIDDK Staff Responsibilities

The NIDDK Program Coordinator will have substantial scientific-
programmatic involvement during conduct of this activity, through 
technical assistance, advice and coordination above and beyond normal 
program stewardship for awards, 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 Coordinator.

o The NIDDK Program Coordinator will have voting membership on the 
Steering Committee and, as determined by that committee, its 
subcommittees.

o The NIDDK Program Coordinator will coordinate and facilitate the BCB 
Consortium programs, will attend and participate as a voting member in 
all meetings of the BCB Consortium Steering Committee, and will provide 
liaison between the Steering Committee, the BCB Consortium, and the 
NIDDK.

o The NIDDK Program Coordinator and the NIDDK will ensure that there is 
an effective, Internet-based mechanism to enable electronic 
communication among the BCB Consortium components and with the NIDDK.

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

o NIDDK and NIH extramural staff with relevant scientific expertise, or 
who manage research grant programs that relate scientifically to the 
goals of the BCB Consortium, will form the NIH Beta Cell Biology Group.  
The Group will meet regularly to review the progress of the BCB 
Consortium and to advise the NIDDK Program Coordinator of scientific 
developments and opportunities that may enhance the achievement of the 
BCB Consortium goals.

o The NIH Beta Cell Biology Group will collaborate with the NIDDK 
Program Coordinator to organize and implement the workshops and 
symposia recommended by the BCB Consortium Steering Committee, and to 
provide a liaison between the diabetes research community and the BCB 
consortium.  

o 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.

o The NIDDK Program Official will review the scientific progress of 
individual awards and review them for compliance with the operating 
policies and procedures developed by the Steering Committee, and may 
recommend withholding of support, suspension, or termination of an 
award for lack of scientific progress or failure to comply with them.

3. Collaborative Responsibilities

Steering Committee

The NIDDK Program Coordinator and the awardees that comprise the BCB 
Consortium will be responsible for forming a Steering Committee as 
defined below.  An arbitration system, as detailed below, will be 
available to resolve disagreements between the NIDDK Program 
Coordinator and the members of the Steering Committee.  The Steering 
Committee will be the main governing board of the BCB Consortium.  It 
will identify technological impediments to success and strategies to 
overcome them, and decide when reagents, assays, and animal models 
generated within the consortium should be made available to the 
research community for individual investigator-initiated projects.

o The Steering Committee will be composed of the PI and a Co-PI or 
other senior investigator from each U19 project and the NIDDK Program 
Coordinator.  The two investigators from each U19 project and the NIDDK 
Program Coordinator will each have one Steering Committee vote.  The 
chairperson, who will be someone other than the NIDDK staff member, 
will be selected by the Steering Committee.

o The Steering Committee may, when necessary, invite additional, non-
voting scientific advisors to the meetings at which research priorities 
and opportunities are discussed.  The NIDDK reserves the right to 
augment the scientific expertise of the BCB Consortium when necessary.  
Some of the steering committee meetings and workshops will require 
interaction with members of the Functional Genomics of the Developing 
Pancreas Consortium and the planned Diabetes Genome Anatomy Project.   

o There will be two Steering Committee meetings annually, one in July 
and the other in October, both in the Washington, DC area. 

o The first meeting of the BCB Consortium will be a Planning Meeting, 
which will take place in the Washington, DC area very shortly after 
award of the U19 awards.  At the Planning Meeting, the Steering 
Committee will be formed and will select a chairperson from among the 
members who represent the U19 awardees.  At the Planning Meeting, the 
Steering Committee must: (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 NIDDK Program 
Coordinator 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 research proposed in the U19 project 
applications and any relevant new information, and set initial 
priorities for reagents to be derived and for new technologies to be 
developed. At the first meeting of the Steering Committee following the 
Planning Meeting, the NIDDK will demonstrate an Internet-based 
electronic communications mechanism for discussion by the Steering 
Committee, and will implement the system for the BCB Consortium with 
any appropriate changes. At the second meeting, the Steering Committee 
will develop a bioinformatics plan by working in close collaboration 
with the bioinformatics expertise that is part of the Functional 
Genomics of the Developing Pancreas Consortium.  At this time, the 
Steering Committee will choose one site that will function as the 
Bioinformatics Coordinating Center. The Bioinformatics Coordinating 
Center will be funded in FY 2002.

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 BCB Consortium scientific objectives consistent with 
progress in the BCB Consortium components and other laboratories.  

o The Steering Committee will plan one or several workshops a year to 
which non-BCB Consortium participants will also be invited to enable 
the BCB Consortium to explore scientific or technologic innovation that 
occurs during the course of the project.

o For the second and subsequent years of operation of the BCB 
Consortium, the Steering Committee will plan a symposium to inform the 
research community of the progress made toward developing a cellular 
therapy for diabetes. The NIDDK Program Coordinator, the NIH BCB Group, 
and other NIDDK staff will provide the Steering Committee with advice 
on participants for the workshops and symposia, and manage the 
logistics for these meetings.

o The Steering Committee may establish subcommittees, as it deems 
appropriate, the NIDDK Program Coordinator will serve on subcommittees 
as appropriate.  NIDDK staff with special expertise may serve on 
subcommittees at the request of the Steering Committee.

4. Arbitration

Any disagreement that may arise on scientific/programmatic matters 
(within the scope of the U19 award) between U19 awardees and the NIDDK 
may be brought to arbitration.  An arbitration panel will be composed 
of three members:  one selected by the Steering Committee (with the 
NIDDK Program Coordinator not voting), or by the individual U19 awardee 
in the event of an individual disagreement, a second member selected by 
the 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 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.

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 OR HUMAN 
PLURIPOTENT EMBRYONIC STEM CELLS

Applicants must adhere to the current NIH policy and state and federal 
laws governing the use of either human fetal tissue or human embryos 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.  
Applicants proposing to use NIH funds to conduct research using human 
pluripotent stem cells derived from human fetal tissue or human embryos 
must adhere to the Human Pluripotent Stem Cell Research Guidelines 
available at: 
(http://stemcells.nih.gov/news/newsArchives/fr25au00-136.asp).  To help 
ensure compliance with these Guidelines, NIH has convened a Human 
Pluripotent Stem Cell Review Group (HPSCRG) which must review 
documentation about the derivation of human pluripotent stem cell lines 
before NIH-funded research can proceed.  Information about HPSCRG is 
available at: 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-050.html).

LETTER OF INTENT 

Prospective applicants are asked to submit, by March 16, 2001, a letter 
of intent that includes 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 NIDDK 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, NIDDK
6707 Democracy Boulevard, Rm. 653 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these awards.  These forms 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: GrantsInfo@nih.gov.

Special Instructions To Applicants

1. General Application Format Instructions

In preparing a Beta Cell Biology Program grant, applicants should 
follow the NIDDK administrative guidelines for preparing a Program 
Project Grant that are available at 
(http://www.niddk.nih.gov/fund/divisions/DEA/review_branch/P01guidelines.htm) 
or from staff listed under Inquiries below.  Note, however, that 
budget caps for the P01 are not applicable to a Beta Cell Biology 
Program grant.  A Beta Cell Biology Program must propose a minimum of 3 
projects. Collectively, these projects should demonstrate essential 
elements of unity and interdependence and result in a greater 
contribution to program goals, as well as to Consortium goals, than 
would occur if each project were pursued individually.  The 
relationship and contributions of each research component and core to 
the overall theme of Beta Cell Biology should be discussed.  These 
programs provide support for research projects as well as common 
resources and facilities (cores) that are available to individual 
projects comprising the program.  Cores must provide essential 
functions, services, techniques, determinations or instrumentation that 
will enhance at least two individual research projects.  An 
administrative core that includes the Data Coordination component 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.  Subcontract budgets should be listed 
on 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 the direct costs associated with each 
subcontract will count toward the direct costs cap of $1,000,000 on the 
budget for the first year.  The total costs for the applications are 
not capped.

2. Additional materials

The “Research Plan” should have a section entitled “Collaboration of 
Investigators within the BCB Consortium and other Consortia.”  In this 
section, applicants should describe how they believe their unique 
expertise can contribute to the collective efforts of the BCB 
Consortium.  Applicants must include their specific plans for 
responding to the “Terms and Conditions of Award” section.  Applicants 
should state their willingness to collaborate and share data freely 
with other BCB Consortium components, to participate in planning and 
attending workshops and symposia, to serve on the Steering Committee 
and be bound by its decisions, particularly those which relate to 
setting priorities, and be able and willing to share data and 
communicate with each other and the NIDDK in an Internet environment.  
Applicants should include copies of the Material Transfer Agreement 
used by all the institutions involved in the study.  Applicants should 
also describe how they will comply with the involvement of the NIDDK 
Program Coordinator, and how they will fulfill the responsibilities of 
Consortium components to work together cooperatively. 

Applicants must budget for travel and per diem that will allow the 
Principal Investigator, and designated Co-PI or senior investigator of 
an individual Beta Cell Biology Program, to participate in two steering 
committee meetings each year.  Applicants should plan that at least 
five investigators will attend a workshop or symposium every year in 
years 2-5.  

BUDGET INSTRUCTIONS

Applicants must follow the NIDDK Administrative Guidelines for the 
Program Project Grant Application in preparing the budget 
(http://www.niddk.nih.gov/fund/divisions/DEA/review_branch/P01guidelines.htm).  
These guidelines include changes in PHS Form 398 and in 
procedures.  Beta Cell Biology Programs cannot request more than $1 
million (direct costs) per year or $5 million (direct costs) over five 
years.  An exception to the cap will apply to program applications that 
include subcontracts.  In such cases, the F&A costs related to the 
subcontracts will be excluded from the requested direct cost levels 
prior to application of the cap. 

o CHECKLIST:  This page should be completed and submitted with the 
application.  If the F&A rate agreement has been established, indicate 
the type of agreement and the date. All appropriate exclusions must be 
applied in the calculation of the F&A costs for the initial budget 
period and all future budget years.

o The applicant should provide the name and phone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review.  

The RFA label available in the PHS 398 (rev. 4/98) application form 
must be affixed to the bottom of the face page of the application.  
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 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 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 time of submission, two additional copies of the application must be 
sent to:

Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 653 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)

Applications must be received by the application receipt date listed in 
the heading of the RFA.  If an application is received after that date, 
it will be returned to the applicant without review. Supplemental 
documents containing significant revision or additions will not be 
accepted, unless applicants are notified by the Scientific Review 
Administrator.  

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 previously 
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 developmental 
biology, mouse genetics, stem cell biology, functional imaging, or beta 
cell biology, a multi-disciplinary team of collaborators, substantial 
interactions among collaborating researchers, demonstration of 
appropriate facilities and resources, and willingness to share data and 
reagents freely. 

Upon receipt, applications will be reviewed for completeness by the 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, all 
applications will receive a written critique and may 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

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease and enhance health. 
Review criteria as detailed in the P01 guidelines will be applied and 
are available at 
(http://www.niddk.nih.gov/fund/divisions/DEA/review_branch/P01guidelines.htm).    

In the written comments reviewers will be asked to apply the five 
standard review criteria (see 1-5 below) to each of the following 
components of the program in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of the 
goals of the RFA.  

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 are expected to address issues identified under SPECIAL 
REQUIREMENTS of the RFA. The peer review group will assess the 
scientific merit of the applications and related factors, including:

1. Significance.  Do the studies proposed address an important need for 
the beta cell biology community?  What is the immediacy of the research 
opportunity?

2. 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? Are the standards chosen to characterize 
and validate a reagent, assay, specific beta cell line or 
stem/progenitors cells, imaging technology, or animal model sufficient 
and appropriate?  Are these standards generally applicable to all 
studies in a particular field?  Is there an adequate bioinformatics 
plan to store, organize, analyze, or visualize data that is generated 
from individual projects?

3. Innovation.  Does the project employ novel concepts, approaches, or 
methods in beta cell biology?  Is the project original and innovative? 
Will the approaches advance the field towards a cellular replacement 
therapy for diabetes?

4. 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 appropriate depth and breadth of 
scientific expertise required for the project?  Will this team of 
investigators contribute unique skills to the overall Consortium?

5.  Environment.  Are the facilities for carrying out the studies 
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?

6.  Interactions.  Are there adequate plans for effective interaction 
and coordination among program components and the NIDDK?  Is there a 
plan outlined to share data?  Do the investigators state their 
willingness to collaborate extensively and share information fully?  
Are the Material Transfer Agreements straightforward, or do they 
involve reach-through agreements?  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 
communications among themselves, with the other components of the BCB 
consortium and with the NIDDK?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

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 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.

Schedule

Letter of Intent Receipt Date:    March 16, 2001
Application Receipt Date:         April 17, 2001
Peer Review Date:                 July, 2001
Council Review:                   September, 2001
Earliest Anticipated Start Date:  September 30, 2001

AWARD CRITERIA

The intent of this RFA is to enable the NIDDK to assemble a Consortium 
composed of highly qualified teams of investigators whose complementary 
scientific skills and expertise will enable them to gain a 
comprehensive understanding of the molecular basis of beta cell 
development and function, and generate new reagents and research tools 
that could result in the prevention and treatment of diabetes. 

Applications recommended by the NIDDK Advisory Council will be 
considered for award based upon (a) scientific and technical merit, (b) 
the importance of the proposed research in beta cell biology, (c) the 
degree of originality and innovation in project design, (d) the 
creativity of the approaches and technologies for the development of 
reagent, assays, and animal models, (e) the likelihood for substantial 
contribution by the applicants to a successful collaborative BCB 
consortium, (f) the evidence for willingness to work cooperatively, (g) 
the quality and availability of research infrastructure and resources, 
(h) program balance, including in this instance, sufficient 
compatibility of features to make a successful collaborative program a 
reasonable likelihood, and (i) 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:

Sheryl M. Sato, Ph.D.
Program Coordinator, Cellular Basis of Metabolic Diseases
DDEM, NIDDK, NIH
2 Democracy Plaza, Room 6105
6707 Democracy Blvd. MSC 5460
Bethesda, MD 20892-5460
Telephone:  (301) 594-8811
FAX: 301 480-3503
E-mail: ss68z@nih.gov

Direct inquiries regarding fiscal matters to:

Ephraim Johnson
Division of Extramural Activities 
NIDDK
2 Democracy Plaza, Room 610
6707 Democracy Boulevard 
Bethesda, MD 20892-5458
Telephone:  (301) 594-8868
E-mail:  ej47e@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.847.  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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