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 301-710-0267, 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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