IMAGING PANCREATIC BETA CELL MASS, FUNCTION, ENGRAFTMENT OR INFLAMMATION
Release Date: August 1, 2001
RFA: RFA-DK-02-002
National Institute of Diabetes and Digestive and Kidney Diseases
Letter of Intent Receipt Date: February 15, 2002
Application Receipt Date: March 15, 2002
THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. USE THE
MODULAR BUDGET INSTRUCTIONS THAT BEGIN ON PAGE 13 IN THE PHS 398
(REVISION 5/2001) AVAILABLE AT
http://grants.nih.gov/grants/funding/phs398/phs398.html.
PURPOSE
This Request for Applications (RFA) is a reissue of RFA DK-99-018
Imaging Pancreatic Beta Cell Mass, Function, or Inflammation , and is
intended to further stimulate the development of techniques or reagents
leading to the ability to image or otherwise noninvasively detect
pancreatic islet beta cells in vivo, and measure their mass, function,
or evidence of inflammation, or to monitor engraftment of transplanted
isolated pancreatic islets. Diabetes results when the insulin
secretory capacity of the beta cell is lost or severely compromised.
It is anticipated that research from funded projects will contribute to
the eventual development of a clinical exam that can be used for
monitoring disease progress and response to therapy in diabetics and in
people strongly at risk for diabetes. Collaboration between
researchers in imaging fields and beta cell biology or diabetology is
strongly encouraged. A 1999 workshop entitled "Imaging the Pancreatic
Beta Cell" was sponsored by NIDDK and Juvenile Diabetes Foundation
International (JDFI). A report can be found at
http://www.niddk.nih.gov/fund/reports/beta_imaging_report_2.htm.
HEALTHY PEOPLE 2010
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2010," a
PHS-led national activity for setting priority areas. This Request for
Applications (RFA), Imaging Pancreatic Beta Cell Mass, Function,
Engraftment Or Inflammation , is related to the priority area of
diabetes and chronic disabling conditions. 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
Specific application instructions have been modified to reflect
"MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been
adopted by the NIH. Complete and detailed instructions and information
on Modular Grant applications have been incorporated into the PHS 398
(rev. 5/2001). Additional information on Modular Grants can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm
This RFA will use the National Institutes of Health (NIH) research
project grant (R01) and Pilot and Feasibility (R21) award mechanisms.
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant. The total
project period for an application submitted in response to this RFA may
not exceed 4 years for the R01 and 2 years for the R21 mechanism.
This RFA is a one-time solicitation. Future unsolicited competing
continuation applications will compete with all investigator-initiated
applications and be reviewed according to the customary peer review
procedures. The anticipated award date is Sept. 30, 2002.
FUNDS AVAILABLE
The NIDDK intends to commit approximately $1.0 million in FY 2002 to
fund 3-5 new grants in response to this RFA. Because the nature and
scope of the research proposed may vary, it is anticipated that the
size of each award will also vary. An applicant may request a project
period of up to 4 years using the R01 mechanism. All applications
requesting $250,000 direct costs per year or less must use the modular
budget format. R21 Pilot and Feasibility grant applications should
request 2 years at up to $100,000 direct costs per year. These
applications should propose innovative high risk, high yield research,
and do not require the extensive preliminary data necessary for an R01
application. Although the financial plans of the NIDDK provide support
for this program, 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. At this
time, it is not known if this RFA will be reissued.
RESEARCH OBJECTIVES
Background
Imaging technology has advanced rapidly in recent years, making it
possible to image small or deep structures that have until now been
impossible. It would be of great benefit to the diabetes community to
be able to image the beta cells of the pancreatic islets. Insulin is
produced in the pancreatic islet beta cell and released in response to
a meal, to elevations in plasma glucose and certain other nutrients,
and new evidence suggests a variety of other signals are involved.
Diabetes results when insulin release is insufficient, and plasma
glucose rises above normal. In type 1 diabetes, this occurs when the
beta cells are selectively destroyed by an autoimmune process that
involves lymphocyte infiltration. Early in the course of type 2
diabetes, as individuals become insulin resistant, beta cell mass
increases to meet the demand for more insulin. The individual becomes
diabetic when the beta cell mass and insulin production can no longer
compensate for the increased need for insulin, and blood glucose begins
to rise. Loss of beta cell mass may then occur as type 2 diabetes
advances.
Through major histocompatibility complex (HLA) typing and measurement
of certain antibodies, it is now possible to identify those individuals
that are at risk for developing type 1 diabetes. Those at risk for
type 2 diabetes can be identified through family history and
measurements of insulin resistance. However, little is known about the
natural history of beta cell mass, turnover and cell lifetime, or the
course of inflammation in diabetes. This is principally because the
pancreas is a highly heterogeneous organ that is difficult to biopsy,
and beta cell mass is only 1-2% of the organ. Insulin secretory
capacity can be measured, but it is a poor reflection of beta cell
mass.
Recent advances in relatively noninvasive imaging techniques such as
Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET),
other nuclear imaging techniques, and optical absorption or
fluorescence spectroscopy and imaging, make it likely that a clinical
exam to monitor beta cell number, mass, function, or lymphocyte
infiltration/inflammatory activity can soon be established. This would
allow high-risk individuals to be monitored prior to onset of diabetes,
patients could be monitored over the course of their disease to
determine the exact stage of their disease, and it would also allow
monitoring responses to therapy.
Type 1 diabetes is being successfully treated using pancreas
transplantation, and researchers are now able to achieve insulin
independence in patients by transplanting healthy, functioning isolated
pancreatic islets into patients. In the course of evaluating this
technique, it would be of great clinical benefit to be able to identify
the location, number, viability, growth and function of these grafts,
and to noninvasively monitor their response to immune modulating
therapy using imaging.
It is unlikely that resolution of any of the noninvasive, clinically
useful imaging technologies is high enough at this point in time to
visualize the pancreatic beta cell directly. However, a variety of
cell and organ properties may be usefully exploited to provide contrast
from surrounding acinar tissue. Antibodies or ligands for unique cell
surface molecules could be tagged with MRI contrast agents, fluorescent
dyes, or positron or gamma emitters. New screening technologies in
functional genomics are helping to identify new genes and their
products, which may be useful, beta cell-specific targets for molecular
imaging. In particular, data produced by the NIDDK-sponsored Endocrine
Pancreas Consortium in the project Functional Genomics of the
Developing Endocrine Pancreas can be found at the EPConDB website,
http://www.cbil.upenn.edu/EPConDB/.
Type 1 diabetes is accompanied by a transient lymphocytic infiltration
that results in beta cell destruction. Lymphocytes may be tagged with
an imaging contrast agent for use in following the course of this
inflammation. Unique aspects of beta cell metabolism can provide
targets for PET studies, or MR spectroscopy could be used to measure
concentrations of metabolites unique to the beta cell. Alternatively,
optical imaging of enzyme activity may directly allow non-invasive
evaluation of lymphocyte-based beta cell destruction. Blood flow
through the microcirculation near the islet cells is increased in
response to glucose and may provide a measure of the number and
location of active beta cells. The capillaries feeding the islets are
fenestrated, and diffusion of water, macromolecules, or contrast agents
may be altered enough near these special cells to be exploited for
imaging them. Type 2 diabetes is often accompanied by large deposits
of amyloid fibrils (IAPP, islet amyloid polypeptide) in and around the
beta cells, which may contribute to their destruction late in the
disease. These macromolecular deposits may be a target for imaging.
Scope and Objectives
The objective of this initiative is to support the development of
imaging techniques and reagents that could be used to measure beta cell
mass, function, or inflammation with the hope that these technologies
can aid in diagnosis and treatment of diabetic and prediabetic patients
in the clinic. A 1999 workshop entitled "Imaging the Pancreatic Beta
Cell" was sponsored by NIDDK and Juvenile Diabetes Foundation
International (JDFI). A report can be found at
http://www.niddk.nih.gov/fund/reports/beta_imaging_report_2.htm or
obtained from the program staff listed at the end of this document, and
should be consulted in conjunction with this announcement. Projects
submitted to this initiative may describe research aimed either at
developing some imaging technique for this application, identifying
unique aspects of the beta cell that could be exploited for imaging, or
the development of new contrast agents that can be targeted
specifically to the beta cell. This initiative can be used to support
research in animal models or in human subjects. Because of the highly
specialized nature of this work, imaging experts, chemists, engineers,
beta cell and diabetes researchers and clinicians are encouraged to
collaborate.
Areas of research emphasis include:
o Development of specific techniques or contrast agents that can be
used with a clinical imaging modality to visualize pancreatic beta cell
mass or number. These include tagged antibodies to the beta cell
surface, ligands for receptors specific to the beta cell, or agents
whose contrast properties are "unmasked" by beta cell enzymes.
o Projects designed to identify specific beta cell surface markers or
create monoclonal antibodies to beta cell surface molecules.
o Development and evaluation of non-radioactive labeling for tracer
imaging.
o Development of imaging assays of beta cell function in response to
glucose or other insulin secretagogues.
o Development of angiographic, perfusion and diffusion techniques for
visualizing changes in blood flow near islets due to functional
activation.
o Identification, characterization and development of transgenic models
with beta cells enhanced for imaging using GFP, luciferase or beta-
galactosidase, which might be useful as controls, for cell mass
assessment during the course of experimental diabetes, and to determine
beta cell lineages throughout development.
o Development of methods to image trafficking of immune cells (T
cells, macrophages) and immune cell enzymatic activity in order to
monitor inflammation and destruction of the beta cellin type 1
diabetes.
o Evaluation of whether or not the IAPP inclusions in the pancreatic
islets in type 2 diabetes can be visualized.
o Development of methods to monitor the location, mass, and function of
engrafted islet cells after transplantation. Also, development of
methods to assess the presence of local inflammation around engrafted
islets.
SPECIAL REQUIREMENTS
Collaborations between experts in appropriate disciplines are highly
encouraged, and money for travel should be specifically requested if
necessary. Successful applicants will be expected to meet together
yearly in Bethesda, MD, to share results and information. Travel funds
should be requested for this meeting.
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of the NIH that women and members of minority groups
and their sub-populations must be included in all NIH-supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification are provided
indicating that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research. This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43).
All investigators proposing research involving human subjects should
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities
as Subjects in Clinical Research," published in the NIH Guide for
Grants and Contracts on August 2, 2000
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a
complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:
The revisions relate to NIH defined Phase III clinical trials and
require: a) all applications or proposals and/or protocols to provide a
description of plans to conduct analyses, as appropriate, to address
differences by sex/gender and/or racial/ethnic groups, including
subgroups if applicable, and b) all investigators to report accrual,
and to conduct and report analyses, as appropriate, by sex/gender
and/or racial/ethnic group differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN
SUBJECTS.
It is the policy of NIH that children (i.e., individuals under the age
of 21) must be included in all human subjects research, conducted or
supported by the NIH, unless there are scientific and ethical reasons
not to include them. This policy applies to all initial (Type 1)
applications submitted for receipt dates after October 1, 1998.
All investigators proposing research involving human subjects should
read the NIH Policy and Guidelines on the Inclusion of Children as
Participants in Research Involving Human Subjects that was published
in the NIH Guide for Grants and Contracts, March 6, 1998, and is
available at the following URL address:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.
Investigators may also obtain copies of these policies from the program
staff listed under INQUIRIES. Program staff may also provide
additional relevant information concerning the policy.
REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS
All investigators proposing research involving human subjects should
read the policy that was published in the NIH Guide for Grants an
Contracts, June 5, 2000 (Revised August 25, 2000), and is available at
the following URL address
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
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.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT
The Office of Management and Budget (OMB) Circular A-110 has been
revised to provide public access to research data through the Freedom
of Information Act (FOIA) under some circumstances. Data that are (1)
first produced in a project that is supported in whole or in part with
Federal funds and (2) cited publicly and officially by a Federal agency
in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has
provided guidance at:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm
Applicants may wish to place data collected under this RFA (PA) in a
public archive, which can provide protections for the data and manage
the distribution for an indefinite period of time. If so, the
application should include a description of the archiving plan in the
study design and include information about this in the budget
justification section of the application. In addition, applicants
should think about how to structure informed consent statements and
other human subjects procedures given the potential for wider use of
data collected under this award.
LETTER OF INTENT
Prospective applicants are asked to submit, by February 15, 2002, 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. 752 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone: (301) 594-8885
FAX: (301) 480-3505
APPLICATION PROCEDURES
The modular grant concept establishes specific modules in which direct
costs may be requested as well as a maximum level for requested
budgets. Only limited budgetary information is required under this
approach. The just-in-time concept allows applicants to submit certain
information only when there is a possibility for an award. It is
anticipated that these changes will reduce the administrative burden
for the applicants, reviewers and NIH staff. The research grant
application form PHS 398 (rev. 5/2001) at
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used
in applying for these grants, with modular budget instructions
beginning on page 13 of the application instructions.
The RFA label available in the PHS 398 (rev. 5/01) 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. 752 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
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by the NIDDK. If the application is not responsive
to the RFA, NIDDK or CSR staff may contact the applicant to determine
whether to return the application to the applicant or submit it for
review in the competition with unsolicited applications at the next
review cycle.
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIDDK in accordance with the review
criteria stated below. As part of the initial merit review, all
applications will receive a written critique and undergo a process in
which only those applications deemed to have the highest scientific
merit, generally the top half of the applications under review, will be
discussed, assigned a priority score, and receive a second level review
by the NIDDK Advisory Councils.
Review Criteria
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.
In the written comments, reviewers will be asked to discuss the
following aspects of the application in order to judge the likelihood
that the proposed research will have a substantial impact on the
pursuit of these goals. Each of these criteria will be addressed and
considered in assigning the overall score, weighting them as
appropriate for each application. Note that the application does not
need to be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score. For example,
an investigator may propose to carry out important work that by its
nature is not innovative but is essential to move a field forward.
(1) Significance: Does this study address an important problem? If
the aims of the application are achieved, how will scientific knowledge
be advanced? What will be the effect of these studies on the concepts
or methods that drive this field?
(2) Approach: Are the conceptual framework, design, methods, and
analyses adequately developed, well integrated, and appropriate to the
aims of the project? Does the applicant acknowledge potential problem
areas and consider alternative tactics?
(3) Innovation: Does the project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or
technologies?
(4) Investigator: Is the investigator appropriately trained and well
suited to carry out this work? Is the work proposed appropriate to the
experience level of the principal investigator and other researchers
(if any)?
(5) Environment: Does the scientific environment in which the work
will be done contribute to the probability of success? Do the proposed
experiments take advantage of unique features of the scientific
environment or employ useful collaborative arrangements? Is there
evidence of institutional support?
In 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: February 15, 2002
Application Receipt Date: March 15, 2002
Peer Review Date: July 2002
Council Review: September 2002
Earliest Anticipated Start Date: September 30, 2002
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit as determined by peer review,
o Availability of funds,
o Programmatic priorities.
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:
Maren R. Laughlin, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 6101 MSC 5460
Bethesda, MD 20892-5460
Telephone: (301) 594-8802
FAX: (301) 480-3503
E-mail: ml33q@nih.gov
Direct inquiries regarding fiscal matters to:
Denise Payne
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 733 MSC 5456
Bethesda, MD 20892-5456
Telephone: (301) 594-8845
FAX: (301) 480-3504
E-mail: dp43b@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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