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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