IMAGING PANCREATIC BETA CELL MASS, FUNCTION, OR INFLAMMATION

Release Date:  July 29, 1999

RFA:  DK-99-018

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  December 21, 1999
Application Receipt Date:  January 21, 2000

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA/PA.

PURPOSE

The purpose of this Request for Applications (RFA) is to 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.  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.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas. This RFA, Imaging Pancreatic Beta Cell
Mass, Function, or Inflammation, is related to the priority area of diabetes
and chronic disabling conditions.  Potential applicants may obtain a copy of
"Healthy People 2000" at http://www.crisny.org/health/us/health7.html

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

This RFA will use the National Institutes of Health (NIH) research project
grant (R01), and the Pilot and Feasibility Research Project Grant (R21) award
mechanisms.  Awards will be administered under NIH grants policy as stated in
the NIH Grants Policy Statement.

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.  Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The total requested
project period for an application submitted in response to this RFA may not
exceed 5 years for the R01 mechanism.

The exploratory/developmental R21 grant can be used for high risk projects
with a minimum of preliminary data.  These awards are to demonstrate
feasibility and obtain preliminary data testing innovative ideas that
represent clear departure from ongoing research interests.  These grants will
not be renewable; continuation of projects developed under this program will
be through the regular research project program (R01).  R21 grants will be
limited to $100,000 direct costs per year and are limited to two years
duration.  The anticipated award date is December 1, 2000.

This RFA will use R01 and R21 mechanisms of support.  However, specific
application instructions have been modified to reflect "MODULAR GRANT" and
"JUST-IN-TIME" streamlining efforts being examined by the NIH.  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 Institute staff. 
Refer to instructions under APPLICATION PROCEDURES, below.  Complete and
detailed instructions and information on Modular Grants can be found at
http://www.nih.gov/grants/funding/modular/modular.htm

FUNDS AVAILABLE

For FY2000, $1.5 million will be committed to fund applications submitted in
response to this RFA.  It is anticipated that 7 to 10 awards will be made. 
However, this funding level is dependent upon the receipt of a sufficient
number of applications of high scientific merit.  Although this program is
provided for in the financial plans of the NIDDK, the award of grants pursuant
to this RFA is also contingent upon the availability of funds for this
purpose.

RESEARCH OBJECTIVES

Background

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, or to elevations in plasma
glucose and certain amino acids.  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 absorption or fluorescence spectroscopy make it likely
that a clinical exam to monitor beta cell number, mass, function, or
lymphocyte infiltration 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 may soon be able to introduce healthy, functioning isolated
pancreatic islet cells into patients.  In the course of development of 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 (A2B5, CD98) or ligands for unique cell surface
molecules, such as the GLP-1, somatostatin, or SUR-1 (sulphonylurea) receptors
could be tagged with MRI contrast agents, fluorescent dyes, or positron or
gamma emitters.  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.  Blood flow through the microcirculation
near the islet cells is increased during insulin secretion 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
recent 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/other/conferences.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 for image trafficking of immune cells (T cells,
macrophages) in order to monitor inflammation and destruction of the beta cell
in 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 subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research. This new 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
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (FR
59 14508-14513) and in the NIH Guide For Grants and Contracts, Vol. 23, No.
11, March 18, 1994, available on the web at:
http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html

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://www.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.

LETTER OF INTENT

Prospective applicants are asked to submit, by December 21, 1999, 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
avoid conflict of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, MD 20892-6600
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 grants. 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: [email protected].

Applicants planning to submit an investigator-initiated new (type 1) competing
continuation (type 2), competing supplement, or any amended/revised version of
the preceding grant application types requesting $500,000 or more in direct
costs for any year are advised that he or she must contact the NIDDK program
staff before submitting the application, i.e., as plans for the study are
being developed.  Furthermore, the application must obtain agreement from the
staff that the NIDDK will accept the application for consideration for award. 
Finally, the applicant must identify, in a cover letter sent with the
application, the staff member and Institute or Center who agreed to accept
assignment of the application.

This policy requires an applicant to obtain agreement for acceptance of both
any such application and any such subsequent amendment.  Refer to the NIH
Guide for Grants and Contracts, March 20, 1998 at
http://www.nih.gov/grants/guide/notice-files/not98-030.html.

For R01 applications, applicants will request direct costs in $25,000 modules
up to a total direct cost request of $250,000 per year.  For R21 applications,
applicants may request 1 or 2 modules per year.  A typical modular grant
application will request the same number of modules in each year.

Application budgets will be simplified.  Detailed categorical budget
information will not be submitted with the application; budget form pages of
the application kits will not be used.  Instead, total direct costs requested
for each year will be presented.  Information, in narrative form, will be
provided only for Personnel and, when applicable, for Consortium/Contractual
Costs.  See the section on budget instructions below.

Additional narrative budget justification will be required in the application
only if there is a variation in the number of modules requested per year.

There will be no routine escalation for future years.  In determining the
total for each budget year, applicants should first consider the direct cost
of the entire project period.  Well-justified modular increments or decrements
in the total direct costs for any year of the project that reflect substantial
changes in expected future activities may be requested.  For example, purchase
of major equipment in the first year may justify a higher overall budget in
the first, but not in succeeding years.

Other Support pages of the PHS 398 will not be submitted with the application.

Information on research projects ongoing or completed during the last three
years of the Principal Investigator and key personnel will be provided as part
of the "Biographical Sketch".  This information will include the specific
aims, overall goals and responsibilities and should include Federal and non-
Federal support.  This information will be used by reviewers in the assessment
of each individual's qualifications for a specific role in the proposed
project.

Following peer review, information about Other Research Support will be
requested by NIH from the applicant for applications being considered for
award.

Additional budget information will be requested only under special
circumstances.

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 your 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.

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
Natcher Building, Room 6AS-37F
45 Center Drive MSC 6600
Bethesda, MD 20892-6600

Applications must be received by January 21, 2000. If an application is
received after that date, it will be returned to the applicant without review. 
Similarly, supplemental documents containing significant revision or additions
will not be accepted after that date, 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.

BUDGET INSTRUCTIONS

The total direct costs must be requested in accordance with the program
guidelines and the modifications made to the standard PHS 398 application
instructions described below:

PHS 398

o  FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (F&A) costs] for the initial budget
period.  Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398.  It is not required and will not be accepted with the
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398.  It is not required
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page.
(See http://www.nih.gov/grants/funding/modular/modular.htm for sample pages.) 
At the top of the page, enter the total direct costs requested for each year.

o Under Personnel, List key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000.  List the individuals/organizations with whom consortium or
contractual arrangements have been made, the percent effort of key personnel,
and the role on the project.  Indicate whether the collaborating institution
is foreign or domestic.  The total cost for a consortium/contractual
arrangement is included in the overall requested modular direct cost amount.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers to assess each individual's qualifications for a specific role in
the proposed project, as well as to evaluate the overall qualifications of the
research team.  A biographical sketch is required for all key personnel,
following the instructions below. No more than three pages may be used for
each person.  A sample biographical sketch may be viewed at
http://www.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

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. It is important to identify all exclusions
that were used 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.

REVIEW CONSIDERATIONS

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the NIDDK in accordance with the review criteria stated below.  As part of the
initial merit review, all applications will receive a written critique and
undergo a process in which only those applications deemed to have the highest
scientific merit, generally the top half of the applications under review,
will be discussed, assigned a priority score, and receive a second level
review by the National Diabetes and Digestive and Kidney Diseases Advisory
Council.

Review Criteria

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, reviewer 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.

o  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?

o  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?

o  Innovation:  Does the project employ novel concepts, approaches or method?
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

o  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)?

o  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.

AWARD CRITERIA

The anticipated date of award is December 1, 2000.  Award criteria that will
be used to make award decisions include:

o  Scientific merit as determined by peer review;
o  Level of interaction between researchers in appropriate disciplines;
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.
Director, Metabolism Program
Division of Diabetes, Endocrinology, and Metabolic Diseases, NIDDK
45 Center Drive MSC 6600, Room 45/5AN-24J
Bethesda, MD 20892-6600
Telephone:  (301) 594-8802
FAX:  (301) 480-3503
Email:  [email protected]

Direct inquiries regarding fiscal and administrative matters to:

Mary Rosenberg
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600, Room 45/6AS-49D
Bethesda, MD 20892-6600
Telephone:  (301) 594-8891
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.847.  Awards are made 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 PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  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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