DIABETES CENTERS OF EXCELLENCE

Release Date:  December 23, 1998

RFA:  DK-99-002

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Allergy and Infectious Diseases
Juvenile Diabetes Foundation International

Letter of Intent Receipt Date:  May 10, 1999
Application Receipt Date:  June 10, 1999

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the
National Institute of Allergy and Infectious Diseases (NIAID), and the Juvenile
Diabetes Foundation International (JDFI) invite investigator-initiated program
project grant applications to establish Diabetes Centers of Excellence to conduct
research relevant to the cure, prevention or improved treatment of type 1
diabetes.  These applications should incorporate an interdisciplinary research
approach to: (1) develop and test strategies of immune intervention for the
prevention or treatment of type 1 diabetes, (2) develop mechanical and/or
cellular approaches to achieve euglycemia in patients with type 1 diabetes, or
(3) develop and test strategies for the prevention of complications in type 1
diabetes.  This RFA is intended to stimulate the application of advances in basic
molecular biology, genetics, immunology, cell biology, and biophysics to the
cure, prevention and treatment of type 1 diabetes and its complications.

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, Diabetes Centers of Excellence,
is related to the priority area of diabetes and chronic disabling conditions.
Potential applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through
the Superintendent of Documents, Government Printing Office, Washington, DC
20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-profit
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

Support will be through the NIH program project grant (P01) award.  Program
project grants are used to support broadly-based multidisciplinary or
multifaceted research programs that have a specific major objective or central
theme.  The award may support research components and core functions. 
Collectively, these components should demonstrate essential elements of unity and
interdependence and result in a greater contribution to the program goals than
if each activity were pursued individually.

Responsibility for the planning, direction, and execution of the proposed project
will be solely that of the applicant.  Awards will be administered under NIH
grants policy as stated in the NIH Grants Policy Statement.

Applicants from institutions that have a General Clinical Research Center (GCRC)
funded by the NIH National Center of Research Resources may wish to identify the
GCRC as a resource for conducting the proposed research.  If so, a letter of
agreement from either the GCRC program director or principal investigator should
be included with the application.

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 total requested
project period for an application submitted in response to this RFA may not
exceed five years.  The maximum dollar request is limited to $750,000 in direct
costs for the initial budget period.  Any application exceeding the direct cost
amount indicated will be returned to the applicant.  The maximum dollar request
is limited to $3.75 million in direct costs (approximately $5 million in total
costs) for the five-year budget period.  The earliest possible award date will
be April 1, 2000.

FUNDS AVAILABLE

For FY 2000, the NIDDK will commit $2.5 million, the JDFI will commit $1.5
million and the NIAID will commit $250,000 (total costs) to fund applications
submitted in response to this RFA.  The NIDDK, NIAID and JDFI will collaborate
in funding four to five domestic Diabetes Centers of Excellence in FY 2000 on a
competitive basis.  In addition, foreign centers will be funded independently by
the JDFI.  This funding level is dependent upon the receipt of a sufficient
number of applications of high scientific merit.  It is anticipated that there
will be six competing continuation applications from six Centers of Excellence
(formerly called "Diabetes Interdisciplinary Research Programs") currently in
existence for which funding will end May 31, 2000.  These six applications will
be in competition with all new applications received in response to this RFA. 
Although this program is provided for in the financial plans of NIDDK and NIAID,
the award of grants pursuant to this RFA is also contingent upon the availability
of funds for this purpose. 

RESEARCH OBJECTIVES

Background

Type 1 diabetes is an autoimmune disease with major genetic influences. 
Individuals with type 1 diabetes have lost the ability to produce insulin because
of immune destruction of the pancreatic beta cells, which secrete insulin in
response to a glucose load.  The incidence of type 1 diabetes appears to be
increasing worldwide. 

It is the intention of the NIDDK, NIAID and JDFI to stimulate the integration of
the most current basic biomedical research approaches into diabetes-related
research by establishing Diabetes Centers of Excellence, through the support of
meritorious, synergistic, multidisciplinary program project applications. 
Research must be relevant to the cure, prevention and improved  treatment of type
1 diabetes and its complications. Applications should include the involvement of
both basic and applied scientists in collaborative endeavors.  Recent advances
in basic biomedical research have revolutionized our ability to study complex
diseases such as diabetes.  Further application of these new capabilities of
molecular biology, genetics, immunology, cell biology and biophysics to diabetes
research is essential.  Increased utilization of these technologies and
approaches will improve our understanding of type 1 diabetes and enhance
development of potential preventive and therapeutic strategies.  Centers must be
supported by a strong basic science research base; in addition, the JDFI has a
strong interest in supporting research with an emphasis on the clinical
application and translation of basic research findings.

Research applications should focus on one or more broad areas of etiology,
pathogenesis, prevention, cure or improved treatment of type 1 diabetes or its
complications. Relevant topics listed below are examples and should not be
construed as mandatory or limiting. 

Scope and Objectives

Targets for Immunomodulation

Much has been learned about the nature of the immune process in the initiation
and propagation of type 1 diabetes but many questions remain.  In September 1997,
the NIH sponsored a conference entitled "Diabetes Mellitus: Challenges and
Opportunities."  This conference highlighted several key emphasis areas of
investigation regarding the immunopathogenesis of type 1 diabetes (see below). 
Further understanding of the immune process could lead to the identification of
new targets that could be used to develop vaccination and immunomodulation
strategies to prevent or treat diabetes.  Such strategies might include the
induction of tolerance to inciting antigens, stimulation of protective
immunoregulatory pathways, or down-regulation of destructive autoimmune
responses.  Studies in animal models suggest that immunomodulation can prevent
or treat type 1 diabetes.  However, tolerance induction in humans is not well
understood, and the optimal therapeutic approach has not been elucidated.  In
addition, it is essential to identify genetic and immune markers that could be
used to identify individuals at risk for the development of type 1 diabetes, who
might benefit from prevention strategies. Areas of interest include:

o  Identification of viral or environmental triggers and mechanisms by which such
triggers initiate an autoimmune response

o  Identification and functional characterization of genes for susceptibility 
to and/or protection from type 1 diabetes

o  Identification and characterization of targets for the autoimmune process in
type 1 diabetes, including identification of beta cell antigens and/or epitopes
that can be used to induce tolerance

o  Identification of mechanisms by which autoreactive T cells against beta cell
antigens are regulated, and development of methods to restore normal regulation
of these autoreactive T cell

o  Identification of costimulatory molecules and/or cytokines involved in the
autoimmune response in type 1 diabetes and development of methods to modulate
this activity

o  Identification of cellular and/or serum markers that can be used to identify
high risk individuals, to track the activity of the autoimmune process and assess
the utility of various strategies of immune modulation

o  Development of animal models of type 1 diabetes which closely parallel the
human disease

Mechanical and Cellular Approaches to Euglycemia

Concurrent with attempts to develop strategies to prevent  type 1 diabetes, it
is essential to focus attention on innovative approaches for treating type 1
diabetes and/or achieving better metabolic control.  The Diabetes Control and
Complications Trial has established the crucial importance of metabolic control
for preventing or delaying the onset of diabetic complications.  However, the
severe hypoglycemia that can accompany tight control has limited its usefulness
to many patients.  Establishing new methods to achieve and maintain euglycemia
will have enormous impact on the health and quality of life of individuals with
diabetes.  To this end, researchers have tried to develop cellular approaches to
insulin replacement.  Islet cell transplantation has been hampered by ongoing
autoimmune destruction; new methods of immune modulation and islet cell isolation
show promise for developing more successful methods of islet transplantation. 
Along with efforts to induce immune tolerance, new techniques in cell biology and
gene therapy may provide novel sources of insulin-secreting cells.  To date,
however, attempts at producing bio-engineered beta cells have been hampered by
a lack of knowledge of the origins, development and regenerative capacity of beta
cells.  Finally, until a definitive cure can be achieved, glucose sensors hold
great promise for improving metabolic control and quality of life for individuals
with diabetes.  Indeed, the single greatest change in the management of diabetes
in the past two decades has been the introduction and widespread implementation
of reliable, accurate and relatively "user-friendly" home glucose monitoring
devices.  At present, however, technology cleanly divides mechanical insulin
delivery devices and glucose sensing technology; the ultimate goal would clearly
be to develop a "closed-loop" delivery system by combining the two technologies.
Potential areas of investigation include:

o  Improved techniques and programs for the isolation, maintenance and
propagation of human islets or beta cells

o  Immunoalteration of beta cells/islets or of the immune response in an attempt
to prevent autoimmune and graft-versus-host destruction of beta cells/islets

o  Identification of genes and their products that mediate and/or can abrogate
autoimmune destruction or graft rejection

o  Development of immunobarrier technology to protect transplanted islets or
engineered insulin-producing cells from autoimmune destruction or rejection

o  Regulation of beta cell differentiation and its role in type 1 diabetes

o  Genetic manipulation of beta cells or surrogate cells to replace the
physiologic insulin secretory capacity that has been destroyed in type 1 diabetes

o  Development of beta cell replacement therapies (glucose sensors, implantable
pumps, bio-artificial pancreas)

Prevention of Complications

At the current time, the long-term complications of diabetes remain a major
public health issue.  Until prevention or a more ideal treatment for type 1
diabetes is developed, it is imperative to develop new approaches to prevent or
ameriorate complications.  There is a great deal of epidemiologic, clinical and
physiologic information on the long-term microvascular, macrovascular and
neurologic complications of diabetes.  Over the last decade, many biochemical
mechanisms by which hyperglycemia may cause damage have been studied, including
increased polyol pathway activity and associated changes in intracellular redox
state, increased diacylglycerol synthesis with consequent activation of specific
protein kinase C isoforms, increased nonenzymatic glycation of both intra- and
extracellular proteins, and increased formation of reactive oxygen species. 
Tissue injury then results from acute changes in protein function and chronic
changes in gene expression.  However, the molecular pathophysiology of altered
protein function and gene expression leading to tissue injury is still unclear. 
The possible interrelationships between the various pathways have not been
systematically explored.  Different mechanisms may play a dominant role at
different stages of disease or in different target tissues.  It is essential to
understand the critical pathways in the pathogenesis of diabetes complications,
so that targets for intervention can be identified.  To date, the development of
interventions for modifying relevant pathways has been limited and must be
further explored.  In addition, despite epidemiologic and clinical evidence of
genetic determinants in the development of complications, very little is known
about the identity or function of specific genes involved. Given the potential
risks attendant with current strategies to prevent complications (e.g.,
hypoglycemia associated with tight control), it is essential to identify those
patients with the highest likelihood of developing complications, to allow
targeted interventions.  Possible research areas include:

o  Identification and functional characterization of genes influencing the
development of long-term complications

o  Identification of basic molecular or cellular processes leading to
complications

o  Determination of the sequence of events in the pathogenesis of hyperglycemia-
induced injury so that potential sites for intervention can be identified

o  Identification of surrogate endpoints which can be used to track complications
or identify patients at risk

o  Development of innovative pharmacologic agents and interventions to prevent
or halt the progression of long-term complications

SPECIAL REQUIREMENTS

Letter of Authorization

Because the domestic applications will be co-funded by the NIH and JDFI, and the
foreign applications by JDFI, all applicants should submit a brief letter to the
NIH indicating that the application and the summary statements for such
applications can be shared with the JDFI.  Letters of authorization should be
prepared by the principal investigator and co-signed by the official signing for
the applicant organization.  This letter may be combined with the Letter of
Intent (see below) or may be submitted as a cover letter accompanying the
application. 

Centers Currently Funded by JDFI

All applications from Diabetes Centers of Excellence (formerly called "Diabetes
Interdisciplinary Research Programs") currently funded solely by JDFI will be
considered as competing continuation applications, not as new applications. 
Applicants must provide summary statements from the original application and
should follow the instructions for competing continuation applications in the
NIDDK Program Project Grants Guidelines and include progress reports with their
applications.

Periodic Meetings

Upon initiation of this program, the NIH and JDFI plan to sponsor periodic
meetings to encourage exchange of information among investigators, to foster
collaborative efforts among program grantees, and to identify resources that
would enhance the productivity of grantees.  For this purpose, applicants should
request travel funds for a two-day meeting each year, probably held in Bethesda,
Maryland.  Applicants should also include a statement in their applications
indicating their willingness to participate in such meetings and to cooperate
with other researchers at other diabetes interdisciplinary research program
sites.

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 is provided 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
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 20, 1994
(FR 59 14508-14513), and in the NIH Guide For Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

Investigators may also obtain copies from these sources or from the program staff
or contact person listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

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:
https://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by May 10, 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,
Suite 6095, Bethesda, MD 20892-7910, telephone 301-710-0267, email:
GrantsInfo@nih.gov.

Applicants should request a copy of the publication entitled "NIDDK Program
Project Grants: Administrative Guidelines."  These guidelines contain important
information on the suggested format of applications and on review criteria.
Prospective applicants may obtain these guidelines from:

Barbara Linder, M.D., Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institutes of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD 20892-6600
Telephone: (301) 594-0021
FAX: (301) 480-3503
Email: LINDERB@extra.niddk.nih.gov

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.

Submit a signed, typewritten original of the application, including the
Checklist, plus 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
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, MD  20892-6600

Applications must be received by June 10, 1999.  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 otherwise 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 NIDDK.  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 NIDDK in accordance with NIH peer review procedures. 
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 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, 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.

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 review with respect to the following:

o  The 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 in relation to the
proposed research.

o  The adequacy of the proposed protection of humans, animals, or of the
environment, to the extent that they may be adversely affected by the project
proposed in the application.

The initial review group will also examine the provisions for the protection of
human subjects and the safety of the research environment.

Schedule

Letter of Intent Receipt Date:  May 10, 1999
Application Receipt Date:       June 10, 1999
Initial Review:                 October/December 1999
Second Level Review:            February 2000
Anticipated Date of Award:      April 1, 2000

AWARD CRITERIA

The anticipated date of award is April 1, 2000.  Awards will be based upon the
following criteria:

--scientific merit as determined by peer review
--availability of funds
--programmatic priorities of the funding institute

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:

Barbara Linder, M.D., Ph.D. 
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-0021
FAX:  (301) 480-3503
Email:  LINDERB@extra.niddk.nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Nancy C. Dixon
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8854
FAX:  (301) 480-4237
Email:  dixonn@extra.niddk.nih.gov

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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