PILOT STUDIES FOR NEW THERAPIES FOR TYPE 1 DIABETES AND ITS COMPLICATIONS

Release Date: January 8, 1999

RFA: DK-99-013

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases
National Center for Research Resources
National Eye Institute
National Heart, Lung and Blood Institute
National Institute of Allergy and Infectious Diseases
National Institute of Child Health and Human Development
National Institute for Dental and Craniofacial Research

Letter of Intent Receipt Date:  March 1, 1999
Application Receipt Date:  March 30, 1999

PURPOSE

This Request for Applications (RFA) encourages applications for pilot and
feasibility studies proposing innovative strategies for prevention or treatment
of type 1 diabetes or its complications.  Applications may also propose to
explore truly novel hypothesis about the pathogenesis of type 1 diabetes or its
complications but only if the hypothesis will identify new targets for
intervention and generate new therapeutic strategies.  Particularly relevant to
this solicitation are proposals for development of surrogate markers, which can
be used as outcome measures for clinical research in diabetes.

This solicitation is especially designed to encourage submission of applications
for high risk/high impact research and to encourage talented new investigators
and established investigators not currently working in the area of diabetes to
apply their expertise to developing new approaches to 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, Pilot Studies to Develop New
Therapies for Diabetes and Its Complications, is related to one or more of the
priority areas.  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 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.

The pilot and feasibility studies are intended to:  (1) provide initial support
for new investigators; (2) allow exploration of innovative new leads or new
directions for established investigators in diabetes; and (3) stimulate
investigators from other areas to lend their expertise to research in this area. 
Pilot and feasibility grants are not intended to support or supplement ongoing
funded research of an established investigator. This program enables
investigators to explore the feasibility of a novel concept related to
development of new therapies for type 1 diabetes and its complications and
generate sufficient data to pursue it through other funding mechanisms.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) exploratory/
developmental grant (R21) award mechanism.  These awards are to demonstrate
feasibility and obtain preliminary data testing innovative ideas that represent
clear departure from ongoing research interests.  Responsibility for the
planning, direction, and execution of the proposed project will be solely that
of the applicant.

FUNDS AVAILABLE

Funding of 25 to 30 applications submitted in response to this solicitation is
anticipated contingent on receipt of a sufficient number of high quality
applications.  $4 million (total costs) are available for this purpose in FY
1999.  Applicants may request up to two years of support and up to $100,000 per
annum in direct costs.  The award is non-renewable.  Continuation of projects
developed under this program will be through the regular research project grant
program.

RESEARCH OBJECTIVES

Background

Type 1 diabetes results from immune destruction of the beta cells of the pancreas
leading to loss of insulin secretion and resultant hyperglycemia. Therapy with
insulin prevents ketoacidosis but does not presently prevent the devastating
complications of diabetes. This RFA is to support pilot projects that focus on
the development of new therapeutic approaches for the prevention or treatment
this disease.

Modulation of the specific immune response(s) leading to diabetes is the most
promising area of research for the prevention of disease.  There is evidence that
arrest of the destructive immune response even after hyperglycemia has occurred
may allow recovery of islet function. Identification of the mechanisms by which
genetic loci place individuals at risk for the development of an autoimmune
response and the mechanism by which some genetic loci protect individuals from
development of disease may lead to new strategies to prevent and treat diabetes. 
It is likely that environmental and/or infectious agents yet to be identified
also play an important role in the pathogenesis of the disease.  The mechanisms
by which these exogenous factors trigger or perpetuate the self-reactive immune
response offer additional avenues for interventions.  Recently identified
regulatory pathways in the immune system, including co-stimulatory molecules,
epitope spreading, cytokines, chemokines, and immunomodulatory networks are
another site for modification of the autoimmune response leading to type 1
diabetes.  This solicitation is intended to capitalize on our current
understanding for the development of new therapies for type 1 diabetes.

Establishing new methods to achieve and maintain euglycemia will have enormous
impact on the health and quality of life of individuals with diabetes.  The
Diabetes Control and Complications Trial has established that metabolic control
is highly effective in preventing or delaying the onset of diabetic
complications.  Unfortunately, present methods for achieving euglycemia are
difficult to implement and expensive.  Innovative approaches for achieving better
metabolic control in type 1 diabetes are urgently needed. þClosed-loopþdelivery
systems combining mechanical insulin delivery devices and glucose sensing
technology hold great promise for improving metabolic control and quality of life
for individuals with diabetes. Cellular approaches to insulin replacement are
under development, including islet transplantation and use of new techniques in
cell biology and gene therapy to provide novel sources of insulin-secreting
cells. Islet cell transplantation has been hampered by limited availability of
viable islets, toxicity of immunosuppressive drugs, and ongoing autoimmune
destruction of transplanted islets.  New methods of immune modulation and islet
cell isolation show promise for developing more successful methods of islet
transplantation. Development of bio-engineered beta cells requires knowledge of
the molecular pathways involved in glucose-regulated insulin secretion and
effective methods of gene transfer.

At the current time, the long-term complications of diabetes remain a major
public health issue. Because current approaches to metabolic control are not
sufficient for achievement of near euglycemia, new approaches are needed to
prevent or ameliorate complications. Over the last decade, many biochemical
mechanisms by which hyperglycemia may cause damage have been studied.  These
include 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. In addition, despite
epidemiological and clinical evidence of genetic determinants in the development
of complications, very little is known about the identity or function of specific
genes involved.  This solicitation is intended to foster the development of
interventions for modifying relevant pathways to prevent, reverse or delay the
complications of diabetes.

Recent advances in basic biomedical research have revolutionized our ability to
study complex diseases such as diabetes. Application of new stratagems of
molecular biology, genetics, immunology, cell biology, bioengineering and
biophysics to diabetes research should lead to the identification of potential
therapeutic strategies. This solicitation for pilot projects to develop and test
these strategies is intended to enhance the development of new approaches to
prevention and treatment of type 1 diabetes and its complications.

Scope and Objectives

R21 applications should focus on the prevention, cure or improved treatment of
type 1 diabetes or its complications.  Studies of etiology and pathogenesis may
be submitted only if the focus is identification of new targets or strategies for
therapy.  Relevant topics listed below are examples and should not be construed
as required or limiting.

o  Development and/or Testing of Strategies to Prevent or Reverse Type 1
Diabetes;

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

o  Capitalization on our present knowledge of beta cell antigens and/or epitopes
and other components of the immune response leading to type 1 diabetes to develop
methods to modulate this immune response to induce tolerance

o  Development of methods to regulate T cells autoreactive against beta cells

o  Development of methods to modulate co-stimulatory molecules and/or cytokines
and thus alter the autoimmune response in type 1 diabetes

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 methods for measurement of beta cell mass or function that
could be used as endpoints in studies of prevention or amelioration of type 1
diabetes

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

o  Development and/or Testing of Mechanical or Cellular Approaches to Achieve
Euglycemia

o  Identification of stem cells and/or methods for regulation of beta cell
differentiation and growth

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

o  Evaluation in vivo of cellular approaches testing for graft rejection and/or
autoimmune destruction

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

o  Integration of sensor, control and delivery systems and creation of a true
artificial pancreas, which may include examination of appropriate parameters for
control of glycemia with insulin, delivered peripherally or intraperitoneally

o  Development of self-regulating implantable systems that are responsive to
blood glucose levels

o  Develop and Test Strategies for Prevention and/or Therapy of Complications

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

o  Definition of the sequence of basic molecular or cellular processes leading
to complications

o  Determination 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 pharmacological agents and interventions to prevent
or halt the progression of long-term complications

o  Development of surrogate markers that could be used as endpoints for studies
to test methods of prevention or amelioration of complications

o  Development of animal models useful to exploring the pathogenesis and therapy
of complications of type 1 diabetes

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
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 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 the following URL address: 
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://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may 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 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 IC staff to estimate the
potential review workload and avoid conflict of interest in the review.

The letter of intent is to be sent by the letter of intent receipt date listed
in the heading of this RFA to:

Joan T. Harmon, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 5AN-18G
Bethesda, MD  20892
Telephone:  (301) 594-8813
FAX:  (301) 480-3503
Email:  Joan_Harmon@NIH.GOV

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98).  Application kits 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 301/435-0714, email: GrantsInfo@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, and five 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)

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR) and responsiveness by the participating Institutes. 
Applications will be evaluated for scientific and technical merit by an
appropriate scientific review group convened in accordance with the standard 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, generally the top half
of applications under review, will be discussed, assigned a priority score, and
receive a second level review by the appropriate national advisory council or
board.

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 and according to the goals of this solicitation.

(1) Significance:  What is the potential of this work to lead to new methods of
prevention and treatment of type 1 diabetes and its complications?  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 method?
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

(4) Investigator:  Expansion of the pool of talented investigators working in
diabetes is a goal of this solicitation.  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  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 for humans, animals or the
environment, to the extent 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.

Since these applications are pilot and feasibility studies, applicants are not
expected to have as extensive preliminary data as would be expected for a regular
research application (R01).  Compelling rational for a novel study or envisioned
high impact of the work if successful could be sufficient justification in the
absence of substantial preliminary data.

Schedule

Letter of Intent Receipt Date:    March 1, 1999
Application Receipt Date:         March 30, 1999
Peer Review Date:                 July 1999
Council Review:                   September 1999
Earliest Anticipated Start Date:  September 1, 1999

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 are encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Joan T. Harmon, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 5AN-18G
Bethesda, MD  20892
Telephone:  (301) 594-8813
FAX:  (301) 480-3503
Email:  Joan_Harmon@NIH.GOV

Dov Jaron, Ph.D.
Biomedical Technology
National Center for Research Resources
6705 Rockledge Drive Room 6160  MSC 7965
Bethesda, MD  20892-7965
Telephone:  (301) 435-0775
FAX:  (301) 480-3659
Email:  BTAdir@ep.ncrr.nih.gov

Peter A. Dudley, Ph.D.
Vision Research Program
National Eye Institute
Executive Plaza South, Room 350
Bethesda, MD  20892
Telephone:  (301) 496-0484
FAX:  (301) 402-0528
Email:  pad@nei.nih.gov

Peter J. Savage, M.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 8104
Bethesda, MD  20892-7938
Telephone:  (301) 435-0421
FAX:  (301) 480-5298
Email:  ps47h@nih.gov

Elaine Collier, M.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4A20
Bethesda, MD  20892-7640
Telephone:  (301) 496-7104
FAX:  (301) 402-2571
Email:  ec5x@nih.gov

Gilman D. Grave, M.D.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11 - MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5593
FAX:  (301) 480-9791
Email:  GRAVEG@HD01.NICHD.NIH.GOV

Dennis Mangan, Ph.D.
Division of Extramural Research
National Institute of Dental and Craniofacial Research
Natcher Building, Room 4AN-32F
Bethesda, MD  20892-6402
Telephone:  (301) 594-2421
FAX:  (301) 480-8318
Email:  ManganD@de45.nidr.nih.gov

Direct inquiries regarding fiscal matters to:

Florence Danshes
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney diseases
Building 45, Room 6AN-38A
Bethesda, MD  20892
Telephone:  (301) 594-8861
FAX:  (301) 480-3504
Email:  DanshesF@extra.NIDDK.NIH.GOV

Louise Amburgey
Office of Grants Management
National Center for Research Resources
6705 Rockledge Drive Room 6086  MSC 7965
Bethesda, MD  20892-7965
Telephone:  (301) 435-0844
Email:  louisem@ep.ncrr.nih.gov

Margie Baritz
Division of Extramural Activities
National Eye Institute
Executive Plaza South, Room 350
Bethesda, MD  20892-6600
Telephone:  (301) 496-5884
FAX:  (301) 496-9997
Email:  Mbaritz@nei.nih.gov

William Darby
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7128
Bethesda, MD  20892-7128
Telephone:  (301) 435-0177
FAX:  (301) 480-3310
Email:  William_Darby@nih.gov

Celeste Kerner
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Blvd.  Room 4B32
Bethesda, MD  20892-7610
Telephone:  (301) 402-6580
FAX:  (301) 480-3780
Email:  ck103k@nih.gov

E. Douglas Shawver
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17 - MSC 7510
Bethesda, MD  20892-7510
Telephone: (301) 496-1303
FAX: (301) 402-0915
Email: SHAWVERD@HD01.NIH.GOV

Martin R. Rubinstein
Division of Extramural Research
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN-44A
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
Email:  Martin.Rubinstein@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.847 (Diabetes, Endocrinology and Metabolism Research), No. 93.371 (Biomedical
Technology), No. 93.867 (Vision Research), No. 93.387 (Heart and Vascular
Disease), No. 93.855 (Immunology, Allergy, and Transplantation Research), No.
93.865 (Research for Mothers and Children) and No. 93.121 (Oral Diseases and
Disorders Research Awards). 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, and 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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