NIH Guide, Volume 26, Number 38, November 21, 1997

RFA:  DK-98-007


National Institute of Diabetes and Digestive and Kidney Diseases
National Center for Research Resources
National Institute of Allergy and Infectious Diseases
National Institute of Child Health and Human Development
National Institute on Aging

Letter of Intent Receipt Date:  February 19, 1998
Application Receipt Date:  March 19, 1998


The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the
National Center for Research Resources (NCRR), the National Institute of Allergy
and Infectious Diseases (NIAID), the National Institute of Child Health and Human
Development (NICHD), and the National Institute on Aging (NIA) invite
investigator- initiated research grant applications to develop therapies to
achieve euglycemia in people with type I diabetes.  These applications could
include: islet and beta cell transplantation; engineering of regulated insulin
secretion in non-beta cell surrogates; hematopoietic stem cell therapy for the
induction of tolerance; or development of technologies to preserve beta cell
function and stimulate beta cell regeneration. Particular emphasis should be
placed on the development of clinically applicable technologies.

This Request for Applications (RFA) is intended to stimulate the application of
advances in cell biology, bioengineering, immunology, molecular biology, gene
therapy and transplantation to the development of safe and effective therapies
to regulate glucose homeostasis in humans.  Collaborative efforts linking
expertise in these disciplines to expertise in diabetes are strongly encouraged. 
Two-year pilot and feasibility applications and interactive research projects,
which will support the efforts of several independent investigators working in
a collaborative manner, are available within this RFA.  It is anticipated that
results obtained from studies supported by this RFA will aid in the development
of improved therapies for the treatment of type I diabetes mellitus.


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, Cellular and Molecular Approaches
to Achieving Euglycemia, 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).


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.


Support of this program will be through the National Institutes of Health (NIH)
Research Project Grant (R01), Interactive Research Project Grant (IRPG), and
Exploratory/Developmental Research Grant (R21) award mechanisms. Guidelines for
preparing IRPG applications are available from the program official or from the
internet at: https://grants.nih.gov/grants/guide/pa-files/PA-96-001.html

The R21 awards are to demonstrate feasibility of a concept and to generate
sufficient preliminary data to pursue it through other funding mechanisms.  These
grants are intended to (1) provide initial support for new investigators; (2)
allow exploration of possible innovative new leads or new directions for
established investigators; and (3) stimulate investigators from other areas to
lend their expertise to research within the scope of this solicitation. 
Applicants for the R21 must limit their requests to $100,000 direct costs per
year and are limited to two years.

Applicants from institutions that have a General Clinical Research Center (GCRC)
funded by the NIH National Center for 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.

Applicants anticipating submitting IRPG applications or applicants requesting
more than $500,000 in direct costs per year for any year should consult with the
NIDDK Program Official listed under "INQUIRIES" at an early opportunity. 
Applicants for R01 mechanism must receive permission from the NIDDK prior to the
submission of an application requesting more than $500,000 in direct costs per
year for any year of the proposed study.  NIDDK staff will coordinate
consideration and acceptance of such large applications by the staff of the
appropriate Institute.

The total requested project period for an application submitted in response to
this RFA may not exceed three years.  Budget escalations in future years are
limited to three percent of recurring costs.  The anticipated award date is
September 30, 1998.  Responsibility for the planning, direction, and execution
of the proposed project will be solely that of the applicant.  Awards will be
administered under Public Health Service (PHS) grants policy as stated in the PHS
Grants Policy Statement.


For FY 1998, $5 million will be committed to fund applications submitted in
response to this RFA.  It is anticipated that 18 to 20 awards will be made. 
However, this funding level is dependent upon the receipt of a sufficient number
of applications of high scientific merit.  The award of grants pursuant to this
RFA is also contingent upon the availability of funds for this purpose.



Diabetes mellitus affects approximately 16 million people in the United States. 
Individuals with type 1 diabetes mellitus have lost their ability to produce
insulin due to immune system-mediated destruction of the insulin producing beta
cells of the pancreas.

On September 4 and 5, 1997, the NIH sponsored a conference entitled "Diabetes
Mellitus: Challenges and Opportunities."  This conference identified research
opportunities in several areas, one of the most important being the need for
innovative therapies for diabetes.  It was noted that intensive treatment of type
1 diabetes, although effective in improving long-term outcome, is difficult to
implement for many patients and does not achieve euglycemia.  The level of
glycemic control achieved using currently available intensive treatment methods
is at best 4-5 standard deviations above the mean value for the nondiabetic
population, as measured by glycated hemoglobin (HbA1c).  Intensive therapy is
also limited by the accompanying increased frequency of severe hypoglycemia and
weight gain, resulting in an increasing prevalence of overweight patients with
type 1 diabetes.

Finally, currently available intensive therapy is particularly problematic in
children and adolescents due to difficulties in getting them to comply with
current treatment regimens.  This is especially troublesome since current
clinical data support early intervention as being most effective treatment
strategy.  Thus, the results of the Diabetes Control and Complications Trial
indicate that maintenance of near normal glycemic levels can reduce and delay the
onset of the devastating complications of diabetes.  Therefore, establishing
methods to achieve and maintain euglycemia will have enormous impact on the
health and quality of life of individuals with diabetes.

Scope and Objectives

Although the ultimate research goal is to prevent the onset of type 1 diabetes,
investigators are currently developing approaches and technology to modulate
blood glucose levels in patients with diabetes and to restore insulin-producing
capacity through transplantation of the whole pancreas, or of islets from the
pancreas.  Today, the only method that offers normal blood glucose levels is
pancreas transplantation.  Several decades ago, islet transplantation was
proposed in the hope of reducing the need for difficult surgical procedures by
allowing intravenous injection of islets.  Initial animal studies on islet
transplantation were encouraging, but subsequent research using larger animals
and humans resulted in lower success rates as defined by exogenous insulin

Unfortunately, the initial promise held out for islet cell transplantation has
not been realized.  Thus, of the 270 adult islet transplants performed by the end
of 1995 in patients with type 1 diabetes, only ten percent of recipients did not
require insulin injections for more than one week, and only five percent remained
off exogenous insulin for more than one year.  In light of these results, studies
are needed to better understand what treatment regimens would allow successful
islet transplantation using the least amount of immunosuppression, thereby
minimizing the toxicity to the islet.  For example, corticosteroids, a mainstay
of immunosuppressive regimens for solid organ transplantation, interfere with the
normal beta cell function to release insulin in response to elevated blood sugar
levels.  In addition, the recurrence of autoimmune- mediated destruction of
transplanted beta cells is problematic, and many researchers are pursuing studies
to abrogate the underlying autoimmunity that has led to type 1 diabetes.

While the "gold standard" for transplant success has been insulin independence,
clinicians are observing a beneficial effect of islet transplantation even in
recipients who have not achieved insulin independence. These patients require
less exogenous insulin and show an improvement in metabolic control, which
equates to fewer episodes of severe hypoglycemia. This effect may also lower the
risk of long-term complications.

Considerable knowledge has accrued from these early studies, including: improved
procedures for handling the donor pancreas to optimize islet survival; improved
methods for preparing large quantities of islets; the development of standardized
solutions of enzymes to dissociate the islets from the other pancreatic tissue;
pre-transplant treatment methods to reduce rejection; cryopreservation
procedures; and evidence of the detrimental effects of immunosuppressive therapy
on islet function and survival.

Other beta cell replacement strategies include bioengineered beta cells, beta
cells grown in continuous or permanent culture to expand the number available for
transplantation, and animal islets.  Bioengineered beta cells could be non-beta
cells that would be transfected with specific genes to mimic beta cell function,
could be "real" beta cells engineered to enhance engraftment or prevent
rejection, or could be a combination cell which functions to release insulin in
response to glucose and prevents graft rejection.  To pursue and evaluate such
strategies, it will be critical to establish those beta cell components that are
required for glucose-regulated insulin secretion.  These functional components
would, of course, include the internal beta cell machinery, but may also include
interactions among beta cells and interactions between beta cells and the
extracellular matrix.  Animal islets, while offering an ample supply of islets,
present additional risks, such as the transmission of animal diseases to humans
and accelerated immune rejection.

Another potentially worthwhile approach to achieving euglycemia involves immune
isolation in conjunction with beta cell replacement procedures under study. 
There are several methods to achieve immune isolation, including implantation in
an immune-privileged site; encapsulating in an immune protective membrane; and
co-transplantation of beta cells with, for example, transfected myoblasts
secreting agents (TNF or Fas-L) to induce apoptosis of the invading cytotoxic
lymphocytes.  All of these methods require further development and evaluation.

In addition to procedures to isolate insulin-producing cells from the immune
system, novel approaches should be developed to eliminate the need for general
immunosuppressive therapies to prevent islet rejection. Such an intervention
might be co-administration of donor hematopoietic stem cells to induce tolerance.

Informed assessment of the efficacy of the various approaches to achieving
euglycemia will require noninvasive methods, such as PET, MRI, or NMR, for
measuring beta cell mass, the degree of autoimmune destruction, and/or islet cell
rejection.  Development of these technologies may require marking the beta cell
to allow detection.  Application of these technologies to diabetes will be
important to assess transplant outcome and enhance understanding of the
pathogenesis of type 1 diabetes.

The scope of this RFA includes methods to enhance the supply and sources of
insulin-producing cells; identification of the cellular components necessary for
glucose-responsive insulin secretion; development of methods to protect insulin-
producing cells via immunoisolation or immunomodulation/tolerance induction; the
application of in vivo or in vitro gene delivery systems; development of
noninvasive procedures to measure islet/beta cell mass/function or destructive
disease processes; and the establishment of hematopoietic stem cell therapies for

Relevant topics for study listed below are examples and should not be construed
as required or limiting.

o  Determination of the optimal site for islet engraftment to minimize the immune
response and maximize graft function

o  Determination of the optimal number of islets necessary to ensure engraftment,
most efficiently

o  Establishment of methods to completely abrogate the non-specific inflammatory
response to infused islets

o  Assessment of how to prevent autoimmune destruction of the transplanted isles,
using molecular or cellular approaches to achieve long-term islet survival

o  Identification of genes and their products that regulate glucose-stimulated
insulin release, including those involved in glucose recognition, stimulus-
secretion coupling mechanisms and exocytic mechanisms

o  Identification of genes and their products that can abrogate allogeneic or
xenogeneic rejection processes

o  Identification of genes and their products that can abrogate autoimmune

o  Development of immunoisolation materials to minimize non-specific inflammatory
damage and shedding of antigen from the internal islets that would initiate an
immune response and rejection, while permitting transport of necessary cell
growth-promoting factors, nutrients and oxygen

o  Development and evaluation of immunosuppressive regimens to optimize patient
safety and promote islet allograft survival

o  Application of gene-therapy, knock-out and anti-sense methodologies to promote
islet cell engraftment and long- term survival, including but not limited to
affecting expression of CD40/CD40L, Fas/FasL, cytokines, adhesins, and other
immune system regulatory molecules

o  Optimization of tolerance induction protocols that would allow indefinite
islet survival

o  Evaluation of xenogeneic islet transplantation with regard to hyperacute
rejection and safety issues, including transmission of non-human infectious
agents to human recipients

o  Development of noninvasive technologies to measure islet/beta cell
mass/function, disease status and/or progression

o  Establishment of novel islet or surrogate cell transplant protocols
incorporating innovative technologies to prevent graft rejection and maintain
glucose-stimulated insulin secretion

o  Develop animal models and/or in vitro models of ductal cell hyperplasia and
islet regeneration for the identification of cytokines and growth factors which
stimulate this process

o  Examination of molecular and cellular mechanisms underlying age-related
changes in islet and beta cell function in older subjects from the perspective
of both a) cellular response to extracellular signals and b) age-related
alterations in hormonal and cytokine milieu

o  Elucidation of the mechanism by which immunological memory against beta cell
antigens persists in type 1 diabetes long after complete destruction of the beta
cell mass

o  Determination of the whether significant insulin gene expression can be
induced by cytokines, growth factors, and transcription factors in surrogate beta


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
rational 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, 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.


Prospective applicants are asked to submit, by February 19, 1998, 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
this RFA.

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 if contains
allows NIH 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 Disease
45 Center Drive, Room 6AS-37F, MSC 6600
BETHESDA, MD  20892-6600
Telephone:  (301) 594-8885
FAX:  (301) 480-3505


The research grant application form PHS 398 (rev. 5/95) 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: 

The RFA label available in the PHS 398 (rev. 5/95) 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.

As indicated under "Mechanism of Support," if a collaboration of individual
investigators is planned, it is necessary to identify one of the investigators
as the group coordinator and to cite this individual in all applications on page
2 of the form PHS 398 (rev. 5/95). Applicants who have entered into collaboration
may submit the applications individually with a cover letter noting their
involvement and listing the other members of the collaboration.

Submit a signed, typewritten original of the application, including the
Checklist, plus three signed photocopies, in one package to:

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 Disease
45 CENTER DRIVE, Room 6AS-37F, MSC 6600
BETHESDA, MD 20892-6600

Applications must be received by March 19, 1998.  If an application is received
after that date, it will be returned to the applicant without review.  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.


Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened 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 whereby
only those applications deemed to have high scientific merit will be discussed,
assigned a priority score, and receive a second level review by the National
Advisory Council of the assigned Institute or Center.

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 review, comments on the following aspects of the application will be made
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 the assignment of the overall score.

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

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 methods? 
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?

o  Appropriateness of the proposed budget and duration in relation to the
proposed research.

o  Adequacy of plans to include both genders and minorities and their subgroups
as appropriate for the scientific goals of the research.  Plans for the
recruitment and retention of subjects will also be evaluated.

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

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 United States resources.

o  For those applications that propose collaborative efforts between several
applicants, additional factors to be considered during the review would include
the efficacy of the collaboration, the commitment of the participants to the
collaboration, the design and responsibilities of the coordinating center, and
the cost effectiveness of the collaborative effort.

R21 applications will have the additional review criteria:

o  Potential for novel and innovative approaches that clearly require additional
preliminary data for their value to be established.

IRPG applications will have these additional review criteria:

o  Each component R01 of the IRPG will be reviewed as above for its independent
scientific merit.

o  The reviewers will assess the intended IRPG interactions, including the
effectiveness and feasibility of the proposed IRPG group interactions, whether
or not they enhance the prospects for reaching the stated objectives of the
group, and the extent of synergy among the various projects.


The anticipated date of award is September 30, 1998.

The factors that will be used to make award decisions include:

o  scientific and technical merit as determined by peer review,
o  availability of funds, and
o  programmatic priorities.


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:

Joan T. Harmon, Ph.D.
Diabetes Research Section
National Institute of Diabetes and Digestive and Kidney Diseases
45 CENTER DRIVE, Room 5AN-18G MSC 6600
BETHESDA, MD 20892-6600
Telephone:  (301) 594-8808
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

Stephen M. Rose, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4A14
Bethesda, MD  20892-7640
Telephone:  (301) 496-5598
FAX:  (301) 402-2571
EMAIL:  sr8j@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

Frank Bellino, Ph.D.
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892-9205
Telephone: (301) 496-6402
FAX: (301) 402-0010
Email: bellinof@gw.nia.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
BETHESDA, MD 20892-6600
Telephone: (301) 594-8854
FAX: (301) 480-4237
E-mail: dixonn@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

Laura Eisenman
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B23
Bethesda, MD 20892-7610
Telephone: (301) 496-7075
Fax: (301) 480-3780
Email: le55d@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

Robert Pike
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  20892
Telephone: (301) 496-1472
FAX: (301) 402-3672
email: pikeb@gw.nia.nih.gov


Letter of Intent Receipt Date:  February 19, 1998
Application Receipt Date:       March 19, 1998
Initial Review:                 June/July 1998
Second Level Review:            September 1998
Anticipated Date of Award:      September 30, 1998


This program is described in the Catalog of Federal Domestic Assistance No.
93.847 (Diabetes, Endocrinology and Metabolism Research), No. 93.855 (Immunology,
Allergy, and Transplantation Research), No. 93.865 (Research for Mothers and
Children), 93.866 (Aging Research) and 93.371 (Biomedical Technology).  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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