Full Text DK-95-005

INFLAMMATORY BOWEL DISEASE AND OTHER AUTOIMMUNE DIGESTIVE DISEASES

NIH GUIDE, Volume 24, Number 3, January 27, 1995

RFA:  DK-95-005

P.T. 34

Keywords: 
  Inflammation 
  Digestive Diseases & Disorders 
  Autoimmunity 


National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  March 24, 1995
Application Receipt Date:  April 25, 1995

PURPOSE

This Request for Applications (RFA) invites new as well as
experienced investigators working in the areas of gastroenterology,
epidemiology, immunology, physiology, molecular and cell biology and
genetics to submit research project grant applications that elucidate
the etiology of autoimmunity in gastrointestinal, hepatic, and
biliary diseases using genetic and molecular biology approaches.
Most notably advances could be generated in autoimmune digestive
diseases such as inflammatory bowel disease (IBD), celiac disease,
autoimmune hepatitis, primary biliary cirrhosis (PBC), and primary
sclerosing cholangitis (PSC).  Also, the RFA encourages investigators
to develop innovative molecular and genetic techniques and apply them
via small clinical studies or pilot clinical trials in the clinical
care of patients having one of the above mentioned autoimmune
digestive diseases.

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,
Inflammatory Bowel Disease and Other Autoimmune Digestive Diseases,
is related to the priority area of chronic disabling conditions.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0) or Healthy People 2000" (Summary
Report:  Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325
(telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, non-profit and
for-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Foreign institutions are not eligible for First INdependent Research
Support and Transition (FIRST) (R29) awards.  Among a team of
applicants, one institution must be proposed as the lead organization
to serve as the Grantee Institution and assume responsibility for the
fiscal and programmatic conduct of this project.  Other members of
the team should be proposed based on individual consortium
agreements.  The grantee organization and any proposed consortium
must have the staff and facilities required for the proposed program.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

The support mechanisms for this research will be the individual
research project grant (R01) and the FIRST Award (R29).  In addition,
planning grants (R21) may be requested for small clinical or pilot
studies.  This is a one-time solicitation.  Subsequent unsolicited
competing continuation applications will compete with all
investigator-initiated applications and will be reviewed according to
customary peer review procedures.  This RFA will provide the
opportunity for investigators to establish support for periods up to
five years for meritorious research projects designed to investigate
the cause, natural history, and treatment of inflammatory bowel
disease and other autoimmune digestive diseases.

This RFA is intended to support primarily new applications; however,
applications for continuation of currently funded projects will be
considered if they meet the objectives of this RFA.  New R01
applications should not request more than $160,000 in direct costs
for the first budget period.  Renewal R01 applications, if funded,
will not be funded at more than 10 percent above their previous
annual award level.  FIRST Award applications must adhere to the R29
administrative guidelines (rev. 9/93) for eligibility, budget, and
period of award.  R21 awards may request no more than $50,000 direct
costs for a one year period.

FUNDS AVAILABLE

The NIDDK plans to support approximately 10 to 12 applications
submitted in response to this solicitation.  Total costs of $2
million (direct and indirect costs) for this program have been
included in the financial plans for fiscal year 1995.  The number of
awards to be made is dependent upon receipt of a sufficient number of
applications of high scientific merit and upon availability of funds.
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.

The National Institute of Allergy and Infectious Diseases (NIAID) is
interested in basic and clinical research into the immune mechanisms
underlying autoimmune gastrointestinal and liver diseases, including
the inflammatory bowel diseases, ulcerative colitis and Crohn's
disease, primary biliary cirrhosis, and autoimmune hepatitis.
Applications that are of mutual interest are likely to be given
secondary assignment to the NIAID in accordance with Division of
Research Grants (DRG) referral guidelines.

RESEARCH OBJECTIVES

Background

This solicitation requests applications for research projects that
will elucidate the etiology and potential therapy of autoimmunity in
gastrointestinal, hepatic, and biliary diseases using genetic and
molecular biology approaches.  A recent advance in the technology of
site-directed mutation in vivo, commonly known as gene knock-out, has
enabled investigators to create null mutations in virtually any
cloned gene of interest.  For digestive diseases with inflammatory
manifestations, numerous genes are candidates for investigation into
the molecular basis of autoimmunity.  These include the family of
cytokines, growth factors, cell adhesion molecules, and cellular
receptors known to participate in systemic autoimmune disease with
subsequent specific organ dysfunction as well as the specific
autoantigens that have been identified in these diseases.

Experimental observations of animals with specific null mutations and
digestive tract disturbance would add significant insight into the
etiology of autoimmune digestive diseases.  The lack of such animal
models for study has remained a major limitation for early diagnosis
and targeted treatment of these disorders.  Gene knock-out models
could be complemented by transgenic animal models that provide
information on gene regulation, development, and gene therapy.
Examples of autoimmune digestive diseases in which notable advances
could be made include inflammatory bowel diseases (IBD), celiac
disease, autoimmune hepatitis, primary biliary cirrhosis (PBC), and
primary sclerosing cholangitis (PSC).  For the two most important
IBDs, ulcerative colitis and Crohn's disease, there is a devastating
attack on the gastrointestinal tract, obscure etiology, and
unsatisfactory response to current therapy.  Therefore, IBD is a
chronic disease.  Celiac disease is a small bowel disorder in which
there is an immune mediated sensitivity to gliadin in foodstuffs that
can only be controlled by life-long strict dietary restrictions.

Autoimmune hepatitis is a disease of unknown cause that typically
affects women and leads to end-stage liver disease.  If not treated,
and even with long term treatment using immunosuppressive agents,
autoimmune hepatitis can lead insidiously to cirrhosis.  PBC is a
disease predominantly of middle-aged women that is characterized by
immune destruction of small bile ducts in the liver causing chronic
cholestasis and ultimately cirrhosis and hepatic failure.  PSC, which
is associated with ulcerative colitis, is another chronic cholestatic
liver disease associated with diffuse inflammation of fibrosis of
medium sized and large bile ducts that leads to end-stage liver
disease.  At present there are no specific therapies of proven
benefit for PBC and PSC.  Understanding the pathogenesis of these
diseases would help design appropriate approaches to treatment or
even prevention of these autoimmune conditions.

In addition to the characterization of the unique genetic variation
that results in autoimmune pathology of the gastrointestinal tract,
hepatic and biliary systems, this solicitation also promotes
applications with the following research aims:

1.  In inflammatory bowel disease, to study the association of acute
phase proteins, as well as IL-1, IL-6, TNF alpha, and other
proinflammatory cytokines with the pathogenesis of chronic
inflammation of the large bowel or gastrointestinal tract.

2.  To elucidate therapeutic mechanisms related to reduced
gastrointestinal inflammation or utilization of cytokine receptor
antagonists, as well as other immune modulators.

3.  To characterize the autoimmunity associated with gene knock-out
mice with mutant TCR alpha and/or TCR beta expression or with MHC
class II mutations as well as disrupted IL-2 and/or IL-10 expression.

4.  In the hepatobiliary system, to use molecular techniques to
characterize the autoantigens of autoimmune hepatitis, PBC, and PSC
and to elucidate the role of cytokines, cytokine antagonists,
adhesion molecules, chemotactic factors, receptors, and signal
transduction molecules in the pathogenesis of these diseases.

5.  In autoimmune chronic hepatitis, to explore the role of growth
factors, cytokines, cytokine antagonists, adhesion molecules and
chemotactic factors in chronic inflammatory liver disease.

6.  To develop and apply innovative molecular and genetic techniques
towards clinical care of patients with autoimmune digestive diseases.

Applicants from institutions that have General Clinical Research
Centers (GCRCs) 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 could be included
with the application.

STUDY POPULATIONS

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) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.

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 reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also may obtain copies of the policy 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 March 24, 1995, 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, and is not binding, and does not enter into the
review of subsequent applications, the information that it contains
is helpful in planning for the review of applications.  It allows
NIDDK staff to estimate the potential review workload and to avoid
possible conflict of interest in the review.

The letter of intent is to be sent to:

Robert Hammond, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6AS-37F
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8886
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  The form is available from most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone (301) 435-0714.  Information describing the FIRST Award
grant may also be obtained from these sources.  The RFA label
available in the PHS 398 application form must be affixed to the
bottom of the face page.  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 2a of the face page of the application
form and check the YES box.

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

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission of the application, two additional copies
of the application must also be sent under separate cover to Dr.
Robert Hammond at the address listed under LETTER OF INTENT.

Applications must be received by April 25, 1995.  If an application
is received after that date, it will be returned to the applicant.
The Division of Research Grants (DRG) 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.  However, it is allowable to submit the same project as
both an R01 (or R29) and as a component project of a program project.
The DRG 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.  Such
applications must not only include an introduction addressing the
previous critique but also be responsive to this RFA.

For investigators applying for support through the FIRST award
mechanisms (R29), three letters of references must be submitted with
the application.  An applicant submitting a revised application in
response to this RFA must again submit reference letters.  FIRST
award applications without the required reference letters will be
returned.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications will be reviewed
for scientific and technical merit by a review group constituted by
the NIDDK especially to review the applications submitted in response
to this RFA.  The review will be carried out in accordance with the
standard NIH peer review procedures.  Following scientific-technical
review, the applications will receive a second-level review by the
NIDDK national advisory council.

As part of the initial merit review, a process (triage) may be used
by the initial review group in which applications will be determined
to be competitive or non-competitive based on their scientific merit
relative to other applications received in response to the RFA.
Applications judged to be competitive will be discussed and be
assigned a priority score.  Applications determined to be
non-competitive will be withdrawn from further consideration and the
Principal Investigator and the official signing for the applicant
organization will be notified.

Review Criteria

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  where human subjects are included, 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.

o  availability of special opportunities for furthering research
programs through the use of unusual talent resources, populations, or
environmental conditions in other countries that are not readily
available in the United States or that provide augmentation of
existing U.S. resources.

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

AWARD CRITERIA

The anticipated date of award is September 30, 1995.  Applications
will compete for available funds with all other recommended
applications submitted in response to this RFA.  The following will
be considered in making funding decisions:  quality of the proposed
projects as determined by peer review, availability of funds, and
program balance and scientific interrelationships among the proposed
projects.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
Inquiries regarding programmatic issues may be directed to:

Frank A. Hamilton, M.D., MPH
Mucosal and Immunology Program
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6AN-12B
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8877
Email:  FAH@DVSGATE.NIDDK.NIH.GOV

Thomas F. Kresina, Ph.D.
Liver and Pancreas Programs
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6AN-12A
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8871
Email:  TFK@DVSGATE.NIDDK.NIH.GOV

Tommie Sue Tralka
DDDN Clinical Trials Program
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6AN-12K
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8879
Email:  TST@DVSGATE.NIDDK.NIH.GOV

Inquiries regarding fiscal matters should be directed to:

Mrs. Thelma Jones
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6AN-44B
45 Center Drive MSC 6600
BETHESDA, MD  20892
Telephone:  (301) 594-8853

Schedule

Letter of Intent Receipt Date:  March 24, 1995
Application Receipt Date:       April 25, 1995
Initial Review:                 June/July 1995
Second Level Review:            September 1995
Anticipated Date of Award:      September 30, 1995

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.848.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, last
amended by Public Law 103-43, 42 USC 285c-8) 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 Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

.

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