Full Text DK-93-15

PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE AND CELIAC DISEASE

NIH GUIDE, Volume 22, Number 1, January 8, 1993

RFA:  DK-93-15

P.T. 34

Keywords: 
  Digestive Diseases & Disorders 
  Immunology 
  Genetics 
  Biology, Cellular 
  Biology, Molecular 
  Epidemiology 


National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date: March 24, 1993
Application Receipt Date:      April 21, 1993

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 in the area of
autoimmune gastrointestinal diseases including ulcerative colitis,
Crohn's disease and celiac disease. Applications are encouraged from
any interested investigators regardless of their prior record of
grant support.

HEALTHY PEOPLE 2000

The NIH 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, Pathogenesis of
Inflammatory Bowel Disease and Celiac Disease, 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 Healthy People 2000" (Summary Report:
Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, D.C.  20402-9325 (telephone
202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, non-profit and
for-profit organizations, whether public or private, such as
universities, colleges, hospitals, laboratories, units of State or
local governments, and eligible agencies of the Federal Government.
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 (subcontracts).  The grantee
organization and any proposed consortium must have the staff and
facilities required for the proposed program. Applications from
minority individuals and women are encouraged.

MECHANISM OF SUPPORT

The support mechanisms for this research will be the individual
research grant (R01) and the First Independent Research Support and
Transition (First) Award (R29). 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 celiac disease.

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.  R01 awards are
expected to average approximately $200,000 per year in total costs.
Note: Foreign institutions are not eligible for FIRST awards.

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 1993.  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.

Applicants for an R01 award must limit their request to not more than
$160,000 direct costs for the initial budget period, and normal
biomedical inflation increments in future years will be allowed.
Applicants for FIRST awards must limit their requests to $350,000
total direct costs across 5 years.  Although this program is provided
for the financial plans of the NIDDK, the award of grants pursuant to
this RFA is also contingent upon the availability of funds for this
purpose.

RESEARCH OBJECTIVES

Background

Inflammatory Bowel Disease (IBD) is a general term given to two
diseases, ulcerative colitis and Crohn's disease, that together are
major causes of morbidity and mortality from gastrointestinal
disorders. It is estimated that 2 million Americans are affected by
IBD, many of them in the younger age groups.  Ulcerative colitis and
Crohn's disease have many similar clinical and pathological features
and are considered to be autoimmune in etiology. However, the
pathogenesis of IBD is complex and not well understood.  Ulcerative
colitis and Crohn's disease appear to be the result of a combination
of factors including genetic predisposition, alterations in the
mucosal immune system and exposure to unknown, triggering exogenous
factors, such as intestinal microbes, toxins, food substances or
drugs. As for most autoimmune diseases, the specific etiology and
pathogenesis of both ulcerative colitis and Crohn's disease remain
unclear. Current therapies for IBD are helpful in ameliorating the
symptoms and complications of these diseases but are, in general,
unsatisfactory and do not provide a specific cure or prevent or alter
the eventual natural history of disease in the majority of patients.

Celiac disease, also known as non-tropical sprue and gluten-sensitive
enteropathy, is another mucosal disease of the gastrointestinal tract
that is believed to be autoimmune in etiology.  Celiac disease
affects approximately a quarter million Americans and usually
presents with clinical symptoms during infancy or childhood. Celiac
disease is triggered by ingestion of gluten products from wheat, rye,
barley and possibly oats, but it also has a major genetic component.
Nevertheless, the primary pathogenesis of celiac disease remains
obscure.  It is not clear how gluten interacts with the intestinal
mucosa and induces injury, what components of gluten are responsible
for the injury, what genetic defect(s) or abnormal gene(s) predispose
to the disorder, or what other exogenous exposures induce this
condition.  Celiac disease represents a paradigm for autoimmunity and
autoimmune diseases in requiring a genetic background, immunologic
disturbance and exogenous exposure (gluten) for its expression.  At
present, the clinical features of celiac disease can be resolved by
avoidance of gluten in the diet. However, the dietary restrictions
for treatment of celiac disease are challenging and require life-long
adherence. Furthermore, there remains an increased incidence of
gastrointestinal lymphoma among patients with celiac disease.

The NIDDK believes that an intensified research effort into defining
the pathogenesis of IBD and celiac disease will help in the
prevention and therapy of these important gastrointestinal diseases.
The NIDDK encourages collaborative research among the multiple
disciplines of gastroenterology, immunology, epidemiology,
physiology, molecular, structural and cell biology and genetics to
help elucidate the etiology and pathogenesis of IBD and celiac
disease. The NIDDK especially encourages new investigators from
different fields of research to apply cutting edge research
technology and innovative approaches to the understanding of these
autoimmune gastrointestinal diseases. Institutions that have
demonstrated experience in both clinical and basic science research
will be considered most favorably for support.   Applications should
be directed at the information needed to fill gaps in our knowledge
concerning the etiology of ulcerative colitis, Crohn's disease and
celiac disease.

Examples of possible topics relevant to this RFA include:

o  the role of the mucosal immune system and its immunoregulation in
gastrointestinal inflammation characteristic of IBD and celiac
disease;

o  the role and status of inflammatory mediators, the cytokine system
and adhesion molecules in IBD and celiac disease;

o  the nature of the autoimmune reactions characteristic of IBD and
celiac disease including definition of the autoantigens and the fine
specificity of autoantibodies that are detected in patients with IBD
and celiac disease;

o  genetic markers and specific gene products associated with IBD and
celiac disease and in particular the molecular genetics of the major
histocompatibility complex in these disorders;

o  epithelial cell biology and its disturbance in gastrointestinal
inflammation characteristic of IBD and celiac disease;

o  the role of luminal bacterial flora and viral infections in IBD
and celiac disease; and

o  the epidemiology of IBD and celiac disease with particular
attention to special populations and risk factors for development of
these diseases as well as their complications such as sclerosing
cholangitis in ulcerative colitis and lymphoma in celiac disease.

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.  In such a case, a letter of agreement from
either the GCRC program director or Principal Investigator could be
included with the application.

STUDY POPULATIONS - SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING
IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND
MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionally affect them.  This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study. This information must be included in the form PHS 398
(Rev. 9/91) in Item 4 (Research Design and Methods) of the Research
Plan and summarized in Item 5, Human Subjects.  Applicants are urged
to assess carefully the feasibility of including the broadest
possible representation of minority groups.  However, NIH recognizes
that it may not be feasible or appropriate in all research projects
to include representation of the full array of United States
racial/ethnic minority populations; i.e., Native Americans (including
American Indians or Alaskan Natives], Asian/Pacific Islanders,
Blacks, Hispanics).

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention [and preventive strategies], diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.  The usual NIH policies concerning research on human
subjects also apply.  Basic research or clinical studies in which
human tissues cannot be identified or linked to individuals are
excluded.  However, every effort should be made to include human
tissues from women and racial/ethnic minorities when it is important
to apply the results of the study broadly, and this should be
addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned without review.  Peer reviewers will
address specifically whether the research plan in the application
conforms to these policies.  If the representation of women or
minorities in a study design is inadequate to answer the scientific
question(s) addressed and the justification for the selected study
population is inadequate, it will be considered a scientific weakness
or deficiency in the study design and reflected in assigning the
priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

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
is being submitted.  Although a letter of intent is not required, 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 by
February 26, 1993 to:

Robert Hammond, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 496-7083
FAX:  (301) 402-1277

APPLICATION PROCEDURES

The research grant application form PHS-398 (revised 9/91) must be
used in applying for these grants.  The form is available from most
institutional business offices or from the Office of Grants
Inquiries, Division of Research Grants, National Institutes of
Health, 5333 Westbard Avenue, Room 449, Bethesda, Maryland 20892;
(301) 496-7441.  Information describing the FIRST Award grant may
also be obtained from these sources.  The RFA label available in the
9/91 revision of 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 your application such that it may not reach the
review committee in time for review.  In addition, the RFA title and
number must be typed on line 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
Westwood Building, Room 240
National Institutes of Health
Bethesda, MD 20892

At the time of submission, two additional copies of the application
should also be sent under separate cover to Dr. Robert Hammond, at
the address shown above.

Applications must be received by April 21, 1993.  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 announcement 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.  Note:
Foreign institutions are inelgible for the R29 award.

REVIEW CONSIDERATIONS

Upon receipt, applications will be initially reviewed by the Division
of Research Grants (DRG) for completeness. Incomplete applications
will be returned to the applicant without further consideration.
Evaluation for responsiveness to the program requirements and
criteria stated in the RFA is an NIDDK staff function.  If the
application is not responsive to the RFA, NIDDK staff will contact
the applicant to determine whether it should be returned to the
applicant, or whether it should be held until the next regular
receipt date and reviewed in competition with all other research
project applications.

Those applications that are complete and responsive will be evaluated
in accordance with the criteria stated below for scientific/technical
merit by an appropriate peer review group convened by the NIDDK.  In
cases where the number of applications is large compared to the
number of awards to be made, a preliminary scientific peer review may
be conducted and applications withdrawn from further competition when
they are not competitive for the award. The NIDDK will notify the
applicant and institutional official of this action.  Those
applications judged to be competitive will be reviewed for scientific
and technical merit in accordance with the usual NIH peer review
procedures by an initial review group specifically convened for this
RFA.

Following this review, the applications will be given a secondary
review by the National Diabetes and Digestive and Kidney Diseases
Advisory Council unless not recommended for further consideration by
the initial review group.  Review criteria for RFAs are generally the
same as those for unsolicited research grant applications.

o  scientific/technical merit criteria specific to the objectives of
the RFA;

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

o  appropriateness and adequacy of the experimental approach 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 resources necessary to perform the research;

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

o  if an application involves activities that could have an adverse
effect upon humans, animals, or the environment, the adequacy of the
proposed means for protecting against or minimizing such effects.

AWARD CRITERIA

The anticipated date of award is September 30, 1993.  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 should be directed to:

Frank A. Hamilton, M.D., MPH
Mucosal and Immunology Program Director, NIDDK
Westwood Bldg, Room 3A16
National Institutes of Health
Bethesda, MD 20892            / Tel. 301 496-7821

Inquiries regarding fiscal matters should be directed to:

Mrs. Thelma Jones
Grants Management Specialist, NIDDK
Westwood Building, Room 649C
National Institutes of Health
Bethesda, MD  20892          / Telephone:  (301) 496-7467

SCHEDULE: Letter of Intent: February 26, 1993
Application Receipt:        April 21, 1993
Initial Review:             June/July 1993
Second Level Review:        September 1993
Anticipated Award:          September 30, 1993

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.848.  Awards are 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.

.

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