Full Text PA-95-019

H. PYLORI: BASIC, PRE-CLINICAL, AND CLINICAL RESEARCH

NIH GUIDE, Volume 24, Number 4, February 3, 1995

PA NUMBER:  PA-95-019

P.T. 34

Keywords: 
  Infectious Diseases/Agents 
  Disease Model 
  0740074 
  Immunology 


National Institute of Allergy and Infectious Diseases
National Institute of Diabetes, Digestive and Kidney Diseases

Application Receipt Dates:  June 1, and October 1, 1995 and February
1, 1996

THIS IS A REPUBLICATION OF PA-95-019, PUBLISHED IN THE NIH GUIDE,
VOL. 24, NO. 1, JANUARY 13, 1995.  DISREGARD PREVIOUS VERSIONS.

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID),
and the National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) invite submission of investigator-initiated research
applications for support of research on the definition of the natural
history of infection, animal models, protective immune responses to
infection, virulence determinants, bacterial genetics, and antibiotic
resistance to Helicobacter pylori.  This bacterium is known to be
associated with chronic gastritis, duodenal and gastric ulcer
disease, and possibly with certain malignancies of the stomach.  The
development of vaccines against this organism is also of interest to
the NIAID.  The mechanisms of support will be the individual research
project grant (R01)
and the FIRST (R29) award.

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 program
announcement, H. Pylori:  Basic, Pre-Clinical and Clinical Research,
is related to the priority area of immunization and infectious
diseases.  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 20402-0325 (telephone
202-783-3238).

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.
Foreign institutions are not eligible for the First Independent
Research Support and Transition (FIRST) award (R29).

MECHANISM OF SUPPORT

The mechanisms of support will be the individual research project
grant (R01) and the FIRST (R29) award.  The total project period for
an application submitted in response to this program announcement may
not exceed five years; a foreign application may not request more
than three years of support.

FUNDS AVAILABLE

The estimated NIAID funds available for the total (direct and
indirect) first-year costs of awards made under this PA will be
$1,000,000.  In Fiscal Year 1996, the NIAID plans to fund four to
five R01 and/or R29 grants.  This level of support is dependent on
the receipt of a sufficient number of applications of high scientific
merit.  Although this program is provided for in the financial plans
of the NIAID, awards pursuant to this program announcement are
contingent upon the availability of funds for this purpose. Funding
beyond the first and subsequent years of the grant will be contingent
upon satisfactory progress during the preceding years and
availability of funds.  The NIDDK has an interest in Helicobacter
pylori research, but does not have set-aside funds for the purpose of
this PA.  Applications received in response to this PA that are
assigned to NIDDK or other PHS funding components will compete with
other applications for funding.

New applications submitted for the June 1 and October 1, 1995 and
February 1, 1996 receipt dates will be eligible for funding under
this program announcement.  Competing continuation applications for
already funded projects will NOT be eligible for award from NIAID
under this program announcement.

RESEARCH OBJECTIVES

Background

In 1983, a spiral shaped, urease producing, Gram negative bacterium,
Helicobacter pylori, was identified in the stomachs of some
individuals.  Since then, there has been increasing evidence for its
association with active and chronic gastritis, peptic ulcers, and
duodenal ulcers.  Effective treatment of the infection with
antibiotics eliminates ulcer recurrences in more than 90 percent of
cases.  An epidemiologic relationship between atrophic gastritis,
which develops in a small percentage of those infected with H.
pylori, and gastric malignancies has also been noted.

H. pylori colonizes the gastric mucosa of greater than 30 percent of
persons in the U.S. and more frequently in African American,
Hispanic, and socioeconomically disadvantaged populations in this
country.  In some developing countries, it is found in almost 100
percent of the population.  Non-ulcer dyspepsia (NUD) and gastric and
duodenal ulcer disease, are among the most common human ailments of
the upper GI tract requiring medical attention.  An estimated 10
percent of people in the United States will develop peptic ulcer
disease, a chronic inflammatory condition of the stomach and
duodenum, sometime in their lifetime.  It is estimated that there are
300,000 new cases, 3.2 million recurrences, and 3,000 deaths due to
duodenal ulcer disease each year in the U.S.  NUD affects even
greater numbers of individuals, but a causal relationship between NUD
and H. pylori has not been definitively established to date.
Defining this relationship, and identifying even a subset of NUD
patients, would facilitate the prescription of appropriate antibiotic
therapy for those individuals.

A recent Consensus Conference sponsored by NIDDK, NIAID, and the NIH
Office of Medical Applications of Research recommended that patients
presenting with duodenal or gastric ulcers, who were also
seropositive for H. pylori, be treated with antimicrobial triple
therapy to eradicate the organism.  The Panel recommended that basic
research should be conducted in order to generate much needed data on
the biology of this organism.  The development of an effective
preventive strategy, including the development of a vaccine should
also be pursued when sufficient information on pathogenesis is
available. This initiative will focus on these basic issues,
including definition of the natural history of infection, animal
models, protective immune responses to infection, virulence
determinants, bacterial genetics, and antibiotic resistance.

It is known that a significant number (approximately 10 percent) of
children under the age of 10 in the U.S. are seropositive for H.
pylori.  The source of infection, modes of transmission,
identification of risk factors, and the consequence of this infection
on the health of the young are not known, and are of special interest
to the NIAID in the context of this program announcement.

Research Objectives and Experimental Approaches

Well-designed basic, pre-clinical and clinical studies are needed to
provide a better understanding of H. pylori biology and pathogenesis
so that effective intervention strategies can be designed.

Topics of interest to the NIAID include, but are not limited to:

o  development or use of animals that can be infected with human
isolates of H. pylori and that serve as models for stages of the
human disease and are amenable to evaluation of prophylactic and
therapeutic strategies;

o  identification of virulence factors of the organism, effect of
deletion of virulence factor genes  on pathogenesis;

o  biomarkers (antigens or nucleic acids) of strains of H. pylori
that may be associated with particular outcomes of infection such as
various forms of NUD, ulcer disease, or asymptomatic carriage;

o  definition of the genetics of the organism including
characterization of plasmids, mechanism of gene transfer, etc;

o  development and mechanism of antibiotic resistance;

o  vaccine development; and

o  natural history of infection, particularly in children, including
risk factors and modes of transmission.

Multidisciplinary studies and collaboration among investigators with
expertise in appropriate disciplines are encouraged.  When
investigators are at different institutions, individual R01
applications may include consortium arrangements.  Collaborative
arrangements with on-going studies that provide patient populations,
specimens and data are encouraged.  Such arrangements should be
clearly delineated, and appropriate letters confirming collaborative
efforts should be included in the application.

The methodologies employed and personnel involved in the study,
including statistical analyses, should be described in the
application and evident in the study design.  The hypothesis(es) to
be tested should be clearly stated.  The measurement of immunological
and bacterial markers is highly dependent on the assay system chosen
and its execution.  Thus, it is very important that applicants
clearly define the methodologies to be used, the rationale for
choosing those methodologies and for validating results as well as
methods of collection, processing, and storage of samples.

The value of studies of patients or their specimens will be directly
related to the care exercised in selection and initial
characterization of cases and controls.  Therefore, a detailed
description of case recruitment procedures, the criteria to be used
for case definition and the manner in which the criteria are to be
applied should be included.  This is particularly true in the case of
non-ulcer dyspepsia for which a generally accepted definition does
not exist.  Similar care should be given to descriptions of
enrollment of comparison groups.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority groups
and their sub-populations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This 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 printed 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.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS
398 (rev. 9/91) and will be accepted on the standard application
deadlines as indicated in the application kit.  Requests for
continued funding of already funded projects (Type 2) will NOT be
considered under this program announcement.  Applications may be
submitted for the following receipt dates:  June 1, and October 1,
1995 and February 1, 1996.  Awards resulting from this announcement
will be made on or about April 1, July 1, and December 1, 1996.
Application kits are available at most institutional offices of
sponsored research and may be obtained from the Office of Grants
Information, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
(301) 710-0267.

Each application must be identified by checking "YES" on line 2a of
the PHS face page, and the number and title of this program
announcement must be typed in section 2a.

The completed original and five legible, single-sided copies of the
application must be sent or delivered to:

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

FIRST (R29) applications must include at least three sealed letters
of reference attached to the face page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
review.

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 Center as a resource for
conducting the proposed research.  If so, a letter of agreement from
the GCRC Program Director must be included in the application
material.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit by study sections of the Division of Research
Grants, NIH, in accordance with the standard NIH peer review
procedures.  Following scientific/technical review, the applications
will receive secondary review by the appropriate national advisory
council.

Applications that are complete and responsive to the program
announcement will be evaluated for scientific and technical merit by
an appropriate peer 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

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  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.

AWARD CRITERIA

Applications assigned to the NIAID will compete for available set-
aside funds provided by the NIAID.  The following will be considered
when making funding decisions:  quality of the proposed project as
determined by peer review, program balance among research areas of
the announcement, availability of funds.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Dennis R. Lang, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A21
6003 Executive Boulevard MSC 7630
Bethesda, MD  20892-7630
Telephone:  (301) 496-7051
FAX:  (301) 402-1456
Email:  dl73v@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Louise Kreh
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B35
6003 Executive Boulevard MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  louise_kreh@exec.niaid.pc.niaid.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.856, Microbiology and Infectious Disease Research.
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 recipients to provide a smoke-
free work place 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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