HELICOBACTER PYLORI PATHOGENESIS

NIH GUIDE, Volume 22, Number 31, August 27, 1993



PA NUMBER:  PA-93-105



P.T. 34



Keywords:

  Infectious Diseases/Agents 

  Pathogenesis 



National Institute of Allergy and Infectious Diseases

National Institute of Diabetes and Digestive and Kidney Diseases



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 basic and clinical studies needed to

establish the role of bacterial and host factors in the pathogenesis

of the various forms of Helicobacter pylori disease, including

infection, gastritis, and duodenal ulceration.



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, Helicobacter Pylori Pathogenesis, is related to the

priority areas of immunization and infectious diseases and 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, 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 or local

governments, and eligible agencies of the Federal government.

Applications from minority individuals and women are encouraged.

Foreign institutions are not eligible for the First Independent

Research Support and Transition (FIRST) award (R29).



MECHANISMS OF SUPPORT



Traditional research project grant (R01) and the FIRST award (R29)

applications may be submitted in response to this announcement.



RESEARCH OBJECTIVES AND SCOPE



Background



Although it was only discovered in 1982, H. pylori has already been

shown to be associated with several gastroduodenal diseases,

including active and chronic gastritis and duodenal ulcers.

Epidemiologic studies have shown that H. pylori colonizes the gastric

mucosa in more that 50 percent of persons and is associated with

disease of the upper gastrointestinal tract in one out of every two

people in the world.  Indeed, these conditions, including gastric and

duodenal ulcer disease, are among the most common human ailments

requiring medical attention.  An estimated 10 percent of people in

the United States will develop peptic ulcer disease, and it is

estimated that there will be 300,000 new cases, 3.2 million

recurrences, and 3,000 deaths due to duodenal ulcer disease each

year.



Most research in this area has focused on seroepidemiological studies

and clinical studies to define the role of H. pylori in various

syndromes and the effect of antibiotic treatment on resolution of

disease.  While these studies have been important in defining the

importance of H. pylori in causing a wide variety of diseases, there

has not been a concomitant emphasis on understanding the pathogenesis

and natural history of these infections.



Research Objectives and Experimental Approaches



The overall goal of this program announcement is to stimulate

innovative research to define the host and bacterial factors involved

in the various phases of H. pylori infection excluding gastric

carcinoma and lymphoma.  These studies may include animal model

studies as well as carefully controlled clinical and epidemiological

studies that could lead to intervention strategies to control and

prevent these infections.



Applicants are encouraged to address the areas mentioned below.  The

list is not all inclusive and applicants may wish to pursue other

areas.  Examples include, but are not limited to, the following:



o  Definition of the virulence determinants of H. pylori.  These

studies may require development of genetic systems to identify the

role of specific bacterial genes such as adhesins, enzymes,

cytotoxins, and other bacterial components in pathogenesis and

virulence.  Use of relevant animal models is especially encouraged.



o  Description of the pathophysiology of H. pylori infection.

Efforts to determine the role of hormones and cytokines in the

aberrations seen in gastric physiology throughout the spectrum of

disease are strongly encouraged.



o  Description of the immunopathology of H. pylori infection.

Efforts to determine the nature of inflammatory and other immune

responses, including the role of specific lymphocyte classes in the

regulation of the host response to infection are strongly encouraged.



o  Definition of the epidemiology of disease in various settings.

These efforts may include population-based studies as well as

detailed clinical studies of the natural history of infection and

disease progression.



Multidisciplinary studies having collaboration among investigators

with expertise in appropriate disciplines is encouraged.  When

individuals are at different institutions, individual R01

applications may include consortium arrangements or utilize the

Interactive Research Project Grant (IRPG) mechanism (NIH Guide, Vol.

22, No. 16, April 23, 1993).



Collaborative arrangements with on-going clinical studies or trials

that provide patient material and data are encouraged.  Such

arrangements should be clearly delineated in the application.



Where statistical analysis is anticipated, the methodologies and

personnel involved should be described in the application and evident

in the study design.



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

that disproportionately 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 should 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 Sections 1-4 of the Research Plan AND summarized in

Section 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).  The rationale

for studies on single minority population groups must be provided.



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 review will be deferred until the information is provided.



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 will be

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.



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.



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.  The title and number of the announcement must be

typed in Section 2a on the face page of the application.



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 to appropriate Institutes, Centers, or

Divisions (ICDs) within NIH 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.



AWARD CRITERIA



Applications will compete for available funds with all other

favorably recommended applications assigned to that ICD.  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 from potential applicants is welcome.



Direct inquiries regarding programmatic issues to:



Leslye D. Johnson, Ph.D.

Division of Microbiology and Infectious Diseases

National Institute of Allergy and Infectious Diseases

Solar Building, Room 3A-06

6006 Executive Boulevard

Bethesda, MD  20892

Telephone:  (301) 496-7051

FAX:  (301) 402-2508



Frank Hamilton, M.D., M.P.H.

Division of Digestive Diseases

National Institute of Digestive Diseases and Kidney

Westwood Building, Room 3A-16

Bethesda, MD  20892

Telephone:  (301) 594-7571



Direct inquiries regarding fiscal matters to:



Mr. Todd Ball

Division of Extramural Activities

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4B35

6003 Executive Boulevard

Bethesda, MD  20892

Telephone:  (301) 496-7075



Ms. Thelma Jones

Grants Management Branch

National Institute of Digestive Diseases and Kidney

Westwood Building, Room 649C

Bethesda, MD  20892

Telephone:  (301) 594-7543



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 grant policies and

Federal Regulations at 42 CFR Part 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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