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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