Full Text PA-97-053 ENTERIC AND HEPATIC INFECTIOUS DISEASES NIH GUIDE, Volume 26, Number 12, April 11, 1997 PA NUMBER: PA-97-053 P.T. 34 Keywords: Digestive Diseases & Disorders Infectious Diseases/Agents Immunology 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 investigator-initiated applications in research emphasis areas focused on infection and disease caused by enteric and hepatic pathogens. The PA identifies organism-specific gaps and opportunities with potential to lead to new diagnostics, vaccines, therapies, or other control strategies. Of special interest are: the protective immune response and strategies to invoke it; mechanisms determining the outcome of infection as well as mechanisms of pathogenesis and persistence; variability and genomic organization and component structure/function; modes of transmission, reservoirs of infection, and molecular epidemiology; and application of new technologies and scientific advances to vaccine and therapy development. Multi-disciplinary research is encouraged. This PA's research emphasis areas for enteric and hepatic diseases were, in part, identified by a comprehensive NIAID external program review conducted in the summer of 1996. The report can be accessed via the Internet through the NIAID HOMEPAGE at URL "http://niaid.nih.gov" or directly at: "http://www.niaid.nih.gov/dmid/enteric_summ.htm" 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 PA, Enteric and Hepatic Infectious Diseases, is related to the priority areas of immunization and infectious diseases and chronic disabling conditions. 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) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-0325 (telephone 202-512-1800). ELIGIBILITY Applications may be submitted by 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. Domestic and foreign institutions are eligible to apply for R01 and R03 grants. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Traditional research project grant (R01), FIRST award (R29), and small research grant (R03) applications may be submitted in response to this program announcement. Applications for R01 grants may request up to five years of support; applications for R29 grants must request five years of support; and applications for R03 grants may request up to three years of support (See APPLICATION PROCEDURES below for instructions on R03 applications). The NIAID and NIDDK use R03 grants to support highly innovative feasibility or pilot projects. R03 applicants are encouraged to establish collaborations with the NIAID supported Hepatitis C Cooperative Research Centers or NIDDK supported Digestive Diseases Centers Program. RESEARCH OBJECTIVES Background Infectious enteric and hepatic pathogens cause many different acute and chronic diseases which affect several organ systems. Enteric Infectious Diseases: Agents infecting the gut cause diarrhea - the second leading cause of morbidity and mortality worldwide. They especially affect children less than five years of age. Vibrio cholera, diarrheagenic E. coli, Campylobacter, Salmonella, Shigella and rotavirus continue to cause tremendous numbers of infections and deaths each year in the developing world as well as significant morbidity in travelers to endemic areas. Some are already public health threats in the United States and some have potential to emerge and become such threats. Sometimes infection with these diarrheagenic agents leads to severe chronic sequelae. Enterohemorraghic Escherichia coli (EHEC) is associated with secondary severe kidney damage (hemolytic uremic syndrome) resulting in death or impaired kidney function. Campylobacter jejuni is the second most common cause of bacterial diarrhea. Infection with it is the most often recognized precedent to Guillain Barre Syndrome (GBS), an acute and chronic neuromuscular disease. Antibiotic resistance to C. jejuni is rapidly increasing. [Check "http://www.niaid.nih.gov/dmid/gbssumfi.htm" on the internet for a summary of a GBS/C.jenuni workshop held at NIH in the summer of 1996.] Finally, infection with the enteric pathogen Helicobacter pylori causes ulcers. Hepatic Infectious Diseases: Viruses cause both the acute and chronic liver disease (hepatitis, cirrhosis) and produce significant morbidity and mortality. Because of their chronic manifestations hepatitis B virus (HBV) and hepatitis C virus (HCV) have the greatest impact. Respectively, there are 250,000 and 150,000 annual infections with HBV and HCV in the United States. Since HCV is more apt to become a chronic infection there are 4,000,000 chronic HCV carriers compared to 1,250,000 chronic HBV carriers in this country. In the United States, each agent causes about $800 million in annual direct health care costs; liver transplants resulting from hepatitis infection add substantial additional costs. Highly effective vaccines to prevent hepatitis B are available but underutilized; better therapies are needed. Effective means to treat chronic carriers and vaccines to prevent hepatitis C are urgently needed. HCV is associated with extra-hepatic disease manifestations. Research Objectives and Scope The Enteric Diseases and Viral Hepatitis programs (NIAID) and the Division of Digestive Diseases and Nutrition (NIDDK) seek to support basic and clinical research with potential to lead to diagnostics, vaccines, therapies, or other control strategies that will reduce the disease burden and health costs associated with enteric and hepatic infectious disease agents. Significant gaps in current research support and opportunities to develop new areas have been identified with the help of external advisors. This Program Announcement solicits applications, including multidisciplinary approaches, from the research community to address these gaps. Specific, significant scientific objectives and opportunities include, but are not limited to: ENTERIC PATHOGENS (see the following references) [1]=http://www.niaid.nih.gov/dmid/enteric_summ.htm [2]=http://www.niaid.nih.gov/dmid/gbssumfi.htm Hemolytic uremic syndrome (HUS) or central nervous system (CNS) damage due to Shiga or Shiga-like toxins: [1] o mechanism(s) of host cell and organ damage o mechanism(s) of toxin transport to the blood stream and strategies to prevent transport o crystal structure of SLT-I and II and their receptor complexes o new therapeutic strategies for treatment of patients presenting with bloody diarrhea Campylobacter jejuni: [1]&[2] o animal models of C. jejuni enteritis o lipopolysaccharide (LPS) structure o virulence factors o role of the organism, its components, and the host immune response in pathogenesis o mechanism(s) of inflammatory diarrhea o improved diagnostics, including LPS-based o epidemiology of the organisms and disease: reservoirs and seasonality o mechanism(s) of antibiotic resistance Clostridium difficile [NOTE: additional study of the toxin is not requested]: [1] o virulence factors o mechanism(s)of pathogenesis o host immune response Helicobacter pylori: [1] o mechanism(s) of colonization and persistence o role of host immune response in pathology o epidemiology: reservoirs and transmission o role of H. pylori induced achlorhydria in increased susceptibility to other enteric pathogens Caliciviruses and Astrovirus: [1] o genomic organization and partial sequence of new isolates as a means to more effective detection and complete epidemiological studies o contribution to incidence of viral diarrhea and clinical significance Immunity and Vaccine Development for Salmonella, Shigella, and diarrheagenic E. coli: [1] [NOTE: For these pathogens significant advances have been made with respect to the identification of virulence factors, understanding of their regulation, and verification of their role in pathogenesis. Molecular and genetic data have spurred vaccine development but effective vaccines are not yet available. High priority will be given to collaborative, multi-disciplinary studies] o understanding of protective immunity particularly at the mucosal surface in animal models and humans and verification of animal model findings in humans o creation of effective vaccine strategies to maximize protective immunity using humans or animal models Gastroenteritis due to Salmonella enteriditis Nucleic Acid Vaccines for: o bacterial enteric pathogens o non-toxic mutants of Shiga toxin(s) o enteric viruses Host Resistance to Enteric Pathogens: [1] o role of normal commensal flora o role of immune tolerance in establishment and maintenance of normal commensal flora o pathogen-flora interaction and impact on host resistance to infection o probiotic alteration of normal flora and role in preventing and treating disease. HEPATIC PATHOGENS: VIRAL HEPATITIS B AND C Viral and host factors and the mechanisms by which they operate and interact to: o determine the outcome of viral infection, o maintain viral persistence, o cause pathogenesis, o influence disease progression, and o alter liver function, physiology, cell biology, and architecture [NOTE that for HBV studies in the woodchuck/woodchuck hepatitis virus model are especially encouraged] [The NIDDK encourages applications with the overall scientific aim is the elucidation of liver physiology and/or pathogenesis] Model Systems o development of in vitro, cell culture and organ-like systems, animal models including novel systems such as mice with human livers. [Special need for HCV.] [NOTE that the NIDDK encourages applications generating new animal models applicable to liver disease-oriented research.] o studies related to examples in previous item, infection and its prevention [Special need for HCV], and replication. Adaptation of research findings to preventive and therapeutic strategies including assay development. Definition of the protective immune response to HCV, i.e., the response leading to recovery including roles of B cells, T cells, and the immune cascade. Vaccine development for HCV. 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 are provided that inclusion is inappropriate with respect to the health of the subjects of the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). 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 the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. Investigators may obtain copies from these sources or 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 for PHS 398 (rev. 5/95) 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 Division of Extramural Outreach and Information, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: asknih@odrockm1.nih.gov. The title and number of the program announcement must be typed in Section 2 on the face page of the application. The completed, signed original and five legible, single-sided copies of applications must be sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. NIAID and NIDDK use small grants (R03) submitted in response to this PA to support small, highly innovative or pilot projects. Applicants for R03 grants may request up to $50,000 annual direct costs for a period not to exceed three years. Funds and time requested should be appropriate for the research proposed. Applicants for R03 grants must follow the special application guidelines and Terms and Conditions of Award in the NIAID SMALL RESEARCH GRANTS brochure (September 1996); this brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/tools/broch.htm ALL APPLICANTS REQUESTING $500,000 OR MORE IN ANNUAL DIRECT COSTS. The NIH Policy Update on Acceptance for Review of Unsolicited Applications that Request More Than $500,000 Direct Cost for Any One Year applies to applications in response to this PA. The Policy Update was published in the NIH Guide for Grants and Contracts, Vol. 25, No. 14, May 3, 1996, and became effective June 1, 1996. Potential applicants must contact the appropriate program staff listed in INQUIRIES to initiate clearance processes for acceptance of their applications. REVIEW CONSIDERATIONS Review Procedures Applications will be assigned on the basis of established PHS referral guidelines. Incomplete applications will be returned to the applicant without further consideration. R01 and R29 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. 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 the applications under review, will be discussed, assigned a priority score, and receive a second level of review by the appropriate national advisory council. R03 applications that are complete will be evaluated by an appropriate peer review group convened by the sponsoring institutes. Review Criteria o scientific, technical, or medical significance and originality of the 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 will compete for available funds with all other favorably recommended applications. For applications assigned to the NIAID and NIDDK, 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 program announcement, and availability of funds. INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Leslye D. Johnson, Ph.D. Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 3A22 - MSC 7630 Bethesda, MD 20892-7630 Telephone: (301) 496-7051 FAX: (301) 402-1456 Email: lj7m@nih.gov Dennis R. Lang, Ph.D. Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 3A21 - MSC 7630 Bethesda, MD 20892-7630 Telephone: (301) 496-7051 FAX: (301) 402-1456 Email: dl73v@nih.gov Frank Hamilton, M.D., M.P.H. Digestive Diseases Program Branch National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8877 FAX: (301) 480-8300 Email: fh14e@nih.gov Thomas F. Kresina, Ph.D. Liver Diseases Program National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8871 FAX: (301) 480-8300 Email: tk13v@nih.gov Direct inquiries regarding fiscal matters to: Mr. Todd Ball Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4B35 Bethesda, MD 20892-7610 Telephone: (301) 402-5512 FAX: (301) 480-3780 Email: tb22j@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.856 and No. 93.848. Awards are made under authorization of the Public Health Service Act, Sec. 301(c), Public Law 78-410, as amended. Awards will be administered under PHS grants policies and Federal Regulations 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 review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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