Full Text PA-96-067 MOLECULAR CORRELATES OF PATHOGENESIS IN PARASITIC DISEASES NIH GUIDE, Volume 25, Number 25, July 26, 1996 PA NUMBER: PA-96-067 P.T. 34 Keywords: 0715151 Pathogenesis 0705048 National Institute of Allergy and Infectious Diseases PURPOSE The National Institute of Allergy and Infectious Diseases gives special consideration for funding to scientifically meritorious applications in response to Program Announcements. Program Announcements (PA) identify areas of ongoing research emphasis for the NIAID. The Division of Microbiology and Infectious Diseases (DMID) of the National Institute of Allergy and Infectious Diseases (NIAID) invites applications for research on molecular correlates of pathogenesis in selected parasitic diseases. The purpose of this PA is to encourage research to identify pathophysiologic mechanisms underlying those features most likely to be associated with adverse clinical outcomes of infection. This information will contribute to the determination of appropriate case definitions, development of new disease intervention strategies, and selection of appropriate endpoints to be used in clinical trials of candidate vaccines and new therapies. Diseases of interest are severe malaria, severe hepatosplenic schistosomiasis, and leishmaniasis (other than self-limited, cutaneous forms of disease). Studies in human populations at risk in endemic areas are particularly encouraged. 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, Molecular Correlates of Pathogenesis in Infectious Diseases, 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 202-512-1800). 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 Traditional research project grant (R01) and FIRST (R29) award applications may be submitted in response to this program announcement. Funds and time requested should be appropriate for the research proposed. RESEARCH OBJECTIVES Background In a wide variety of infections, especially those that are chronic in nature, disease is a result of complex host-pathogen interactions. The identification of specific factors, e.g., host genetic markers or specific host responses, which correlate with clinical expression of disease may lead to defining selected subgroups of patients at greater risk of morbidity and mortality as a result of infection. Such well-characterized factors may serve as sentinel markers of accelerating disease, as useful indicators that can be monitored for clinical management and probable outcomes, and as surrogate endpoints in clinical studies. Thus, the expected advances from studies supported under this initiative would be the identification and validation of molecular markers associated with a particular clinical outcome, and demonstration of their utility in case detection or case management in malaria, schistosomiasis, and leishmaniasis. Studies have identified a number of potential molecular correlates of pathogenesis in selected animal models of human parasitic diseases. For example, either deficient induction of Interferon-gamma (IFN-g) or increased production of TGF-beta, IL-4 or IL-10 is associated with progressive leishmaniasis in mice. Correlative studies have suggested a similar pathogenetic picture occurs in man. Treatment with recombinant IFN-g has proven beneficial in leishmaniasis patients. NIAID-supported work has already demonstrated that plasma levels of the cytokine tumor necrosis factor (TNF) are elevated in adults with severe malaria and in children with acute Plasmodium falciparum infections. Other work has demonstrated that a polymorphism in the TNF-alpha promoter controls the level of gene expression and correlates with severe malaria. TNF-alpha has pleiotropic effects and may therefore contribute to the multisystem pathology seen in severe malaria. Other cytokines, however, have also been shown to be elevated and may play important roles in pathology in this disease. Consistent with this latter view are recent observations that infusion of monoclonal antibodies to TNF-alpha results in a reduction in fever without a significant effect on other outcomes. Recent studies of HLA associations with severe malaria have enabled investigators to use reverse immunogenetic approaches to construct novel candidate vaccines. In these parasitic diseases, however, molecular markers have not been identified, confirmed or validated in humans. A broad-based initiative encouraging multidisciplinary studies focussed on the pathologic outcomes is therefore warranted to define at the molecular level pathogenetic mechanisms operating on both sides of the host-parasite interaction. The results obtained will subsequently be of benefit in devising new interventions as well as in identifying surrogate markers of efficacy. For example, reliable and precise case definitions of malaria have proven particularly problematic in recent clinical trials, resulting in substantial controversy over the interpretation of results. The availability of relevant surrogate markers could contribute substantively to accelerated development and clinical evaluation of novel interventions, enhance the acceptability and application of such interventions where appropriate, and improve the effectiveness and reduce the cost of applying such interventions by permitting targeting of populations at risk. Furthermore, such results will provide important applications and insights for other diseases in which similar pathogenic mechanisms operate. Research Objectives and Experimental Approaches The objective of this initiative is to identify and delineate at the molecular level the pathophysiologic mechanisms underlying adverse outcomes and their associated clinical features in malaria, schistosomiasis, and leishmaniasis. An improved understanding of the pathophysiology of these clinical manifestations would facilitate targeted, rational development of new biologic and pharmacologic intervention. In addition, for development of vaccines, it will be beneficial to understand and thus avoid these pathologic mechanisms. Molecular markers of pathogenesis may also serve as surrogates for determining the efficacy of candidate vaccines and other prophylactic or therapeutic interventions. Studies in human populations are particularly encouraged. For example, relevant projects would address one or more of the following objectives: o Identification of molecular genetic markers indicative of an increased susceptibility to an adverse outcome, e.g., cerebral malaria, severe malarial anemia, severe schistosomiasis-associated hepatosplenomegaly, and assessment of their utility in a clinical setting o Identification and/or validation at the molecular level of cytokine responses that by their nature, magnitude or kinetics, contribute to pathologic outcomes, and their detection and assessment of utility in the clinical setting o Identification of specific moieties of parasite origin that are associated with increased pathogenicity, and their detection in the clinical setting o Demonstration of the clinical utility of selected, assayable molecular markers in the medical management of severe disease or for assessment of the need for prophylaxis 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 Applicants may call NIAID program staff with any questions regarding the responsiveness of their proposed project to the goals of this PA. Applications are to be submitted on the grant application form 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 Grants Information Office, Office 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.od.nih.gov. 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. The RFA label available in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the 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 2 of the face page of the application form and the YES box must be marked. 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 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) 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. 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 review by the appropriate national advisory. 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. 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 (eligibility and responsiveness) issues to: B. Fenton Hall, M.D., Ph.D. Division of Microbiology an Infectious Diseases National Institute of Allergy and Infectious Diseases Solar Building, Room 3A-09 6003 Executive Boulevard MSC 7630 Bethesda, MD 20892-7630 Telephone: (301) 496-2544 FAX: (301) 402-0659 Email: bh24q@nih.gov Direct inquiries regarding fiscal matters to: Todd Ball Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B-35 6003 EXECUTIVE BOULEVARD MSC 7610 BETHESDA MD 20892-7610 Telephone: (301) 496-7075 FAX: (301) 480-3780 Email: tb22j@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 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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