Full Text PA-97-079 INNATE IMMUNITY NIH GUIDE, Volume 26, Number 24, July 25, 1997 PA NUMBER: PA-97-079 P.T. 34 Keywords: Immunology National Institute of Allergy and Infectious Diseases National Institute of Dental Research PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Dental Research (NIDR), National Institutes of Health (NIH), invite applications for research studies of the innate immune system. Two general systems of immune recognition have been selected through evolution: innate immunity and acquired immunity. The innate immune system provides broad, but relatively nonspecific host defenses that lack the properties of antigenic specificity and immunologic memory that characterize acquired immunity. However, recent discoveries point to many robust mechanisms of innate immunity and have highlighted important functional links between the innate and acquired immune responses. The purpose of the PA is to support basic and preclinical studies of the mechanisms of innate immunity in order to: a) develop new strategies to augment antimicrobial defenses; b) develop novel approaches for immunomodulation in chronic infectious and inflammatory disorders; and c) identify new methods, based on mechanisms of innate immunity, to modulate acquired immune responses (e.g., to enhance vaccine efficacy). 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, "INNATE IMMUNITY", is related to the priority areas of Immunization and Infectious Diseases and Diabetes and Chronic Disabling 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 20402-9325 (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. Foreign institutions are not eligible for FIRST awards (R29). Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Traditional research project grant (R01) and FIRST award (R29) 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. Responsibility for the planning, direction, and execution of the proposed research will be solely that of the applicant. RESEARCH OBJECTIVES Background This PA will support studies of the mechanisms of innate or "natural" immunity. The innate immune system provides rapidly activated host defenses triggered largely by cell-surface carbohydrates found only on microorganisms. These carbohydrates are structurally and immunologically distinct from the surface carbohydrates of mammalian cells. Innate immunity is phylogenetically older and has often been viewed as a vestige of ancient antimicrobial systems made redundant by the evolution of acquired immunity. This notion is now being challenged by the elucidation of key mechanisms of innate immunity and by the discovery of important functional connections between innate and acquired immune responses. Research Objectives and Scope The objective of this PA is to support innovative research on mechanisms of innate immunity. The scope of research to be supported by this PA includes, but is not limited to, the following broad areas: o the role of the innate immune system in regulating the onset, duration, magnitude, and character of acquired immune responses; o studies of the structure and function of antimicrobial products of the innate immune system; o characterization of newly recognized mechanisms and effectors of innate immunity; and o studies of the genetic control of innate resistance to infection. Progress in these general areas would provide a better understanding of the functional links between innate and acquired immunity, and would lead to new approaches for immunomodulation, vaccine development, and design of broad-spectrum antimicrobial agents. Examples of specific advances and promising areas for further investigation include, but are not limited to, the following: o studies to define the mechanisms by which complement binding promotes antigen trapping and antigen presentation and renders microbial antigens orders of magnitude more immunogenic for humoral immune responses; o design and development of novel vaccine candidates incorporating complement components; o studies of the antimicrobial activities of leukocyte and epithelial defensins and design and development of defensin-like antimicrobials; o studies of the genetic regulation, structure, and function of mannose binding protein (MBP), a serum opsonin that promotes the ingestion and killing of bacteria and viruses; production of MBP is genetically controlled, varies widely in man, and correlates with innate resistance to infection; o studies to determine the mechanisms of mast cell mediated antimicrobial defenses, a newly identified function of mast cells; and based on this knowledge, development of novel strategies to boost respiratory, gastrointestinal, and urogenital immunity; o studies of a recently identified gene, called Nramp1, that regulates murine innate resistance to intracellular pathogens; Nramp1 homologs have been found in species ranging from Drosophila to man, but their role in determining susceptibility to human infectious diseases remains to be established. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority group 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 or the purpose of the research. This policy results from the NIH Revitalization Act 1993 (Section 4928 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 on the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the 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.nih.gov. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES". The PA number and the PA title must also be typed in section 2. The completed, signed original and five (5) 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) R29 applications must include at least three (3) 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 Centers (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 Review Procedures Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants. 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 review by the appropriate national advisory council. Review Criteria The five criteria to be used in the evaluation of grant applications are listed below. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; 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, and availability of funds. INQUIRIES Written, electronic and telephone inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Daniel Rotrosen, M.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Solar Building, Room 4A24 6003 Executive Blvd. Bethesda, MD 20892-7640 Telephone: (301) 496-8974 Fax: (301) 402-0175 Email: dr17g@nih.gov Dennis F. Mangan, Ph.D. Division of Extramural Research National Institute of Dental Research Bg. 45, Room 4AN-32F Bethesda, MD 20892-6402 Telephone: (301) 594-2421 (equipped with 24hr voice mail) FAX: (301) 480-8318 Email: Dennis.Mangan@nih.gov Direct inquiries regarding fiscal matters to: Maryellen Connell Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B28 6003 Executive Blvd. Bethesda, MD 20892-7610 Telephone: (301) 402-5576 Fax: (301) 480-3780 Email: mc40u@nih.gov Mr. Martin Rubinstein Division of Extramural Research National Institute of Dental Research Natcher Building, Room 4AN-44A Bethesda, MD 20892-6402 Telephone: (301) 594-4800 FAX: (301) 480-8301 Email: Martin.Rubinstein@nih.gov AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301(c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citation is No. 93.855 - Immunology, Allergy, and Transplantation Research, and No. 93.121 - Oral Diseases and Disorders Research. Awards will be administered under PHS grants policies and Federal Regulations 24 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 Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace 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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