Full Text PA-97-091 IMMUNOLOGIC BASIS OF FOOD ALLERGY NIH GUIDE, Volume 26, Number 26, August 8, 1997 PA NUMBER: PA-97-091 P.T. 34 Keywords: Hypersensitivity Immunology Immunotherapy National Institute of Allergy and Infectious Diseases National Institute of Child Health and Human Development National Institute of Diabetes and Digestive and Kidney Diseases PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Child Health and Human Development (NICHD), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite applications for research studies on: (a) the mechanisms of mucosal immunity and of tolerance as they apply to food allergy; (b) the genetic basis of food allergy; (c) the molecular identification of food allergens and their epitopes; and (d) immunotherapeutic approaches to treating food allergy. The results of these investigations will be used to develop strategies to prevent food allergy and treat food-allergic patients. 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 (PA), Immunologic Basis of Food Allergy, is related to the priority area of nutrition. 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 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. Foreign institutions are not eligible for First Independent Research Support and Training (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) and FIRST award (R29) applications may be submitted in response to this PA. Applications for R01 grants may request up to five years of support; applications for FIRST (R29) awards must request five years of support. Responsibility for the planning, direction, and execution of the proposed research for all applicable mechanisms of support will be solely that of the applicant. RESEARCH OBJECTIVES Background This PA will support research to investigate mechanisms of allergic responses in food allergic individuals and to develop new strategies to prevent or diminish allergic responses in these individuals. Allergic diseases represent a major cause of morbidity and disability in the United States. Clinically significant food allergy, confirmed by blinded oral challenge, is associated with IgE antibodies to food and occurs in 1-2% of adults and in about 8% of American children under age 6. Life-threatening anaphylactic reactions occur in food-allergic individuals of all ages. Food allergy is the most frequent single cause of emergency room visits for anaphylaxis. Seven foods (milk, eggs, soy, fish, shellfish, nuts and peanuts) are associated with most food allergies, including severe reactions. For those at risk of severe allergic reactions to food, the only effective treatment is strict dietary avoidance, but deaths may occur even in individuals who attempt to avoid suspect foods. Deaths from severe food allergic reactions occur because: some patients are undiagnosed and/or unaware of their risk; some food products and some components of processed foods are not properly labeled; commercial food processing may allow trace (but unlabelled) contamination; and some food allergens are cross-reactive. Although allergen immunotherapy is useful for treating some allergic diseases, immunotherapy has not been proven beneficial in food allergy. Studies in animal models have defined components of the gastrointestinal mucosal immune system and have begun to characterize the circumstances and immunologic mechanisms whereby oral ingestion of antigen stimulates tolerance. However, there are no good animal models, analogous to human food allergy, in which oral ingestion of food stimulates IgE antibody responses. Research Objectives and Scope Research into the underlying mechanisms of food allergic reactions is needed because many important clinical observations about food allergy lack a sound scientific foundation. For example, some individuals become allergic to foods, even though the induction of oral tolerance is the normal response to repetitive dietary challenge. Although several food allergens have been cloned, it is not apparent from their primary structures why only a small number of allergens cause most food-allergic reactions. Allergy to some foods (e.g., milk, eggs) remits in childhood, while allergy to other foods(e.g., peanuts) persists throughout life. Recent research advances suggest that more effective approaches for controlling food allergies might now be developed by integrating basic studies, on such topics as mucosal immunity and tolerance, with clinical studies of food-allergic patients. These advances include: i) the ability to eliminate certain food allergens or allergenic epitopes from the food supply through genetic engineering; ii) the availability of transgenic and knockout mice to test the importance of specific cells and mediators; iii) the identification and cloning of an IgE-dependent histamine releasing factor, a molecule which is linked to severe allergies including allergies to foods; iv) novel approaches to immunization, such as DNA vaccines, which might preferentially stimulate TH1 responses and thus inhibit IgE antibody responses (which are TH2 dependent); and v) identification of a negative signal transduction pathway in basophils and mast cells, activated by cross-linking by immune complexes of both IgE and IgG receptors. Stimulation of negative signalling pathways may be a mechanism by which standard immunotherapy for allergic diseases is effective. Examples of research topics of interest and promising areas of investigation include, but are not limited to, the following: o tolerogenic mechanisms that can modulate immune responses to ingested antigens o studies of signalling pathways that mediate inhibition of mast cells, basophils, and T- and B-cells involved in food allergic responses o development of immunotherapeutic approaches which will result in effective treatment of food allergy o genetic analysis of food allergic patients o cloning and epitope analysis of food allergens o elucidating the mechanism(s) by which allergies to milk and eggs remit during childhood; and o development of animal model(s) of food allergy, including gastrointestinal IgE antibody responses to foods Since food allergies are most prevalent in infancy and childhood, applicants are encouraged to include pediatric populations in studies of the mechanisms of food allergies. 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. 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 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. 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 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) FIRST (R29) award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST (R29) award 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. 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 (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 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 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: Marshall Plaut, M.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4A25 Bethesda, MD 20892-7640 Telephone: (301) 496-8973 FAX: (301) 402-0175 EMAIL: mp27s@nih.gov Gilman D. Grave, M.D. Center for Research for Mothers and Children National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B-11 Bethesda, MD 20892-7510 Telephone: (301) 496-5593 FAX: (301) 480-9791 EMAIL: gg37v@nih.gov Frank A. Hamilton, M.D., M.P.H. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 6AN-12B, MSC-6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8877 FAX: (301) 480-8300 EMAIL: fh14e@nih.gov Direct inquiries regarding fiscal matters to: Sharie Bernard Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B32 6003 Executive Blvd. Bethesda, MD 20892-7610 Telephone: (301) 496-7075 Fax: (301) 480-3780 EMAIL: sb34k@nih.gov E. Douglas Shawver Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A-17, MSC-7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1303 Fax: (301) 402-0915 EMAIL: ds117g@nih.gov George Tucker Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 6AS-49B 45 Center Drive, MSC-6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8853 Fax: (301) 480-3504 EMAIL: gt35v@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance Nos. 93.855, 93.865, and 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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