Full Text PA-97-091
NIH GUIDE, Volume 26, Number 26, August 8, 1997
PA NUMBER:  PA-97-091
P.T. 34


National Institute of Allergy and Infectious Diseases
National Institute of Child Health and Human Development
National Institute of Diabetes and Digestive and Kidney Diseases
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.
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).
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.
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.
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
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
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.
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
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.
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) 435-0714, email:
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:
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
the proposed research.  If so, a letter of agreement from the GCRC
Program Director must be included in the application material.
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
(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.
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
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
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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