Full Text PA-97-079
NIH GUIDE, Volume 26, Number 24, July 25, 1997
PA NUMBER:  PA-97-079
P.T. 34


National Institute of Allergy and Infectious Diseases
National Institute of Dental Research
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).
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).
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.
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
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
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
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.
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
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.
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:
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:
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
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
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
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
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.
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, 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
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
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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