Full Text PA-97-073
 
MUCOSAL IMMUNITY IN PATHOGENESIS/PREVENTION OF HUMAN DISEASE
 
NIH GUIDE, Volume 26, Number 23, July 18, 1997
 
PA NUMBER:  PA-97-073
 
P.T. 34

Keywords: 
  Immunology 
  Pathogenesis 
  Disease Prevention+ 

 
National Institutes of Health
 
PURPOSE
 
The National Institutes of Health (NIH) invite applications for
investigator initiated basic and preclinical research into the human
mucosal immune system and its regulation. Included are the
gastrointestinal, oral, respiratory, reproductive, and urinary
mucosa, with their specialized lymphoreticular structures and cells.
The goal of this announcement is to increase high quality research on
the mechanisms of response of the human mucosal immune system to
disease specific antigens.  Use of primate models may be appropriate.
Increased understanding of the human mucosal immune system and its
response in disease and to exogenous factors should allow the design
of more rational immunotherapies and vaccines for the treatment or
prevention of autoimmune and infectious diseases, including HIV
infection and its complications.
 
HEALTHY PEOPLE 2000
 
Each NIH PA addresses one or more of 22 Health Promotion and Disease
Prevention priority areas identified.  These areas can be found via
the WWW at URL:  http://www/crisny.org/health/us/health7.html
 
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 Transition (FIRST) awards (R29).  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
 
MECHANISMS 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 and applications for R29 grants 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
 
The mucosal surface, which includes the oral, respiratory, synovial,
gut, urinary and reproductive epithelium, is one of the first
important interfaces between pathogens and the host, and as such is
critical in prevention of infectious disease.  M cells, specialized
epithelial cells at the mucosal surface, serve as a portal of entry
for proteins, peptides, and microbes.  Further understanding of the
regulation and role of these cells could lead to new approaches to
prevent infection.
 
IgA is the major immunoglobulin found at the mucosal surface, but
other immunoglobulins may play a role in protection against infection
at mucosal surfaces.  Recently, it has been suggested that IgA, in
addition to its traditional role in the lumen, may be important in
the intraepithelial neutralization of viruses.  As IgA traverses the
epithelial cell, it may encounter virus intracellularly, where it has
the potential to neutralize the pathogen.  This idea could lead to
innovative approaches to prevent infectious diseases, particularly
those caused by intracellular pathogens.
 
Mucosal inflammation underlies several human diseases.  Recently,
various animal models of intestinal inflammation have been produced.
One interesting finding is that several of these animal models do not
develop disease if kept in germ-free conditions, suggesting that
environmental microbes are involved in the activation of mucosal
inflammation.  Further investigation of these animals should provide
more insight into the pathogenesis of inflammatory bowel diseases.
In addition, it has recently been found that Helicobacter pylori
infection is responsible for mucosal inflammation leading to
development of gastric and duodenal ulcers.  Further understanding of
the interaction of this organism with the mucosa could offer insight
into the balance involved between prevention of infection and
initiation of pathological mucosal inflammation. Chronic inflammation
can result from the interaction of pathogens or other exogenous
agents and urogenital cells.  Further understanding of these
responses could lead to a significant increase in the quality of
women's health.
 
There is increasing use of the oral route for administration of
antigens for production of immunity to infectious agents.
Paradoxically, oral antigen administration may also result in the
development of tolerance to prevent or treat various autoimmune
diseases.  Factors that determine whether the outcome is immunity or
tolerance induction and the mechanisms responsible for each outcome
are not well defined.  Evidence that communication and coordination
among the various mucosa, i.e., nasal, respiratory, gut, urinary, and
genital, occur is now becoming persuasive.
 
Immunization in the gut may induce immunity in the reproductive
tract. The mechanisms responsible for such communication are not
known, but further understanding could lead to new approaches to
vaccines for induction of immunity or novel immunotherapies leading
to tolerance.
 
Lymphocytes that traffic to the mucosa express specific proteins
called integrins, while high endothelial venules of Peyer's patches
and mesenteric lymph nodes, but not peripheral lymph nodes, express
specific addressins, which are the receptors for the integrins.
Thus, these molecules are involved in the homing of specific
lymphocytes to the mucosa.  Increased information about this homing
system, including regulation of these molecules, may allow
manipulation to prevent detrimental mucosal inflammation or target
immune responses.
 
Defensins, which are antimicrobial and cytotoxic peptides, are
produced by phagocytes and by epithelial cells of the lung, the gut,
the oral cavity, and possibly the genitourinary tract.  These natural
antibiotics can kill microorganisms and offer another defense for the
host at mucosal surfaces.  The discovery of new defensins important
in the reproductive, respiratory, and genitourinary tract, and more
detailed understanding of their regulation may allow new approaches
to the control of pathogens.
 
Research Objectives and Scope
 
The goal of this Program Announcement is to increase basic
understanding of the human mucosal immune system and its regulation.
Studies that focus on the pathogenesis of human diseases related to
dysregulation of this system are also sought.
 
This information should allow the development of novel immune
therapies for treatment or prevention of autoimmune and infectious
diseases, including HIV infection and associated opportunistic
infections.
 
Examples of areas of research interest responsive to this PA include,
but are not limited to:
 
o  trafficking and homing of lymphocytes to and from mucosal surfaces
and the role of such trafficking in human infection, disease, and
recovery;
 
o  characteristics of relevant antigen and/or antigen presentation
that lead to the development of systemic tolerance or immunity when
antigen is administered orally;
 
o  role of IEL (intraepithelial lymphocytes) in the development of
tolerance or immunity;
 
o  production, secretion, and function of IgA and other
immunoglobulins in human mucosal immunity;
 
o  characterization of defensins and their function in the immune
response to foreign antigen at mucosal surfaces;
 
o  role of microbes in initiating mucosal inflammation;
 
o  mechanisms by which the normal microbial flora becomes
established, avoids immune clearance, establishes tolerance, and
affects the immune response to a pathogen;
 
o  mechanism of pathogen strain differences that increase or decrease
infectivity at mucosal versus systemic sites;
 
o  identification of humoral and cellular immune responses that might
be effective in preventing microbe or viral  transmission via mucosal
surfaces;
 
o  development and analysis of various vectors and vaccine strategies
designed to induce a specific mucosal immune response to disease
antigens that could protect against infection;
 
o  refinement and development of additional methods and reagents to
evaluate mucosal immunity in humans.
 
Animal models, including primate models, are appropriate in response
to this PA ONLY if they have clear relevance to the human system.
Use of primate models in defining the immunobiology of protection
against immunodeficiency viruses is within the scope of this PA.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
See NIH Guide of March 18, 1994 for requirements for inclusion of
Women and Minorities in research.  It is available via the WWW at
URL: http://www.nih.gov/grants (select NIH Guide for Grants and
Contracts).
 
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.  The PHS 398
application kit can be accessed from the World Wide Web at:
http://www.nih.gov/grants/funding/phs398/phs398.html
 
For purposes of identification and processing, item 2 on the face
page of the application must be marked "YES".  The PA number and
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 APPLICANTS ONLY.  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.
 
ALL APPLICANTS REQUESTING $500,000 OR MORE IN ANNUAL DIRECT COSTS.
The NIH Policy Update on Acceptance for Review of Unsolicited
Applications that Request More Than $500,000 Direct Cost for Any One
Year applies to applications in response to this PA.  The Policy
Update was published in the NIH Guide for Grants and Contracts,
Volume 25, No. 14, May 3, 1996, and became effective June 1, 1996.
Potential applicants must contact the appropriate program staff
listed in INQUIRIES below to initiate clearance processes for
acceptance of their applications.
 
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 to NIH Institutes and Centers 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
 
The goals of NIH-supported research are to advance our understanding
of biological systems, improve the control of disease, and enhance
health.  In the written review, comments on the following aspects of
the application will be made 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 in the assignment of the overall score.
 
(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?
 
In addition, the adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific
goals of the research will be reviewed.  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, the safety of the research
environment, and conformance with the NIH Guidelines for the
Inclusion of Women and Minorities as Subjects in Clinical Research.
 
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.
 
SPONSORS AND INQUIRIES
 
Each sponsoring Institute/Center is identified below.  A staff
contact for electronic and telephone is listed and inquiries
regarding programmatic (research scope, eligibility and
responsiveness) issues are encouraged.  The opportunity to clarify
any issues or answer questions from potential applicants is welcome.
 
National Heart, Lung, and Blood Institute
Hannah Peavy, M.D.
Tel:  (301) 435-0222
Fax:  (301) 480-3557
Internet: hp8z@nih.gov
 
National Institute on Aging
Anna McCormick, Ph.D.
Tel: (301) 496-6402
Fax: (301) 402-0100
Internet:  am38k@nih.gov
 
National Institute of Allergy and Infectious Diseases
Allergy, Immunology, and Transplantation
Elaine Collier, M.D.
Tel: (301) 496-7104
Fax: (301) 402-2571
Internet:  ec5x@nih.gov
 
AIDS
Patricia Fast, M.D., Ph.D.
Tel: (301) 435-3727
Fax: (301) 402-3684
Internet:  pf13i@nih.gov
 
Microbiology and Infectious Diseases
Dennis Lang, Ph.D.
Tel: (301) 496-7051
Fax: (301) 402-1456
Internet:  dl73v@nih.gov
 
National Institute of Arthritis and Musculoskeletal and Skin
Diseases
Susana Serrate-Sztein, M.D.
Tel: (301) 594-5032
FAX: (301) 480-4543
Internet:szteins@ep.niams.nih.gov
 
National Institute on Deafness and Other Communication
Kenneth Gruber, Ph.D.
Tel: (301) 402-3458
FAX: (301) 402-6251
Internet:  kg37m@nih.gov
 
National Institute of Dental Research
Dennis F. Mangan, Ph.D.
Tel:  (301) 594-2421
FAX:  (301) 480-8318
Email:  Dennis.Mangan@nih.gov
 
National Institute of Diabetes, Digestive and Kidney
Frank A. Hamilton, M.D., M.P.H.
Tel:  (301) 594-8877
FAX: (301) 480-8300
EMAIL: hamiltonf@ep.niddk.nih.gov
 
Office of Research on Women's Health, NIH
Katrina Johnson, Ph.D.
Tel:  (301) 402-1770
FAX:  (301) 402-1798
EMAIL:  kj48y@nih.gov
 
AUTHORITY AND REGULATIONS
 
Research under this announcement will be supported under program
cited in the Catalog of Federal Assistance (CFDA).  The PHS portion
of the CFDA is available at URL:
http://odphp.osophs.dhhs.gov/cfda/index.htm.  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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