THE PATHOGENESIS OF CHRONIC SINUSITIS

Release Date:  February 25, 1998

PA NUMBER:  PA-98-034

P.T.

National Institute of Allergy and Infectious Diseases
National Institute on Deafness and Other Communication Disorders

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID) and the
National Institute on Deafness and Other Communication Disorders (NIDCD),
National Institutes of Health (NIH), invite applications for basic, preclinical
or clinical studies to investigate the mechanisms of inflammation in chronic
sinusitis and, in particular, the role of viral and bacterial infections and of
non-infectious stimuli. This knowledge will be used to develop new strategies to
prevent or treat sinusitis.

Applications submitted in response to Program Announcements are assigned
according to established PHS referral guidelines.  When the subject of an
application is of interest to more than one component of NIH, dual assignments
are made.

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, The Pathogenesis of Chronic
Sinusitis, is related to the priority area of immunization and infectious
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 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.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

Traditional research project grant (R01) applications may be submitted in
response to this program announcement.  Applications for R01 grants may request
up to 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

Sinusitis is an important clinical problem, particularly because of its high and
increasing prevalence; it is the most frequently reported chronic disease in the
United States.  Sinusitis is classified into acute, subacute and chronic on the
basis of symptom duration. The distinctions between acute, subacute and chronic
forms are not clearly defined. In general, the term "chronic" sinusitis implies
a symptom duration of more than 12 weeks. The pathogenesis of chronic sinusitis
is not well understood and such patients are often difficult to treat
effectively.

Current understanding of sinus inflammation is limited and is based on human
models. The normal sinus is now known to be a major upper respiratory source of
nitric oxide, a molecule with antimicrobial activity which also probably
contributes to local inflammation. Eosinophils are the predominant inflammatory
cell type in sinus tissues of patients with chronic sinusitis, suggesting an
immunologic and possibly allergic etiology, although many patients with chronic
sinusitis are not sensitized to common aeroallergens. Patients with chronic
sinusitis also have rhinitis, and many have impaired smell sensitivity,
suggesting that nasal inflammation and abnormalities of the olfactory sensory
epithelium contribute to sinusitis. The stimuli which induce exacerbations of
sinusitis may include bacterial and viral infections, but the role of infection
in chronic sinusitis is uncertain. Non-infectious stimuli (such as antigens, and
also volatile substances including odorants and particulates) may induce immune
and inflammatory responses; however, the relevance of such stimuli to sinusitis
is also unknown. Patients with chronic sinusitis have elevated IgE levels. Many
patients with chronic sinusitis also have asthma, but the relationship between
these two diseases is not understood.

Several new technologies and experimental advances suggest that important
progress in understanding the pathogenesis of sinusitis can be achieved in the
near future. These include: (a) highly sensitive and specific assays (e.g., PCR)
to detect and identify infectious agents; (b) improved ability to measure
mediators and gene expression in epithelial and inflammatory cells from small
tissue samples; (c) imaging techniques, such as magnetic resonance imaging, to
detect sinus inflammation; (d) nasal endoscopy for sampling sinuses; and (e) new
insights into inflammatory mechanisms in asthma which may be useful for designing
studies in sinusitis.

Research Objectives and Scope

This PA is intended to foster research to investigate the mechanisms of
inflammation in chronic sinusitis, including associated inflammation of the nasal
and olfactory sensory epithelia and to develop new strategies to prevent or treat
sinusitis. Promising areas of research include, but are not limited to, studies
to:

o  Determine the inflammatory mediators produced by, and the inflammatory cells
recruited by, cells from normal versus inflamed sinuses;
o  Define the role of specific viruses and bacteria, and of odorants and
particulates, in the induction and/or exacerbation of sinus inflammation (e.g.,
analogous to rhinovirus-induced exacerbation of asthma);
o  Determine interactions of infectious and non-infectious (immunologic) stimuli
with host cells/receptors in inducing sinusitis, rhinitis and impairments in the
olfactory sensory epithelium;
o  Modulate the immune and/or inflammatory response to reverse chronic sinus
inflammation; and
o  Investigate the mechanisms and paranasal site of action of antiinflammatory
drugs, such as corticosteroids, that are used in the treatment of chronic
sinusitis.

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.

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 in 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@od.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 and five copies of appendices must be sent or delivered to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)

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 Center for Scientific Review.  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 Center for Scientific Review, 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.  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 among research areas of the announcement, 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 (research scope and eligibility) 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) 402-2571
Email:  mp27s@nih.gov

Rochelle Small, Ph.D.
Division of Human Communication
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400C MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 402-3464
FAX:  (301) 402-6251
Email:  rochelle_small@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Lesia Norwood
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B34
Bethesda, MD  20892-7610
Telephone:  (301) 402-6581
FAX:  (301) 480-3780
Email:  ln5t@nih.gov

Ms. Sharon Hunt
Division of Extramural Activities
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400B, MSC 7180
Bethesda, MD  20892-7170
Telephone:  (301) 402-0909
FAX:  (301) 402-1757
Email:  sh79f@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.855 and 93.173.  Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410), as amended by Public Law 99-
158, 42 USC 241 and 285) and administered under PHS grants policies and Federal
Regulations 42 CFR Part 52 and 45 CFR Part 74 and supported under authorization
of the Public Health Service Act, Sec. 301, as amended.  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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