ASTHMA AND ALLERGIC DISEASES RESEARCH CENTERS

Release Date:  April 13, 1998

RFA:  AI-98-005

P.T.

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  August 17, 1998
Application Receipt Date:  November 24, 1998

APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST BE PREPARED
USING A MULTI-PROJECT GRANT APPLICATION FORMAT; SPECIFIC INSTRUCTIONS FOR
COMPLETING THE APPLICATION ARE IN AN NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR
APPLICATIONS FOR MULTI-PROJECT AWARDS.þ

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID), National
Institutes of Health (NIH), invites applications for Asthma and Allergic Diseases
Research Centers (AADRCs). This program is designed to support basic and clinical
research on mechanisms of, and treatment and prevention of, asthma and allergic
diseases. Applications are to be designed around a central scientific theme
demonstrating relevance to one or more of these diseases. A minimum of three
biomedical research projects must be proposed.

Under this RFA, competitive supplements will also be supported, for clinical
investigations of new tolerogenic and immunomodulatory approaches to prevent and
treat asthma and/or allergic diseases.

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 RFA, Asthma and Allergic Diseases
Research Centers (AADRC), is related to the priority areas of environmental
health, food and drug safety, diabetes and chronic disabling diseases, and
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 REQUIREMENTS

Research grant applications may be submitted by domestic for-profit and non-
profit organizations, public and private institutions, such as universities,
colleges, hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Foreign organizations are not
eligible to apply.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The mechanism of support will be the program project (P01) grant.  This type of
award supports broadly based multidisciplinary research programs that have a
well-defined central research focus or objective.  The program project grant
consists of a minimum of three interrelated individual research projects that
contribute to the program objective.  An important feature is that the
interrelationships among the individual scientifically meritorious projects will
result in a greater contribution to the overall program goals than if each
project were pursued individually. The award also can provide support for certain
common resources termed cores.  Such resources should be utilized by two or more
projects within the award.

Responsibility for the planning, direction, and execution of the proposed
projects will be solely that of the applicant.  The total project period may not
exceed five years.  At this time, the NIAID is administratively limiting the
duration of P01 grants to four years; this administrative limitation may change
in the future.  The earliest anticipated award date is September 1, 1999.

FUNDS AVAILABLE

The estimated total funds (direct and indirect) available for the first year of
support for this RFA will be $3,000,000.  In fiscal year 1999, the NIAID plans
to make approximately four awards related to this RFA.  This level of support is
dependent on the receipt of a sufficient number of applications of high
scientific merit.  Applications requesting budgets in excess of $750,000 in total
(direct and indirect) costs in the first year must obtain approval from the
Program Contact listed under INQUIRIES, prior to submission.

Limited Competition for Supplements.  In addition, there may be an estimated
total funds (direct and indirect) of $600,000 available for the first year of
support for competitive supplements, to grants funded by this RFA or to grants
which are already funded under the existing RFA for Asthma, Allergic and
Immunologic Diseases Cooperative Research Centers (RFA AI-96-005).  These
supplements will be for a maximum of two years of support.  In fiscal year 1999,
the NIAID plans to make approximately one or two of these supplemental awards. 
This level of support is dependent on the receipt of a sufficient number of
applications of high scientific merit.

The usual PHS policies governing grants administration and management will apply. 
Although this program is provided for in the financial plans of the NIAID, awards
pursuant to this RFA are contingent upon the availability of funds for this
purpose.  Funding beyond the first and subsequent years of the grant will be
contingent upon satisfactory progress during the preceding years and availability
of funds.  At this time, the NIAID has not determined whether or how this
solicitation will be continued beyond the present RFA.

RESEARCH OBJECTIVES

Background

Program Project Applications.  The Asthma, Allergy and Inflammation Branch of the
NIAID Division of Allergy, Immunology and Transplantation supports basic and
clinical research on mechanisms of hypersensitivity and inflammation and their
application to the diagnosis, prevention and treatment of asthma and allergic
diseases, including research on the immunologic mechanisms which induce and
regulate these diseases.  Recent advances in understanding the etiology and
pathogenesis of asthma and allergic and immunologic diseases present important
opportunities to gain fundamental knowledge and enhance its clinical application.

The NIAID's current Asthma, Allergic and Immunologic Diseases Cooperative
Research Centers (AAIDCRC) program supports ten extramural centers for research
on asthma and allergic diseases and two centers focusing on immunologic diseases. 
The AADRC program to be supported by this RFA is intended to replace the AAIDCRC
program by focusing on asthma and allergic diseases and immune and inflammatory
mechanisms related to these diseases.  Autoimmunity, immune deficiency, and
Demonstration and Education Research Projects are not within the scope of this
RFA.

The purpose of the AADRC program is to accelerate the development and application
of fundamental knowledge of the immune system to investigations of asthma and
allergic diseases.  The AADRCs provide an infrastructure and a collaborative
environment which make it possible to investigate complex clinical problems.  The
major goals of the program are to: 1) advance understanding of the etiology and
pathogenic mechanisms of asthma and allergic diseases, and 2) apply an expanded
knowledge base to the development of improved methods of diagnosis, treatment,
and prevention of asthma and allergic diseases.

Competing Supplement Applications.  Asthma and allergic diseases are excellent
models for devising approaches to alter the human immune response because many
of the important allergens have been identified, purified, cloned and expressed
as biologically active recombinant proteins.  Purified allergens and crude
allergen extracts can be given safely via mucosal and cutaneous routes in humans. 
Approaches that combine non-antigen-specific methods (e.g., second signal
blockade, cytokine modulation) and antigen-specific tolerance have not been
studied and may be uniquely effective in these diseases.  With these reagents,
timing, dose, route and molecular form of the allergen can be tightly controlled.

Although allergen immunotherapy has clinical efficacy, the value of
immunotherapy, and its benefits and risks, are controversial because of several
recent studies which demonstrate only modest or minimal beneficial effects of
immunotherapy in asthma.  One possible explanation is that conventional
immunotherapy does not induce sufficient alteration in the human immune response
to produce optimal clinical benefit.  Several strategies to induce immune
tolerance now appear promising in vitro and in animal models of allergic disease. 
For example, "DNA vaccines," comprised of plasmid DNA encoding recombinant
allergens, induce long-lasting allergen-specific tolerance in mice.

Research Objectives and Scope

Program Project Applications.  Applications must propose a minimum of three
research projects. The goal of this RFA is to support multidisciplinary research
programs focused on studies of human asthma and allergic diseases, including
investigations of the immunologic and other mechanisms underlying these diseases.
Projects that incorporate clinically relevant animal models may be included. At
least one of the research projects must focus on human immunologic studies.

Research topics of interest include, but are not limited to, the following:

o  the induction of T cell-mediated immune tolerance for asthma prevention and
treatment;

o  Fc-gamma-RIIB and other receptors that mediate negative signaling in mast
cells and other immune and inflammatory cells, thereby down-regulating allergic
responses;

o  the molecular and cellular mechanisms by which viruses and other þnon-
allergicþ stimuli cause airways inflammation in asthma;

o  identification and amelioration of the underlying genetic variants which
predispose to asthma and allergic diseases;

o  delineation of the role of cytokines and chemokines, T cell subsets and/or
adhesion molecules in human asthmatic and allergic inflammation and IgE
responses;

o  definition of the immune mechanisms for the development of hypersensitivity
diseases such as food allergy and drug reactions; and the identification of
experimental approaches to block these allergic diseases and, at the same time,
avoid the adverse reactions of standard immunotherapy; and

o delineation of the role of particulates and other pollutants in stimulating
immunologically mediated inflammation, including synergistic interactions with
allergens and viruses.

Competing Supplement Applications.  This RFA will also support supplements, with
a maximum of two years of support. Only those centers which have been funded
under this RFA or under the existing RFA for Asthma, Allergic and Immunologic
Diseases Cooperative Research Centers (RFA AI 96-005) are eligible to apply for
these supplements.  These supplements are for clinical studies for
immunologically based interventions in asthma and/or allergic diseases. For
further information, contact the Program Contact listed under INQUIRIES.

The objective of the clinical research to be supported is to assess the safety,
efficacy, mechanisms of action, and therapeutic effect of multiple approaches to
modulate the human immune response and/or induce antigen-specific tolerance in
asthma and/or allergic diseases, including, but not limited to, the following:

o  second signal blockade

o  cytokine modulation

o  DNA vaccines

Applications for competitive supplements should include the following components:

o  A proposed protocol for evaluating the safety and efficacy of novel and
promising tolerogenic and immunomodulatory interventions, including (1) the
rationale for the patient population, (2) the statistical calculations and
considerations in determining sample size, (3) the study design and the
therapeutic approach(es) selected for study, and (4) an assessment of how the
anticipated study results can be expected to contribute to improvements in
clinical outcome; and

o  Proposed adjunct studies of underlying mechanisms of action of the therapeutic
approaches proposed for evaluation.

Applications may also include proposed studies of immune and/or surrogate markers
of disease activity and/or responsiveness to therapy.

Applications for clinical components may by submitted by single institutions or
consortia of institutions.  Applications integrating clinical components with one
or more of the basic research components of the Program Project grant (under the
present RFA) and/or of the Cooperative Research Centers grant (under RFA AI 96-
005) are encouraged.

Provisions for a Data and Safety Monitoring Board should be included if indicated
by the scope of the proposed research.

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.

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators may obtain copies from these sources or from the Program Contact
person listed under INQUIRIES who may also provide additional relevant
information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by August 17, 1998, a letter of
intent that includes a descriptive title of the overall proposed research, the
name, address and telephone number of the Principal Investigator, and the number
and title of this RFA.  Although the letter of intent is not required, is not
binding, does not commit the sender to submit an application, and does not enter
into the review of subsequent applications, the information that it contains
allows NIAID staff to estimate the potential review workload and to avoid
conflict of interest in the review.  The letter of intent is to be sent to Dr.
Kevin Callahan at the address listed under INQUIRIES.

The letter of intent should also state whether the applicants intend to apply for
a competitive supplement for clinical investigation.

APPLICATION PROCEDURES

Program Project Applications must be submitted separately from Competing
Supplement Applications.

Program Project Applications.

Applications are to be submitted on the standard research grant application form
PHS 398 (rev. 5/95).  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 435-0714, email:
asknih@od.nih.gov.

For purposes of identification and processing, item 2 on the face page of the
application must be marked "YES" and the RFA number "AI 98-005" and the words
"ASTHMA AND ALLERGIC DISEASES RESEARCH CENTERS" must be typed in.

Applicants for P01 grants must follow special application guidelines in the NIAID
Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS
(September 1997); this brochure is available from NIAID staff listed in INQUIRIES
below and via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm

Applications must be received by November 24, 1998.  Applications that are not
received as a single package on the receipt date or that do not conform to the
instructions contained in PHS 398 (rev. 5/95) Application Kit (as modified in,
and superseded by, the NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR
MULTI-PROJECT AWARDS"), will be judged non-responsive and will be returned to the
applicant.  The RFA label available in the application form PHS 398 must be
affixed to the bottom of the face page.  Failure to use this label could result
in delayed processing of the application such that it may not reach the review
committee in time for review.

Competing Supplement Applications.

Applications are to be submitted on the standard research grant application form
PHS 398 (rev. 5/95).  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Grants Information
Office, Office of Extramural Outreach and Information, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301)
435-0714, email: asknih@od.nih.gov.

For purposes of identification and processing, item 2 on the face page of the
application must be marked "YES" and the RFA number "AI 98-005" and the words
"AADRC Competing Supplement" must be typed in.  Awardees under RFA AI 96-005 must
include the grant number of their parent AAIDCRC grant.

Applications must be received by November 24, 1998.  Applications that are not
received as a single package on the receipt date or that do not conform to the
instructions contained in PHS 398 (rev. 5/95) Application Kit will be judged non-
responsive and will be returned to the applicant.  The RFA label available in the
application form PHS 398 must be affixed to the bottom of the face page.  Failure
to use this label could result in delayed processing of the application such that
it may not reach the review committee in time for review.

Applicants from institutions that have a General Clinical Research Center (GCRC)
funded by the NIH National Center for Research Resources may wish to identify the
GCRC as a resource for conducting the proposed research.  If so, a letter of
agreement from either the GCRC program director or principal investigator could
be included with the application.

It is highly recommended that the appropriate NIAID Program Contact be consulted
before submitting the letter of intent and during the early stages of preparation
of the application.  (See program contact under "INQUIRIES").

Submit a signed, typewritten original of the application (P01 or Competing
Supplement), including the checklist, and three signed, exact, single-sided
photocopies, in one package to:

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

At the time of submission, two additional exact copies of the P01 grant
application and/or competing supplement application and all five sets of any
appendix material must be sent to Dr. Kevin Callahan at the address listed under
INQUIRIES.

Concurrent submission of an R01 and a Component Project of a  Multi-project
Application:  Current NIH policy permits a component research project of a multi-
project grant application to be concurrently submitted as a traditional
individual research project (R01) application.  If, following review, both the
multi-project application and the R01 application are found to be in the fundable
range, the investigator must relinquish the R01 and will not have the option to
withdraw from the multi-project grant.  This is an NIH policy intended to
preserve the scientific integrity of a multi-project grant, which may be
seriously compromised if a strong component project(s) is removed from the
program.  Investigators wishing to participate in a multi-project grant must be
aware of this policy before making a commitment to the Principal Investigator and
awarding institution.

SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO THIS RFA

Program Project (P01) Applications.  Applicants for P01 grants must follow
special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR
APPLICATIONS FOR MULTI-PROJECT AWARDS (September 1997); this brochure is
available via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm.

The brochure presents specific instructions for sections of the PHS 398 (rev.
5/95) application form that should be completed differently than usual.  For all
other items in the application, follow the usual instructions on pages 5-20 of
the PHS 398 booklet.

Competing Supplement Applications.  Applicants must use the specific instructions
in the PHS 398 (rev. 5/95) application.

REVIEW CONSIDERATIONS

Review Procedures

Upon receipt, applications will be reviewed for completeness by the NIH Center
for Scientific Review and for responsiveness by NIAID staff.  Incomplete and/or
non-responsive applications will be returned to the applicant without further
consideration.

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the NIAID in accordance with the review criteria stated below.  As part of the
initial merit review, a process may be used by the initial review group in which
applications will be determined to be competitive or non-competitive based on
their scientific merit relative to other applications received in response to the
RFA.

Applications judged to be competitive will be discussed and be assigned a
priority score.  Applications determined to be non-competitive will be withdrawn
from further consideration and the Principal Investigator and the official
signing for the applicant organization will be notified.  The second level of
review will be provided by the National Advisory Allergy and Infectious Diseases
Council.

Review Criteria

Program Project Applications.

The general criteria for P01 grant applications are presented in the NIAID
brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS
(September 1997).

Competing Supplement Applications.

The five criteria to be used in the evaluation of competing supplement
applications are listed below.  To put those criteria in context, the following
information is contained in instructions to the peer reviewers.

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; adequacy of
plans for including children as appropriate for the scientific goals of the
research; the provisions for the protection of human and animal subjects; and the
safety of the research environment.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and technical merit as
determined by peer review, program balance, and the availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.  The
opportunity to clarify any issues or questions from potential applicants is
welcome.

Requests for the NIAID brochure "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT
AWARDS" as well as 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) 402-2571
Email:  mp27s@nih.gov

Direct inquiries regarding preparation of the application and review issues, and
address the letter of intent to, and mail two copies of the application and all
five sets of appendices to:

Kevin Callahan, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C20
Bethesda, MD  20892-7610
Telephone:  (301) 496-8424
FAX:  (301) 402-2638
Email:  kc92t@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Sharie Bernard
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B32
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  sb34k@nih.gov

Schedule

Letter of Intent Receipt Date:  August 17, 1998
Application Receipt Date:       November 24, 1998
Scientific Review Date:         March 1999
Advisory Council Date:          May 1999
Earliest Date of Award:         September 1, 1999

AUTHORITY AND REGULATIONS

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.  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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