INNOVATIVE RESEARCH IN HUMAN MUCOSAL IMMUNITY

Release Date:  July 19, 1999

RFA:  AI-99-011

National Institute of Allergy and Infectious Diseases
National Institute of Dental and Craniofacial Research
Crohn's and Colitis Foundation of America

Letter of Intent Receipt Date:  October 15, 1999
Application Receipt Date:  November 16, 1999

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

The National Institute of Allergy and Infectious Diseases NIAID) and the
National Institute of Dental and Craniofacial Research (NIDCR), National
Institutes of Health (NIH) and the Crohn's and Colitis Foundation of America
(CCFA) invite applications for exploratory/developmental research project
grants to attract new investigators and support novel research into
understanding the human mucosal immune system.  The projects should involve a
high degree of innovation, risk and novelty, as well as a clearly articulated
potential to improve understanding of the human mucosal immune system. 
Investigators new to the field of human mucosal immunity are particularly
encouraged to develop projects in this area.  Research projects will be
supported with the exploratory/developmental research grant mechanism, which
provides the resources to carry out preliminary tests of feasibility for new
research hypotheses, and a rapid and streamlined review and award process.

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, Innovative Research in Human
Mucosal Immunity, is related to the priority area(s) of immunization and
infectious diseases; HIV infection; and sexually transmitted diseases.
Potential applicants may obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign 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.  Racial/ethnic
minority individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.

MECHANISM OF SUPPORT

Specific application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and detailed instructions and information on Modular Grant
applications can be found at
https://grants.nih.gov/grants/funding/modular/modular.htm

The mechanism of support will be the Exploratory/Developmental Research
Project Grant (R21) award.  The total requested project period for an
application submitted in response to this RFA may not exceed two years.

Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant.

NIAID and NIDCR use R21 grants to provide short-duration support for
preliminary studies of a highly speculative nature, which are expected to
yield, within this time frame, sufficient information upon which to base a
well-planned and rigorous series of further investigations.

Applications will request direct costs in $25,000 modules, up to a total
direct cost request of $150,000 per year.  A typical modular grant application
will request the same number of modules in each year.

This RFA is a one-time solicitation.  Future competing renewal applications
will compete with all investigator-initiated applications and will be reviewed
according to customary referral and review procedures.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for the first
year of support for all awards made under this RFA will be $3,100,000.  In
Fiscal Year 2000, approximately 15 awards are expected to be awarded by the
co-sponsors.  The usual PHS policies governing grants administration and
management will apply.  Although this program is provided for in the financial
plans of the NIAID, NIDCR, and CCFA, awards pursuant to this RFA are
contingent upon the availability of funds for this purpose and the receipt of
a sufficient number of applications of high scientific merit.  Funding for the
second year of the grant will be contingent upon satisfactory progress during
the preceding year and availability of funds.

RESEARCH OBJECTIVES

Background

The mucosal surface, which includes the oral, respiratory, gut, and urogenital
epithelia, is the first and most important interface between pathogens and the
host. The majority of infectious agents enter the body through mucosal
surfaces in these sites.  However, the immune system must distinguish between
potentially harmful agents and numerous innocuous environmental and food
antigens.  In fact, it has been recognized for a number of years that exposure
to antigen via the oral route can result in unresponsiveness or tolerance. 
Thus, there is increasing interest in the use of the oral administration of
antigens to induce tolerance to prevent or treat various autoimmune diseases. 
In contrast, it is known that oral administration of certain infectious agents
such as poliovirus can elicit protective systemic immunity, and this route is
now encouraged in vaccines for the production of immunity to infectious
agents.

The specific mechanisms by which one antigen leads to tolerance and another to
immunity are unknown.  Evidence that communication and coordination occur
between the various mucosa, i.e., oral, gut, nasal, and genital, is now
becoming clear.  Further understanding of the mechanisms by which immunization
via the gut induces immunity in the reproductive tract could lead to new
approaches to both vaccines for induction of immunity or tolerance.

Much is known about the details of the mouse mucosal immune system.  However,
the human immune system is inherently more complex and there are major
differences in the frequency of cell types and anatomy between the species
which limit the ability to use knowledge of murine immunology to advance
understanding or prevention of human disease. This is particularly relevant to
human inflammatory diseases of the intestine. Several murine models of mucosal
inflammation have fortuitously arisen from genetically engineered animals with
defects in regulatory T cell populations or cytokines.  Whereas the systemic
immune system appears to tolerate these deletions, the mucosal immune system
responds with an active inflammatory process.  Understanding the differences
in systemic versus mucosal immune regulation would go along way in helping us
to understand the pathogenesis of inflammatory bowel disease.

Research Objectives and Scope

The objective of this initiative is to increase our understanding of the human
mucosal immune system through two practical goals: 1) increase the number of
innovative and novel projects on human mucosal immunity, and 2) attract new
investigators to this field.  Research projects will be supported with the
exploratory/developmental research grant mechanism.  This provides
short-duration support for preliminary studies of a highly speculative nature
which are expected to yield, within the 2 year time frame, sufficient
information upon which to base a well-planned and rigorous series of further
investigations.

Relevant research includes, but is not limited to, the following:

Identification of mucosal antigen specific cells and characterization of the
expression of receptors and cytokines by these cells during tolerogenic vs.
immunogenic responses.

Antigen processing, presentation, and expression of co-stimulatory molecules
by mucosal antigen-presenting cells.

Evaluation of mechanisms for communication and trafficking between the various
sites of the common mucosal immune system and between the mucosal and systemic
immune systems.

Characterization of novel types of immunoregulatory cells in mucosa, including
the role of gamma delta T cells, mucosal dendritic cells, macrophages,
epithelial cells, and other cells in mucosal immune responses.

Application of cutting edge non-invasive or minimally invasive technologies
(e.g. microarray technology, various forms of bioimaging) to mucosal sites.

Assessment of regulatory defects in human and murine models of mucosal
inflammation, such as those which might occur in inflammatory bowel disease.

Role of mucosal immunity in mediating or ameliorating destructive inflammatory
responses.

Interactions of acquired mucosal immunity with the host natural innate immune
system, such as macrophages, cytokines and defensins.

Studies on regionalization with regard to functional links between inductive
sites and effector sties of mucosal immunity.

The areas outlined above are not intended to be all-inclusive.

NOTE: Studies in animal models are not within the scope of this RFA.  Studies
involving infectious agents, including HIV, are not specifically excluded, but
the focus must be on the human mucosal immune system.

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,
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 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", 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 which is available via the WWW. at:
https://grants.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html

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 which is available at the following
URL address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by October 15, 1999, 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 NIH 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. Madelon Halula at the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applicants are strongly encouraged to call NIH staff with any questions
regarding the responsiveness of their proposed project to the goals of this
RFA.

APPLICATION PROCEDURES

The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach.  The
just-in-time concept allows applicants to submit certain information only when
there is a possibility for an award. It is anticipated that these changes will
reduce the administrative burden for the applicants, reviewers and Institute
staff.

The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants, with the modifications, including a 15-page limit
for the research plan, noted below.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $150,000 per year.  The total direct costs must
be requested in accordance with the program guidelines and the modifications
made to the standard PHS 398 application  instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $150,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative  (F&A) costs] for the initial budget
period Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required and
will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample
pages.) At the top of the page, enter the total direct costs requested for
each year.  This is not a Form page.

o Under Personnel, List key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided. However, the applicant should use the NIH appropriation language
salary cap and the NIH policy for graduate student compensation in developing
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000. List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of key personnel, and the role
on the project. Indicate whether the collaborating institution is foreign or
domestic. The total cost for a consortium/contractual arrangement is included
in the overall requested modular direct cost amount.  Include the Letter of
Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for all
key personnel, following the instructions below. No more than three pages may
be used for each person. A sample biographical sketch may be viewed at:
https://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

RESEARCH PLAN - The research plan (a-d) is limited to 15 pages.  Applications
that exceed the page limit will be returned without review.  An appendix may
be included in the application; however, the appendix is not to be used to
circumvent the page limit of the research plan.

o CHECKLIST - This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the type
of agreement and the date. All appropriate exclusions must be applied in the
calculation of the F&A costs for the initial budget period and all future
budget years.

o The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED
UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.

Applications are to be submitted on the grant application for PHS 398 (rev.
4/98).  These forms are available at most institutional offices of sponsored
research; from the Division of Extramural Outreach and Information Resources,
National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD
20892-7910, telephone 301/710-0267, email: grantsinfo@nih.gov; and on the
internet at https://grants.nih.gov/grants/funding/phs398/phs398.html.

For purposes of identification and processing, item 2a on the face page of the
application must be marked "YES" and the RFA number "AI-99-011" and the words
"INNOVATIVE RESEARCH IN HUMAN MUCOSAL IMMUNITY" must be entered on the face
page.

The RFA label and line 2 of the application should both indicate the RFA
number.  The RFA label 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.

The sample RFA label available at:
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to
allow for this change.  Please note this is in pdf format.

Applications must be received by November 15, 1999.

Applications not received as a single package on the receipt date or not
conforming to the instructions contained in PHS 398 (rev. 4/98) Application
Kit (as modified in, and superseded by, the special instructions below, for
the purposes of this RFA), will be judged non-responsive and will be returned
to the applicant.

If the application submitted in response to this RFA is substantially similar
to a grant application already submitted to the NIH for review, but that has
not yet been reviewed, the applicant will be asked to withdraw either the
pending application or the new one.  Simultaneous submission of identical
applications will not be allowed, nor will essentially identical applications
be reviewed by different review committees.  Therefore, an application that is
essentially identical to one that has already been reviewed cannot be
submitted in response to this RFA .  This does not preclude the submission of
substantial revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.

Submit a signed, typewritten original of the application, 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 mail or courier service)

At the time of submission, two additional exact copies of the grant
application and all five sets of any appendix material must be sent to Dr.
Madelon Halula at the address listed under INQUIRIES.

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 should be included with the application.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness and adherence to
the Special Instructions above by the NIH Center for Scientific Review and for
responsiveness by NIH staff; those judged to be incomplete or not in the
format specified in this RFA will be returned to the applicant without review. 
Those considered to be non-responsive will be returned without review.

Those applications that are complete and responsive may be subjected to a
triage by an NIH peer review group to determine their scientific merit
relative to other applications received in response to this RFA.  The NIH will
withdraw from competition those applications judged to be non-competitive for
award and will notify the applicant and institutional business officials.

Those applications judged by the reviewers to be competitive for award will be
reviewed for scientific and technical merit by a review committee convened by
the Division of Extramural Activities, NIAID.  The second level of review will
be provided by the National Advisory Allergy and Infectious Diseases Council
and the National Advisory Dental and Craniofacial Research Council.

Review Criteria

The five criteria to be used in the evaluation of grant 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 children, 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.

The personnel category will be reviewed for appropriate staffing based on the
requested percent effort. The direct costs budget request will be reviewed for
consistency with the proposed methods and specific aims. Any budgetary
adjustments recommended by the reviewers will be in $25,000 modules. The
duration of support will be reviewed to determine if it is appropriate to
ensure successful completion of the requested scope of the project.

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. 
The earliest anticipated date of award is July 1, 2000.

INQUIRIES

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

Direct inquiries regarding programmatic (research scope and eligibility)
issues to:

Elaine Collier, M.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Room 5135 - MSC 7640
Bethesda, MD  20892-7640
Telephone:  (301) 496-7104
FAX:  (301) 402-2571
Email:  ec5x@nih.gov

Dennis F. Mangan, Ph.D.
Division of Extramural Research
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN-32F
Bethesda, MD 20892-6402
Telephone: 301 594-2421
Fax: 301 480-8318
Email: Dennis.Mangan@nih.gov

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

Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Room 2150 - MSC 7616
Bethesda, MD  20892-7616
Telephone: 301-402-2636
Email: mhalula@niaid.nih.gov

Direct inquiries regarding fiscal matters to:

Sharie Bernard
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Room 2246 - MSC 7614
Bethesda, MD  20892-7614
Telephone: 301-402-5540
Fax: 301-480-3780
Email: sb34k@nih.gov

Martin R. Rubinstein
Division of Extramural Research
National Institute of Dental Research
Building 45, Room 4AN-44A
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
Fax:  301 480-8301
Email:  Martin.Rubinstein@nih.gov

Schedule

Letter of Intent Receipt Date:  October 15, 1999
Application receipt date:       November 16, 1999
Scientific review date:         March 2000
Advisory Council date:          June 2000
Earliest award date:            July 1, 2000

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 Citations are Sec. 93.856, Microbiology and Infectious
Diseases Research, No.93.121 - Oral Diseases and Disorders Research, and 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 Public Health Service 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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