HOST IMMUNE RESPONSE TO OROPHARYNGEAL CANDIDIASIS

Release Date:  December 15, 1999

RFA:  DE-00-001

National Institute of Dental and Craniofacial Research 
http://www.nidr.nih.gov/ 

Letter of Intent Receipt Date: February 15, 2000
Application Receipt Date: March 15, 2000

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 Dental and Craniofacial Research (NIDCR) invites 
experienced and new investigators to submit research grant applications for 
basic and clinical investigations to further the understanding of the host 
immune response to oropharyngeal candidiasis (OPC).  Research in this 
targeted area will improve our understanding of infection, virulence and host 
responses to OPC, and lead to improved diagnosis, prevention and treatment 
strategies.  Collaborative projects that bring together investigators 
studying OPC in diverse scientific disciplines including microbiology, 
mycology, yeast genetics, innate and acquired immunology, biochemistry, 
pathology, genomic sequencing, imaging technology, and mathematical modeling 
are encouraged.  Applications that include collaboration with foreign 
scientists conducting unique research on OPC are also encouraged. 

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 Request for 
Applications (RFA), Host Immune Response to Oropharyngeal Candidiasis, is 
related to the priority area of Oral Health.  Potential applicants may obtain 
a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000.

ELIGIBILITY REQUIREMENTS

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.  Although an application must be submitted from a single 
institution, collaborative arrangements with other institutions are 
encouraged

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project 
grant (R01) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  The 
total project period for an application submitted in response to this RFA may 
not exceed 5 years.  This RFA is one-time solicitation.  Future unsolicited 
competing continuation applications will compete with all investigator-
initiated applications and be reviewed according to the customary peer review 
procedures.  New investigators are strongly encouraged to apply.  They should 
identify their status on the cover page for the application.  The anticipated 
award date is September 29, 2000. 

FUNDS AVAILABLE

The NIDCR intends to commit approximately $2 million in FY 2000 to fund 6 or 
7 new and/or competitive continuation grants in response to this RFA.  An 
applicant may request a project period of up to 5 years and a budget for 
direct costs of up to $200,000 per year.  Applicants with collaborative 
agreements at other domestic universities can apply for direct costs of up to 
$225,000, since facilities and administrative (F&A) costs on the consortium 
are included in the direct costs of the applicant.  Because the nature and 
scope of the research proposed may vary, it is anticipated that the size of 
each award will also vary.  Although the financial plans of the NIDCR provide 
support for this program, awards pursuant to this RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of applications 
of outstanding scientific and technical merit. 

RESEARCH OBJECTIVES

Background

Oropharyngeal candidiasis (OPC) (oral candidiasis, or thrush) occurs as an 
overgrowth of Candida, a yeast normally found in low numbers on the mucus 
membranes of the mouth and throat.  Disturbance in the commensal flora of the 
oral cavity or inadequate host immunity provides favorable conditions for OPC 
to occur.  Those at highest risk of OPC include persons with immunodeficiency 
(e.g. HIV-infected, AIDS), patients receiving antibiotics, or chemotherapy, 
neonates, diabetics, smokers and denture wearers.  OPC can lead to blood 
stream infections with subsequent severe and even fatal systemic diseases 
such as endocarditis, septicemia and meningitis.  OPC affects quality of life 
in that the white patches in the mouth are not only esthetically displeasing 
but also are associated with painful lesions that causes difficulty in 
chewing and swallowing, and thus affect nutrition.

An increase in the incidence of OPC was seen during the first part of the 
last decade as a result of the human immunodeficiency virus (HIV) type 1 
epidemic.  In one prospective study 84% of HIV infected patients had 
oropharyngeal colonization by Candida species on at least one occasion and 
55% developed clinical thrush.  Candida albicans is the organism isolated 
from most patients although other yeasts may sometimes cause clinical 
disease.  Most OPC infections are endogenously acquired, although in some 
cases, Candida can be transmitted from person to person.  While the incidence 
of OPC has decreased as a result of combined therapy, OPC is still an 
independent predictor of immunodeficiency in patients who have AIDS and may 
also be a predictor in patients with debilitated immune systems due to other 
disease processes. 

OPC is commonly treated with topical or systemic antifungal agents that 
ameliorate the disease, but do not necessarily eradicate colonization.  Thus, 
clinical recurrence of the disease is common.  It has been recently reported 
that azole drugs are failing to contain recurrent cases of OPC indicating 
that some Candida organisms may be developing drug resistance.  Other factors 
that might play a role in clinical resistance are diminished cellular 
immunity, drug interactions, or decreased drug absorption.  Re-establishment 
of cellular immunity reduces the incidence of OPC, providing hope that 
immunotherapies can be used to control this disease.  

The infective Candida strains tend to be genetically identical over time.  It 
has been reported that the same strain of Candida was isolated from 11 of 17 
patients with recurrent OPC infections, as measured by DNA probe analysis.  
Another study has shown that 60% of patients were colonized with one dominant 
strain of C. albicans and 74% of those patients were re-colonized with the 
same strain even after fungal therapy.  The strain of Candida that most 
commonly infects HIV positive patients also causes disease in those patients 
who do not have HIV infection.  These findings suggest that effective 
therapies, including immunization, might be targeted against selected strains 
of Candida that cause OPC.

The precise immunologic processes that control OPC in humans are not known.  
Research shows that innate immunity, including complement, histatins, 
defensins, and neutrophils, as well as adaptive immunity (antibodies and 
cellular immunity) are involved in host protection.  Immunological responses 
might also participate in the pathogenesis of OPC. Inflammation and tissue 
damage can also occur as a result of allergic or specific immune responses to 
Candida antigens.  

Host immunity to OPC represents an important yet understudied area for new 
research.  An improved awareness of the underlying mechanisms of host defense 
to Candida should lead to more effective diagnostic approaches and provide a 
better means of prevention and treatment for these organisms. The studies 
might ultimately lead to development of safe and effective vaccines.  
Understanding the host response may lead to new ideas about the management of 
this disease through immunotherapy or stem cell reconstitution.

Research Objectives and Scope

Research proposals submitted in response to this RFA must demonstrate that 
they are relevant to OPC and one or more of the following immunological 
topics:

? Candida antigenicity 
? Candida genetics (as it relates to immunity)
? Inflammation or wound healing 
? Neutrophils, macrophages, or other leukocytes
? Innate immunity
? Humoral immunity
? Cellular immunity
? Mucosal immunity
? Hypersensitivities/allergies
? Tolerance
? Autoimmunity 
? Immunization (passive or active) 
? Immunodeficiency
? Immunogenetics

Basic, clinical, epidemiological and behavioral research could be responsive 
to this RFA.  Although appropriate animal models may be used to acquire and 
evaluate the experimental data obtained, the development of a new animal 
model should not be the major focus of proposals submitted in response to 
this RFA.  Studies addressing solely the structure, physiology or genetics of 
Candida albicans would not be responsive to this RFA.

SPECIAL REQUIREMENTS

Awardees will be invited to attend a meeting to present the progress of the 
work funded under this program.  Details of this meeting will be provided 
post-award.  Applicants should include travel funds in their budgets for a 
two-day meeting every year, most likely to be held in Bethesda, Maryland, to 
meet with other NIDCR-supported researchers studying the oral complications 
of HIV-infection and AIDS. Applicants should also include a statement in 
their applications indicating their willingness to participate in these 
meetings.


INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women, members of minority groups and their 
sub-populations must be included in all NIH supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification is 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 in the NIH Guide 
for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the 
web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.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 is available at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.  
Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, and the number and title of the RFA in 
response to which the application may be submitted. Although a letter of 
intent is not required, is not binding, and does not enter into the review of 
a subsequent application, the information that it contains allows NIDCR staff 
to estimate the potential review workload and avoid conflict of interest in 
the review process.

The letter of intent receipt date is listed in the heading of this RFA and
is to be sent to the program staff listed under INQUIRIES.

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 (revised 4/98) is to be 
used in applying for these grants, with the modifications noted below.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $200,000 per year ($225,000 for applicants 
with consortium arrangements with other domestic universities.)  The modular 
budget request must be in accordance with 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 $200,000) 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 http://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 a 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:  
http://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;

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. 

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application. 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. In addition, the RFA 
title and number (DE-00-001) must be typed on line 2 of the face page of the 
application form and the YES box must be marked.  The RFA number must be 
typed on the label as well.

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

The NIAID also has active basic and clinical research programs focused on 
candidiasis, and will accept assignments in accordance with referral 
guidelines.

Submit a signed, typewritten original of the application, including the 
Checklist, and three (3) signed, photocopies, in one package to:

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

The telephone number is (301) 435-0715.  

At the time of submission, two (2) additional copies of the application must 
be sent to:

Dr. H. George Hausch
Scientific Review Branch 
Division of Extramural Research
National institute for Dental and Craniofacial Research 
45 Center Drive, Room 4AN-38D- MSC 6402
Bethesda, MD 20892-6402

Applications must be received by the application receipt date listed in the 
heading of this RFA. If an application is received after that date, it will 
be returned to the applicant without review.  The Center for Scientific 
Review (CSR) will not accept any application in response to this RFA that is 
essentially the same as one currently pending initial review, unless the 
applicant withdraws the pending application. The CSR will not accept any 
application that is essentially the same as one already reviewed. This does 
not preclude the submission of substantial revisions of applications already 
reviewed, but such applications must include an introduction addressing the 
previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness and 
responsiveness by the CSR and NIDCR.  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 NIDCR in accordance with the review criteria stated below.  
As part of the initial merit review, a process will be used by the initial 
review group in which applications 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 National Advisory Dental and Craniofacial Research 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 comments reviewers will be asked to discuss the following aspects 
of the application 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 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 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?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research. Plans for the recruitment and retention of subjects will also be 
evaluated.

o The reasonableness of the proposed budget and duration in relation to the 
proposed research

o The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project 
proposed in the application.

SCHEDULE: 

Letter of Intent Receipt Date: February 15, 2000
Application Receipt Date: March 15, 2000
Peer Review Date: May 2000
Council Review: August 2000
Earliest Anticipated Start Date: September 29, 2000

AWARD CRITERIA

Award criteria that will be used to make award decisions include:
o-scientific merit (as determined by peer review)
o-availability of funds
o-programmatic priorities.

INQUIRIES

Inquiries concerning this RFA are encouraged. The opportunity to clarify any 
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Denise Anne Russo, Ph.D. 
Infectious Diseases and Immunity Branch
Division of Extramural Research,
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-18B 
Bethesda, MD 20892-6402
Telephone: (301) 594-2617 
FAX: (301) 480-8318
Email: Denise.Russo@nih.gov

Direct inquiries regarding fiscal matters to:

Mr. Kevin Crist
Grants Management Branch
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-44A, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
FAX:  (301) 480-8301
Email: Kevin.Crist@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.121, Oral Diseases and Disorders Research Awards.  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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92. This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant 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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