COMPETITIVE SUPPLEMENTS: ORAL DIMENSIONS OF HIV TRANSMISSION, THERAPIES, AND
OUTCOMES

NIH GUIDE, Volume 26, Number 40, December 19, 1997

RFA:  DE-98-001

P.T.

National Institute of Dental Research

Letter of Intent Receipt Date:  March 1, 1998
Application Receipt Date:  March 26, 1998

PURPOSE

The National Institute of Dental Research (NIDR) invites competitive grant
supplement applications to address critical gaps in knowledge concerning the
role of the oral environment in HIV transmission, the etiology and treatment
of HIV- related oral symptoms and neuropathic pain, and dental interventions
which may contribute to treatment adherence or clinical outcomes.  These
supplements are expected to enrich scientifically or to extend the scope of
relevant NIH-funded research grants supporting biological, biomedical,
behavioral, or epidemiological studies.  The primary (parent) grants being
supplemented may be funded by any of the Institutes or Centers of the National
Institutes of Health (NIH).

Through this Request for Applications (RFA) NIDR seeks to stimulate
collaborative studies capitalizing on current NIH- wide investments in HIV
research by building upon resources already available (e.g., tissue samples,
cohorts of HIV+ or high risk subjects with well- delineated medical data,
pediatric or adult clinical trials testing drugs or drug combinations). 
Studies are specifically encouraged on oral mucosal immunity, mechanisms
underlying the development of HIV-related oral opportunistic infections,
prevention of oral HIV transmission, improved therapies for oral opportunistic
infections, mechanisms underlying and treatments for HIV-related neuropathic
pain, and dental care-based interventions to enhance prevention, symptom
management, or clinical outcomes in HIV.

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, Competitive Supplements: Oral
Dimensions of HIV Transmission, Therapies, and Outcomes, is related to the
priority areas of HIV infection and oral health.  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 Office, Washington, DC 20402-9325
(telephone 202-512-1800.

ELIGIBILITY REQUIREMENTS

Supplements may only be made to NIH-supported research project (R01), program
project (P01), and cooperative agreement (U01) grants.  The principal
investigator for the grant identified for supplementation (i.e., "parent"
grant) must provide assurances that the proposed project is technically and
administratively feasible as an adjunct to the ongoing project. For example,
if collaborative expertise or research resources (e.g., tissue samples, data
sets, or access to HIV+ or high-risk cohorts) are required to implement the
supplement project successfully, documentation of the characteristics,
quality, and availability of these resources must be fully addressed in the
application.

The minimum number of years remaining on the parent grant should be no less
than one year at the award date for the supplement application (March 26,
1998). Projects are expected to fit within the broad aims of the approved,
funded parent grant and extend to dental/oral research. Grants related to
dental/oral research topics may also be supplemented (e.g., to expand the
specific aims or use new methods), although supplement applications that
merely propose minor methodological changes or expansions in sample size will
not be considered responsive.

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 or local governments, and eligible
agencies of the Federal Government.  Foreign organizations that have current
NIH-support grants are eligible to apply, and domestic applications may
include international components.  The NIDR encourages applications that
include investigators who are racial/ethnic minority individuals, women, and
persons with disabilities.

MECHANISM OF SUPPORT

The competitive supplement (S1) mechanism will be utilized. Total costs are
expected to be significantly less than they would be if the proposed project
were an independent R01.

Supplement applications proposing secondary analyses of existing data, pilot
studies, small clinical studies or any projects with total budgets (direct and
indirect) less than $50,000 may follow an abbreviated application format
outlined under Application Procedures.  All other competitive supplement
applications will be expected to utilize the usual application format for R01
submissions, irrespective of the size or duration of the requested support.

This RFA may be re-issued in FY 1999.

FUNDS AVAILABLE

The estimated total costs (directs plus indirect costs) available for
applications submitted in response to this RFA will be up to $1.5 million. The
NIDR plans to support a total of up to 15 competitive supplements in response
to this RFA in FYs 1998.  The total number of awards will be contingent on the
receipt of high quality competitive supplement applications and the
availability of funds.  Applications may not request more than three percent
annual increases for inflation over subsequent years. Usual PHS policies
governing grants administration and management will apply.  Funding beyond the
first and subsequent years of the supplement grant will be contingent upon
satisfactory progress during the preceding year and the availability of funds.

RESEARCH OBJECTIVES

Background

The HIV pandemic has already had a major impact on health and health care
demands both world-wide and in the U.S. According to the World Health
Organization, 22 million men, women and children are infected with HIV-1
worldwide, and the number of infected people is expected to exceed 40 million
by the year 2000.  It is estimated that 8,500 new HIV infections occur every
day.

The NIDR is already committed to supporting research projects on the oral
manifestations of HIV infection  and AIDS. Specifically, the Institute
supports a modest number of studies examining biological mechanisms underlying
the establishment of oral pathologies associated with HIV infection, as well
as studies on the progression of the infection to AIDS in different patient
groups.  NIDR also supports studies characterizing the inhibitory salivary
proteins and the importance of oral fluids as sources of HIV inhibitory
factors and non-invasive diagnostic tests for HIV,  identifying oral
diagnostic markers for HIV, investigating the molecular events that transform
candida and other oral organisms from non-pathogenic to pathogenic forms,
sequencing the C. albicans genome, and developing new therapeutic strategies
to combat reoccurrence of Candida infections.  Also supported are studies on
oral mucosal immunity, salivary leukocyte protease inhibitor (SLPI),
mechanisms of retrovirus infection in exocrine tissue, and the use of
transgenic mice and other methods to elucidate the effect of HIV infections on
selected oral tissues.

In order to identify future opportunities in the areas of AIDS research
relevant to the mission of the NIDR an Ad Hoc Panel on AIDS Research was
convened April 24-25, 1997.  Panel members were drawn from academia, industry,
NIDR Council, other NIH Institutes and Federal agencies. The panel indicated
that the NIDR is uniquely positioned to pursue three important areas of AIDS
research, namely those involving oral transmission of HIV, opportunistic
infections of the oral cavity, and mucosal immunity and the development of
vaccines. In addition, supplements to HIV and non-HIV grants to apply
reagents, technologies and models for HIV were recommended.

Research Objectives and Scope

The overall objective of this RFA is to expand our understanding of the role
of oral factors in HIV transmission, therapies, and outcomes by supplementing
ongoing research grants.

The following research topics are provided as examples that would extend
research been funded by NIH in related areas. They are not listed in any
priority order and are not intended to be inclusive or restrictive.

Examine the role(s) that oral pathogens and oral co-morbidities play in
potentiating infection with HIV or in influencing treatment outcomes,
including response to the new antiretroviral therapies.

Assess tissue responses in bronchial, vaginal, rectal and other mucosal sites
as compared with the oral cavity in order to characterize unique and common
immunological parameters critical to HIV infection and HIV-associated
pathologies; explore the presence of chemokine receptors as well as the levels
of cytokines in these sites.

Assess viral load in oral fluids and compare with other body fluids (e.g.,
cervical/vaginal, breast milk, blood, semen) during both primary and chronic
HIV infection to determine whether or not it is sufficient to provide a
significant risk for infection via the oral route.

Develop improved measures to prevent or reduce risks for oral HIV transmission
(e.g., vertical transmission from HIV positive mothers to breast- feeding
infants).

Examine molecular mechanisms underlying HIV- associated immunosuppression
resulting in oral complications; elucidate the molecular mechanisms by which
HIV or HIV-associated immunosupression might affect the phenotypic variability
and pathogenesis of candida and the reactivation of HCMV, HSV, HPV, EBV, and
HHV8.

Determine effects of antiretroviral therapies as related to oral
manifestations of HIV infection or the expression of salivary genes and
proteins; determine whether tonsilar or other oral tissues serve as a
reservoir of HIV and monitor viral loads in specific oral tissues during
antiretroviral therapies.

Develop appropriate animal models and experimental strategies to assess events
underlying characteristics of HIV infection within oral tissues and HIV-
associated oral pathologies.

Determine the pathogenesis of opportunistic oral infections and analyze select
genomes (e.g., Candida and HHV8).

Determine the prevalence and clinical correlates of neuropathic pain in
medically and immunologically well-defined populations of HIV patients. 
Elucidate underlying mechanisms and test promising preventive or therapeutic
interventions.

Determine associations or common mechanisms which may exist between central
manifestations of neurotoxicity, such as HIV-related dementia and the
development of HIV-related neuropathic pain.

Develop innovative, improved measures to prevent or treat oral symptoms
impairing quality of life or causing discomfort/pain in patients undergoing
therapies for HIV or living with HIV; characterize relationships between oral
symptom relief and adherence to oral or systemic therapies.

Develop appropriate, effective palliative measures for oral symptom management
at the end of life or for use in settings such as hospices.

Develop and test interventions utilizing oral health care settings or oral
health personnel to deliver and reinforce health education messages pertinent
to HIV prevention or risk reduction.

Determine how oral symptoms (oral opportunistic infections, oral lesions,
xerostomia) or dental treatments influence eating behaviors, nutritional
status, or systemic health outcomes in HIV positive individuals.

Characterize the roles of socioeconomic status, age, dental hygiene,
behaviors, and poor nutrition in oral transmission.

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 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," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18,
1994, Volume 23, Number 11.

LETTER OF INTENT

Prospective applicants are asked to submit, by March 1, 1998, a letter of
intent that includes a descriptive title of the proposed research; the name,
mailing address, FAX number, email address, and telephone number of the
Principal Investigator; the identifies of other key personnel and
participating institutions and departments; and the number and title of this
program announcement.

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 is helpful in planning for the timely review of the applications.  It
helps NIDR staff to estimate the potential review workload and to avoid
possible conflicts of interest in the review.

The letter of intent is to be addressed to Dr. Eleni Kousvelari at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

The grant application form PHS 398 (rev. 5/95) is to be used in applying for
these competitive supplement grants. These forms are available at most
institutional offices of sponsored research and may also 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
301-710-0267, email ASKNIH@od.nih.gov. The forms are also available on the NIH
World Wide Web Home Page at
https://grants.nih.gov/grants/funding/phs398/phs398.html.

The RFA label available in the PHS 398 application kit must be affixed to the
bottom of the face page of the original and the original must be placed on top
of the entire package.  Failure to use this label could result in delayed
processing of the application such that it may no reach the review committee
in time for review.  In addition, in order to identify the application as a
response to the RFA, the RFA title (Competitive Supplements: Oral Dimensions
of HIV Transmission, Therapies, and Outcomes) and the number DE-98-001 must be
typed in item 2 of the face page of the application form and the face page of
the application form and the YES box must be checked.

The instructions accompanying Form PHS 398 must be followed as far as
possible.  However, applicants submitting competitive supplements with direct
costs budgets totaling less than $50,000 may follow an abbreviated application
format as summarized below:

o  the research plan (specific aims, background, significance, preliminary
studies, and research design and methods) may not exceed ten pages;

o  brief statements must be included indicating how the proposed supplement
will utilize resources available through the parent project and providing
assurance of access to collaborations or research resources available through
the parent grant;

o  graphs, diagrams, tables, charts and photographs must be included in the
body of the application.

Applicants must attach a letter from the program official of the Institute or
Center responsible for the parent grant indicating concurrence with the
request for consideration of the supplement.

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

CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants)
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 copies of the application must also
be sent to:

Dr. H. George Hausch
Extramural Program
National Institute of Dental Research
Natcher Building, Room 4AN-38D
45 Center Drive MSC 6402
Bethesda, MD  20892-6402

Applications must be received by the receipt date (March 26, 1998) in order to
receive consideration for funding in FY98.

REVIEW CONSIDERATIONS

Review Procedures

Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR), NIH.  Incomplete and/or unresponsive applications
will be returned without further consideration.

Applications that are complete and fit the requirements specified in this RFA
will be evaluated for scientific and technical merit by a special emphasis
panel convened by the Scientific Review Branch, NIDR.  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
National Advisory Dental Research Council.

Review Criteria

The five criteria to be used in the evaluation of grant applications are
listed below (see NIH GUIDE, Vol. 26, No. 22, June 27, 1997).  An additional
criterion, specific for this RFA, evaluates the relevance of the supplement to
overall aims of the parent grant, as well as the likelihood of integrating the
supplemental study successfully into the ongoing research of the parent grant.
To put the criteria in context, the following information is provided 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 and 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.

Relevance to the parent grant: Is this proposed competitive supplement
relevant to the overall aims the parent grant? Are the plans for integrating
the parent project and the supplement feasible? Is there evidence that the
principal investigator of the parent project will provide appropriate
cooperation and support to the investigator conducting the oral research
component(s) supported by the supplement? Does the investigator proposing the
supplement demonstrate an understanding of the strengths or limitations of
data from the parent study, as directly pertinent to the proposed study?

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?

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?

Innovation:  Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

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)?

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 will also examine the appropriateness of proposed 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

The earliest anticipated date of award is September 30, 1998. Applicants
should be aware that, in addition to scientific merit, program priorities and
program balance, the total cost of the proposed project and the availability
of funds will be considered by the NIDR staff and the National Advisory Dental
Research Council in making funding recommendations.  In addition, the NIDR
values complementary funding from other public and private sources including
foundations and industrial concerns.  When applications have similar
scientific merit, but vary in cost- competitiveness, the NIDR is likely to
select the more cost-competitive application for funding.

INQUIRIES

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

For information concerning supplements which aim to focus on genetic,
molecular, or biological aspects of oral response to HIV/AIDS please contact:

Dr. Eleni Kousvelari
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN 18A
Bethesda, MD  20892-6402
Telephone:  (301) 594-2427
FAX:  (301) 480-8318
Email:  kousvelari@de45.nidr.nih.gov

Inquiries regarding applications on interventions within oral health care
settings, of prevention and management of oral symptoms, including pain or
inquires regarding applications addressing social, behavioral, cultural,
epidemiological, economic, or environmental issues relevant to oral
complications of HIV or HIV-associated neuropathies may contact:

Dr. Patricia Bryant
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN-24E
Bethesda, MD  20892-6500
Telephone:  (301) 594-2095
FAX:  (301) 480-8318
Email:  BryantP@DE45.nidr.nih.gov

Inquiries regards grants management issues should be directed to:

Mr. Martin R. Rubinstein
Division of Extramural Research
National Institute of Dental Research
45 Center Drive, Room 4AN-44A, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
Email:  RubinsteinM@DE45.nidr.nih.gov

Schedule

Letter of Intent Receipt Date:  March 1, 1998
Application Receipt Date:       March 26, 1998
Scientific Review Date:         June 1998
Advisory Council Date:          September 1998
Earliest Award Date:            September 30, 1998

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.121.  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 52 and 45 CFR Part 74.  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 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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