Full Text DE-94-008

RESEARCH ON PERIODONTAL COMPLICATIONS OF DIABETES MELLITUS

NIH GUIDE, Volume 23, Number 27, July 22, 1994

RFA:  DE-94-008

P.T. 34

Keywords: 
  Diabetes 
  Periodontal Diseases 
  Pathogenesis 
  Etiology 


National Institute of Dental Research
National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  October 21, 1994
Application Receipt Date:  November 22, 1994

PURPOSE

The National Institute of Dental Research (NIDR) and National Institute
of Diabetes and Digestive and Kidney Diseases (NIDDK) invite
investigator-initiated grant applications to conduct multidisciplinary
basic and clinical research on the periodontal complications of
diabetes mellitus (DM).  One purpose of this initiative is to further
our understanding of the pathogenesis of periodontal diseases
associated with DM.  Another purpose is to increase research on the
effects of periodontal diseases on glucose metabolism in diabetics.
Investigators who are well-trained in the modern techniques of cellular
and molecular biology are encouraged to focus their expertise and work
closely with oral clinicians on issues directly related to the
diagnosis, etiology, pathogenesis, and treatment of periodontal
diseases associated with DM.

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), Research on Periodontal Complications of
Diabetes, is related to the priority areas of oral health and diabetes
and chronic disabling conditions.  Potential applicants may obtain a
copy of "Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0)
or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, non-profit and
for-profit, public and private organizations, such as dental or medical
schools, universities and research institutions.  Foreign institutions
are not eligible for the First Independent Research Support and
Transition (FIRST) (R29) Award.  Applications from minority individuals
and women are encouraged.

MECHANISM OF SUPPORT

The mechanisms available for the support of research in response to
this RFA are the traditional research project grant (R01), and the
FIRST (R29) award.  Responsibility for the planning, direction, and
execution of the projects will be solely that of the applicants.  This
RFA is a one-time solicitation.  Future unsolicited continuation
applications will compete with all investigator-initiated applications
and be reviewed according to the customary peer review procedures.  The
project period for applications submitted in response to this RFA may
not exceed five years for R29 grants and four years for R01 grants.  A
maximum of three years may be requested for foreign awards.  Applicants
for R01 grants must limit their request to not more than $160,000
direct costs for the initial budget period.

FUNDS AVAILABLE

For Fiscal Year 1995, $1.0 million total costs will be committed by the
NIDR to fund applications submitted in response to this RFA.  An
additional $200,000 will be committed by the NIDDK.  Depending on the
receipt of a sufficient number of applications of high scientific
merit, an estimated five awards will be made.  Although this program is
provided for in the financial plans of the NIDR and the NIDDK, the
award of grants pursuant to this RFA is contingent upon the
availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

In April 1993, the NIDR convened a Dental Research Programs Advisory
Committee (PAC) in Bethesda, Maryland, which addressed the issue of
research on the periodontal complications of systemic diseases.  The
PAC recognized that diabetes may affect the progression and treatment
of periodontal diseases.  A subsequent review of the literature
published since 1985 indicated that there have been approximately 260
publications on oral complications or conditions associated with DM.
Approximately 75 percent of the papers reported investigations on the
effects of DM on periodontal disease.  In particular, the incidence of
aggressive and difficult to treat forms of periodontitis is
well-documented in patients with DM.  Epidemiological studies have
clearly shown that periodontal diseases tend to be more prevalent, more
severe, and progress more rapidly in persons with diabetes than in
non-diabetic subjects.

Periodontitis is now recognized as one of the six major complications
of diabetes.  It appears that although all diabetics may be at a higher
risk for periodontal diseases than the general population, certain
subgroups are at particularly high risk, including individuals who do
not maintain good oral hygiene, individuals with other complications of
diabetes such as retinopathy, neuropathy, individuals with a history of
poorly controlled diabetes, and teenagers and pregnant women undergoing
fluctuations in hormonal levels.  A detailed epidemiological analysis
of periodontitis and tooth loss in the Pima Indians showed that the
incidence of diabetes-specific complications, poor glycemic control,
and severity of Type 2, non-insulin dependent diabetes mellitus (NIDDM)
are associated with increased risk of periodontitis.  Careful control
of blood glucose/insulin levels seems to reduce the periodontal
complications associated with DM.  Thus, the prevalence of periodontal
diseases in well-controlled diabetics is reportedly no higher than that
found in healthy control subjects.  The molecular and cellular basis
for the pathogenesis of periodontal diseases in uncontrolled DM
patients remains to be investigated.

While DM appears to have an impact on periodontal diseases, it also
appears to be true that oral infections associated with periodontitis
may destabilize the metabolic balance of the diabetic.  Diabetics with
infections tend to have difficulty in maintaining normal blood
glucose/insulin levels, and often experience hyperglycemia.
Understanding the association between infections in the oral cavity and
impaired metabolic control is central to attaining effective therapy
for the diabetic patient.

Scope

Applications may address any objective that would advance the
diagnosis, etiology, pathogenesis or treatment of periodontal
complications of diabetes.  Because research in this area can involve
several scientific specialties, including microbiology, immunology,
physiology, endocrinology, cell biology, and clinical medicine and
dentistry, collaboration of investigators having expertise in these and
other appropriate disciplines is encouraged.  Large-scale
epidemiological studies and clinical trials are specifically excluded
from this RFA.

Because Type 1, insulin-dependent diabetes mellitus (IDDM) and NIDDM
are pathologically and genetically different, studies that examine the
molecular and cellular basis of periodontal complications of both types
of diabetes are encouraged.

A selection of research topics appropriate for responses to this RFA is
given below.  This list is illustrative and not exclusive, restrictive,
or in priority order.  Investigators are encouraged to submit
scientifically meritorious applications in any area of research
responsive to the overall research objectives of this RFA.

o  Identification of unique host products in the gingival crevicular
fluid or saliva of diabetics that can be used as a non-invasive
prognostic or diagnostic indicators of periodontal diseases.

o  Molecular and cellular characterization of the effects of diabetes
on the humoral and cellular immune effector systems in the oral cavity.

o  Oral tissue regeneration and wound healing in subjects with
diabetes.

o  Identification of drugs, growth factors, cytokines, or biological
response modifiers that can be used therapeutically to repair the
damaged periodontal tissues.

o  Development of well-characterized diabetic animals systems and ex
vivo and in vitro tissue models to study periodontal complications.

o  Clarification of the microbiological and biochemical role of
calculus in the onset of periodontitis in diabetic subjects.

o  Characterization of the effect of diabetes on the periodontal
vasculature.

o  Role of diabetes in abnormal collagen metabolism in the
periodontium.

o  Characterization of the immune response of diabetics to purified
oral microbial components.

o  Studies that specifically address periodontal diseases in minority
populations at high risk for DM (e.g. Hispanics, African-Americans and
Native Americans).

o  Investigations on the association of periodontal diseases with
gestational diabetes.

o  Role of periodontal diseases in control of glucose metabolism in
diabetics.

STUDY POPULATIONS

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 new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43)
and supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations, and Concerning the Inclusion
of Minorities in Study Populations) which have been in effect since
1990.  The new policy contains some new provisions that are
substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research", which has been published in the Federal
Register of March 9, 1994 (FR 59 11146-11151), and reprinted in the NIH
GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the program
staff or contact person listed below.  Program Staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are encouraged to submit, by October 21, 1994,
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 this RFA.

Such letters are requested only for the purpose of providing an
indication of the number and scope of applications to be reviewed;
therefore their receipt is usually not acknowledged.  A letter of
intent is not binding, and it will not enter into the review of any
application subsequently submitted, nor is it a necessary requirement
for the application.

The letter of intent is to be sent to Dr. Dennis Mangan at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form, PHS 398 (rev. 9/91), is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research, as well as from the Office
of Grants Information, Division of Research Grants (DRG), National
Institutes of Health, Westbard Building, Room 449, Bethesda, MD 20892,
telephone (301) 710-0267.

The RFA label available in the PHS 398 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 must be typed on line 2a of the face page of
the application form and the YES box must be marked.

Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete and
will be returned without 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 should be included with the application.

A signed original copy of the application, and three signed
photocopies, must be submitted in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Also send two copies of the completed application to:

H. George Hausch, Ph.D.
National Institute of Dental Research
Westwood Building, Room 519
Bethesda, MD  20892
Telephone:  (301) 594-7632
FAX:  (301) 594-7601

Applications must be received by November 22, 1994.  If an application
is received after that date, it will be returned to the applicant
without review.  The DRG 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.
Applications that have been reviewed, but not funded, can be
resubmitted provided substantial revisions have been made and the
application contains an introduction section addressing the previous
critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG and
responsiveness by NIDR and NIDDK.  Incomplete applications will be
returned to the applicant without further consideration.  If NIDR or
NIDDK staff find that the application is not responsive to the RFA, it
will be returned 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 NIDR in accordance with the review
criteria stated below.  As part of the initial merit review, a process
(triage) 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 promptly notified.  Following scientific-technical
review, competitive applications will receive a second level review by
the NIDR and NIDDK Advisory Councils unless not recommended for further
consideration by the initial review group.

Review criteria for this RFA are generally the same as those for
unsolicited research grant applications and include:

o  scientific, technical, or clinical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal Investigator
and staff, particularly, but not exclusively, in the area of the
proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  responsiveness to the RFA objectives.

Schedule

Letter of Intent Receipt Date:   October 21, 1994
Application Receipt Date:        November 22, 1994
Initial Scientific Review:       March 1995
Council Review of Applications:  May 1995
Earliest Possible Funding:       September 1, 1995

AWARD CRITERIA

The anticipated award date is September 1, 1995.   The following will
be considered in making funding decisions:

o   Merit of the proposed project as determined by peer review
o   Availability of funds
o   Program priorities of the funding ICD

The value of complementary funding from other public and private
sources, including foundations and industrial concerns, for activities
that will complement and expand those supported by the NIDR and NIDDK
is appreciated.

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 and address
the letter of intent to:

Dennis F. Mangan, Ph.D.
National Institute of Dental Research
Westwood Building, Room 509
Bethesda, MD  20892
Telephone:  (301) 594-7641
FAX:  (301) 594-9720
Email:  UFD@CU.NIH.GOV

Dr. Charles A. Wells
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 622
Bethesda, MD  20892
Telephone:  (301) 594-7505
FAX:  (301) 594-9011

Direct inquiries regarding fiscal matters to:

Ms. Theresa Ringler
National Institute of Dental Research
Westwood Building, Room 510
Bethesda, MD  20892
Telephone:  (301) 594-7629
FAX:  (301) 594-7600

Ms. Betty E. Bailey
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649
Bethesda, MD  20892
Telephone:  (301) 594-7543
FAX:  (301) 594-7594

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 Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

.

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