Full Text DE-94-009


NIH GUIDE, Volume 23, Number 34, September 23, 1994

RFA:  DE-94-009

P.T. 34

  Oral Diseases 
  Biology, Molecular 

National Institute of Dental Research

Letter of Intent Receipt Date:  December 15, 1994
Application Receipt Date:  January 18, 1995


The National Institute of Dental Research (NIDR) encourages studies
leading to a better understanding of the reactions of the pulp-dentin
complex in health and disease and how these tissues are involved in
responding to various challenges.  A thorough understanding of pulp
biology, its normal function and physiology, and its pathology and
its interaction with the immune system is decisive for the success of
operative dentistry and endodontics.  The intent of this Request For
Application (RFA) is to stimulate research in both basic and applied
disciplines of dentistry by multi-methodological approaches.  This
aim can be achieved through interactions by researchers in such
fields as cell biology, neurophysiology, operative dentistry, and
endodontics, in academia, government, and industry.


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,
Research on the Biology of the Pulp, is related to the priority area
of oral health.  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).


Applications may be submitted by domestic and foreign, for-profit and
non-profit, public and private organizations, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Foreign institutions and organizations are not eligible for the First
Independent Research Support and Transition (FIRST) awards (R29).
Domestic applications may include international components.
Applications from minority individuals and women are encouraged.
Applicants must meet special eligibility requirements specified in
the pertinent guidelines for the various mechanisms available for
support of this program.


This RFA will use the National Institutes of Health individual
research project grant (R01) and the FIRST (R29) award.  The earliest
possible date for funding is December 1, 1995.  Because the nature
and scope of the research proposed in response to this RFA may vary,
it is anticipated that the size of an award will vary also.  This RFA
is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all other
investigator-initiated research grant applications and may be peer
reviewed according to the customary peer review procedures.

Responsibility for the planning, direction and execution of the
proposed research will be solely that of the applicant.  The total
project period for applications submitted in response to the present
RFA may not exceed five years.


Approximately $800,000 to $1,000,000 in direct costs per year for up
to five years will be committed to fund applications that are
submitted in response to this RFA.  It is anticipated that six to
seven awards will be made.  The level of funding is dependent on the
receipt of a sufficient number of applications of high scientific
merit.  Although this program is provided for in the financial plans
of the NIDR, the award of grants pursuant to this RFA is also
contingent upon the availability of funds for this purpose.



Over twenty seven million root canal treatments costing more than $3
billion were performed in the United States during the last decade.
This number will increase in the future due to population growth and
greater numbers of teeth being preserved in older patients.  In
addition to conditions requiring removal of the pulp, many people
experience dentin hypersensitivity in reaction to normally
non-painful heat or mechanical stimulation.  This has been attributed
to a variety of causes, including pulp-dentin pathology, fluid
movements through tubules, and excessive nerve excitability.

An unusual combination of features makes the dental pulp a unique
model for research.  The pulp is extensively supplied with nerve
fibers, a rich blood supply, and is surrounded by dentin making it an
important model for the study of pain, inflammation, and the movement
of fluids, bacteria, or their products through the dentinal tubules.
The tooth is a hollow, porous hard tissue embedded in bone,
projecting through an epithelial membrane into a septic environment.
However, in spite of research advances during the last decade, there
is limited understanding of the reactions of the pulp-dentin complex
during pathologic states such as acute or chronic inflammation,
dentin hypersensitivity and nerve excitation.  This leads to an
inability to diagnose correctly the pathologic state of the pulp
according to clinical symptoms.  More information is needed on pulpal
reactions to restorative procedures and consequent regeneration and
repair reactions.

Although significant advances in the field have been made, further
research is needed.  For example, immunohistochemical analyses have
led to a better understanding of the mechanisms of antigen
presentation and processing, but little is known about pulpal
reaction to infection and immunologic responses or pulpal injury, in
general, in both normal and immunocompromised patients.  Future
studies should focus on possible interactions between immune cells in
the pulp and the pulpal neurovascular system.  Using molecular
biology techniques, significant progress has been made in
understanding the mechanisms which regulate the terminal
differentiation of odontoblasts.  However, the mechanism of action of
non-collagenous proteins of odontoblast origin in dentogenesis, and
in mineralization, in particular, is not well understood.  More
research is needed in this area to determine how these proteins
modulate odontoblast differentiation, migration, adhesion,
extracellular matrix production and secretion during both development
and repair of dentin.  Biochemical analysis is providing information
about the neurochemical and humoral factors involved in the control
of pulpal blood flow and the factors important in tissue response to
damage, but continued studies are needed.

Based on recommendations from the NIDR Long-Range Research Plan for
the Nineties, as well as recommendations of both the NIDR's Dental
Research Programs Advisory Committee and the International Conference
on Pathobiology of the Dentin/Pulp Complex, the NIDR plans to
strengthen its support of both basic and clinical research in the
broad area related to this announcement.  Accordingly, applications
are invited for individual research project grants, and FIRST Awards,
related to, but not limited to, the following areas:

Dentin Hypersensitivity

o  hydraulic conductance of dentinal tubules and the dynamics of
hydrodynamic stimulation of mechanoreceptor nerves.

o  the effect of oral hygiene procedures and non-invasive operative
procedures on dentin sensitivity.

o  the etiology of dentin hypersensitivity as a function of age and
immune suppression.

Pulpal Reactions to Restorative Materials

o  the effect of nerve innervation on pulp reactions and pulp

o  the reactive sprouting of sensory nerves in the pulp as a result
of operative procedures and restorative materials.

o  the effect of hydraulic conductance in the dentinal tubules on the
odontoblast layer, the junctional complexes between odontoblasts, and
the release of neuropeptides.

o  the stimulation of secondary odontoblast differentiation and their
function in reparative dentin formation.

Reactivity of Periapical Pulp Tissue

o  the difference between the structure and function of the apical
portion of the pulp and those of the radicular pulp and the apical
periodontal membrane.

o  the reactivity and healing capacity of periapical tissues.

o  nerve sprouting in periapical tissue following trauma.

o  the application of immunohistochemical techniques in the studies
of dentin resorption.

Normal and Abnormal Dentinogenesis

o  development of odontoblast cell lines in vitro to elucidate the
genetic regulatory mechanisms involved in odontoblast
differentiation, modulation and regulation of odontoblast function,
secretion of the dentin matrix, and its mineralization to make
normal, reparative, and peritubular dentin.

o  development of cell cultures from undifferentiated pulp cells to
study mechanisms involved in their differentiation into functional

o  characterization of the protein matrix formed by secondarily
differentiated odontoblast and its effect on mineralization of

Dentin/Pulp Complex Reactions

o  the role of growth factors in normal pulp-dentin development and
in pathological states.

o  cell-cell communication in the pulp among odontoblasts,
mesenchymal cells, immune-competent cells, neurons, endothelial and
perivascular cells.

o  the ultrastructure of normal and reparative dentin in response to
growth factors and their receptors, as a function of age.

o  nerve distribution, nerve type and expression of nerve growth
factors, cell-cell communication between and among odontoblast,
neurons and endothelial cells in health and disease.

o  assessment of the healing potentials of the pulp at different ages
and under a variety of experimental conditions using
multi-methodological approaches.

o  the dynamics of wound healing and repair in the pulp at various
ages, including the synthesis and assembly of proteins and their

Pulpal Reactions:  Regulatory and Immunological Factors

o  immunodefenses in the pulp, including mechanisms of antigen
presentation, processing and responses, and changes in these
processes as a function of normal aging and in immunocompromised

o  development of pulpal and periapical models to identify and
characterize the bacteria and bacterial products that cause
inflammation.  The conditions under which pulpal disease may be
reversible.  The long-term consequences of chronic periapical
inflammation on bone and pulpal nerves(neuromas).

o  the use of dentinal fluid to indicate the state of pulpal
metabolism and/or the presence of pulpal inflammation by measuring
changes in the levels of immunoglobulins, cytokines, or lysosomal

o  the expression and regulation of stress or heat shock proteins in
pulpal tissues.

o  determination of the way in which the regulatory proteins modulate
odontoblast differentiation, migration,  adhesion and matrix
synthesis, secretion and its mineralization.


o  the role of nitric oxide in the control of pulpal blood flow and
the effects of free radicals in the pulpal response to injury.
Definition of the role of neuropeptides and endogenous mediators of
inflammation on neurovascular activity of the normal tooth pulp,
following injury and during repair.

o  development of noninvasive methods to quantitatively determine
pulpal blood flow, dentin fluid flow and composition, and sensory
functions in animals and humans, in acute and chronic disease states.

o  the effects of systemic vascular diseases, such as sickle cell
anemia and diabetes, on pulpal circulation.

o  the development of the microcirculation, innervation, and dentin
ultrastructure and the effect of aging on the dental pulp.

o  the transport of various sized molecules through the dentin into
the systemic circulation and vice versa,  in innervated and
denervated teeth.

Sensory Physiology

o  definition of the role and characteristics of inflammatory
mediators, neuropeptides, and the autonomic nervous system, in the
normal tooth pulp, after injury and during repair.

o  the mechanisms of sensory transduction within the pulp in normal
and pathological states.

o  clarify the role of A and C fibers in tooth pulp, to determine the
central pathways, relay centers, and reflex responses evoked by their
activation, to determine the mechanisms of sensory transduction in
pulpal nerves in normal and in pathological states.

o  the effects of tooth pulp pathophysiology on central nervous
system processing of pulpal nerve input, such as the relation between
tooth pulp loss and chronic pain, referred pain, and altered central
nervous system excitability following periapical inflammation.


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

Investigators also may obtain copies from of the policy from the
program staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.


Prospective applicants are asked to submit, by December 15, 1994, 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 NIDR 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. Joyce A. Reese at the address listed


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; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
(301) 710-0267.  The RFA label available in the PHS 398 (rev. 9/91)
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 YES box must be
checked and the RFA number and the words, "Research on the Biology of
the Pulp" must be typed in Section 2a on the face page of the

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

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

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

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

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

Applications must be received by January 15, 1995.  If an application
is received after that date, it will be returned to the applicant.


Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by NIDR staff.  Incomplete applications will be
returned to the applicant without further consideration.  If NIDR
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/program director
and the official signing for the applicant organization will be
promptly notified.  Secondary review will be by the National Advisory
Dental Research Council.

Major factors to be considered in the evaluation of applications

o  scientific, technical, or medical 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 resources necessary to perform research;

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


The anticipated date of award is September 1, 1995.  Applicants
should be aware that, in addition to scientific merit, program
priorities and program balance, the total cost of the project to the
NIDR will be considered by NIDR staff and the Council in making
funding recommendations.  Furthermore, the NIDR appreciates 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.  Such
circumstances will be considered in making any award.


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:

Joyce A. Reese,  D.D.S, M.P.H.
Extramural Program
National Institute of Dental Research
Westwood Building, Room 509
Bethesda, MD  20892
Telephone:  (301) 594-7648

Direct inquiries regarding fiscal matters to:

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

Inquiries regarding review issues may be directed to Dr. H. George
Hausch at the address listed under APPLICATION PROCEDURES.


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 78410, 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

The Public Health Service strongly encourages all grant recipients to
provide a smoke-free work place 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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