Full Text DE-93-003


NIH Guide, Volume 22, Number 15, April 16, 1993

RFA:  DE-93-003

P.T. 04

  Oral Diseases 
  Molecular Genetics 
  Gene Therapy+ 
  Biology, Molecular 

National Institute of Dental Research

Letter of Intent Receipt Date:  September 24, 1993
Application Receipt Date:  October 21, 1993


The National Institute of Dental Research (NIDR) invites applications
for the support of Craniofacial Anomalies Research Centers to conduct
multidisciplinary, fundamental, and epidemiological research on genetic
aspects of the etiology of craniofacial anomalies.  The NIDR is
currently supporting three Craniofacial Anomalies Research Centers
whose approved funding periods will end on September 19, 1994.  The
present announcement establishes a new round of competition for a
five-year period of funding beginning as early as September 20, 1994.
This competition will be open to all domestic institutions, including
those proposing new Craniofacial Anomalies Research Centers as well as
those with existing centers.


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), Craniofacial Anomalies Research Centers, 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 non-profit, public and
private organizations, such as dental or medical schools, universities
and research institutions.  Applications from foreign institutions are
not eligible.  However, domestic applications may contain international
components. Applications from minority individuals and women are


The Craniofacial Anomalies Research Centers will be supported by
specialized center research grants (P50) for a period of five years,
commencing as early as September 20, 1994.  Responsibility for the
planning, direction, and execution of the proposed project 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.  This RFA is a one time solicitation.  Issuance of a
subsequent request for new and competing continuation applications is
contingent upon program needs and the availability of funds.  Further,
it is unlikely that the NIDR will be able to fund P01 grant
applications resulting from the amendment of unfunded applications
responding to this RFA.  A fuller statement of this policy is found in
the section titled "Amended Applications" prior to the end of this


It is estimated that $2,250,000 in total costs will be committed for
the first year of support for this program.  However, award of grants
is contingent upon receipt of appropriated funds for this purpose.  It
is anticipated that three awards may be made, some of which may be
competing continuation awards.

Applicants may request up to $500,000 in direct costs for the first
year.  Where indirect costs are assigned to a subcontract and counted
as direct costs on the parent grant, the allowable direct cost maximum
of $500,000 may be exceeded by the amount of indirect costs assigned to
the subcontract.  Applications that exceed these limits will be
returned without review.  Budget increases of no more than four percent
may be requested for each of the subsequent four years.  Policies
governing research grant programs of the National Institutes of Health
(NIH) will prevail.



Congenital malformations remain an important public health issue in the
United States.  Approximately five percent of newborn infants require
treatment for malformations associated with various parts of the body.
Prominent among these defects are structural, functional, or
biochemical abnormalities involving the head or face.  Cleft lip, with
or without cleft palate, and isolated cleft palate are among the most
widely known and common of these craniofacial defects, occurring in
approximately one in every 700 live births.

While syndromic cleft lip and/or palate can be associated with maternal
exposure to teratogens such as phenytoin and vitamin A derivatives, the
majority are nonsyndromic and are best explained by major autosomal
gene effects that may, in turn, determine susceptibility to exposures
to as yet unidentified teratogenic environmental factors.  Up to 20
percent of individuals with cleft lip or palate are associated with
syndromes characterized by defects affecting other body parts.  More
than 300 such syndromes have been identified with more than 50
appearing to be single gene disorders.  The gene in autosomal dominant
cases of nonsyndromic cleft lip, with or without cleft palate, has
recently been linked to chromosome 6.

Recent research has also identified the genetic basis for a variety of
disorders each of which involve the cleft lip and/or palate.  Genes for
Waardenburg syndrome, Van de Woude syndrome, and Stickler syndrome have
been isolated.  In contrast, only the chromosomal location of genes for
Treacher Collins syndrome, recessive cleft palate, Wolf-Hirschorn
syndrome, Rieger syndrome, diastrophic dysplasia, holoprosencephaly,
EEC syndrome, Smith-Magenis syndrome, and Shprintzen/VCF/George
syndrome has been determined.  Although genes for the latter disorders
have yet to be isolated and cloned, genes have recently been cloned for
fragile X syndrome, Marfan syndrome, osteogenesis imperfecta, and
Waardenburg syndrome.

A second major component of the public health problem associated with
congenital malformations is the fact that craniofacial anomalies other
than cleft lip and palate occur in one of every 1,600 newborns in the
United States.  These include jaw deformities, malformed or missing
teeth, defects in the ossification of facial or cranial bones, and
facial asymmetries.  A small proportion of these craniofacial
malformations can be traced to specific genetic or chromosomal
disorders.  Another group of malformations may result from
environmental factors such as malnutrition, maternal disease, exposure
to drugs and problems in pregnancy and delivery.  For the most part,
however, craniofacial malformations are viewed as having a
multifactorial basis, an interactive process in which particular genes
alter the ability of the developing fetus to adapt to environmental
factors.  For example, identical twin studies have clearly established
the role of both genetic and environmental factors in isolated cleft
lip or cleft palate.

Dentofacial malrelations present yet another public health problem with
nearly 50 percent of U.S. children requiring treatment for such
problems.  About five percent have sufficiently severe orthodontic or
orthognathic problems that they are considered to be functionally and
psychosocially handicapped.  While the relative importance of heredity
and environment in determining facial form is far from resolved, there
are indications that genetic influences are important.  For example,
genetic factors have been implicated in determining tooth size,
morphology and number.  Further, genes coding for proteins involved in
tooth structure, mineralization, production of collagens, as well as
other proteins of cartilage and bone have been characterized.  Most
recently, the gene for dentinogenesis imperfecta, associated with a
family with juvenile periodontitis, has been identified and the gene
for amelogenesis imperfecta has been cloned.

The previous RFA for Craniofacial Anomalies Research Centers acted as
a catalyst in bringing together teams of multidisciplinary researchers
to focus their expertise in investigating the mechanisms underlying
craniofacial development as well as to uncover the genes responsible
for several craniofacial and dental disorders.  In the three years
since the centers were established and funded, progress has included:
(1) development of a population-based model for studies of
gene-environment interaction for facial cleft defects; (2)
demonstration of an association between TGF-alpha and isolated cleft
palate alone (viewed as both embryologically and genetically distinct),
which is considered to be an important step in developing a unified
theory for craniofacial development; (3) isolation of several new
candidate genes, from a human fetal cDNA library, that are likely to
play an important role in early craniofacial development; (4)
identifying a cleft palate susceptibility gene (cps-1) in mice that
maps to a locus very similar to the corresponding interval in the human
genetic map; (5) improved understanding of the regulation of gene
expression during enamel organ development; (6) mapping of the Nance
Horan Syndrome locus to the short arm of X chromosome and
identification of a potential mouse mutant model (Xcat) for NHS; (7)
molecular genetic mapping of Treacher Collins Syndrome, known to be
located on chromosome 5; (8) characterization of the mouse Hox 8 gene
located on mouse chromosome 13, that has a distinct expression pattern
during early embryonic development; the location of the homologous
human gene is being sought; (9) development of a system for studying
unique gene regulatory mechanisms in the head and neck by injection of
plasmid DNA into adult mouse tongue muscles; (10) improved
understanding of the mechanisms of glucocorticoid effects in the
palatal shelf system; (11) studies of members of the transforming
growth factor family which are implicated as potent regulators of
embryonic growth and differentiation, including the size of the dental
tooth organs during tooth formation; and regulation of the size of the
Meckel's cartilage during mandibular morphogenesis; and (12) studies of
the cell cycle state of epithelial cells of the palatal midline, that
have been shown to clearly transdifferentiate into ectomesenchyme and
that have implications for understanding the developmental processes of
mandibular and palate formation.

Since issuance of the previous RFA for Craniofacial Anomalies Research
Centers, there have been many important advances in techniques and
strategies of developmental biology and molecular genetics.  With the
increased array of approaches now available, we are in a better
position to gain an improved understanding of many of the crucial
mechanisms of craniofacial development and to pinpoint the genes
responsible for many craniofacial, oral and dental anomalies.  A review
of the literature indicates that approximately 70 genes related to
craniofacial disorders, 30 genes related to dental disorders, 20
related to clefting disorders, and 3 related to craniosynostosis have
been mapped.  At the same time, however, only approximately 20 genes
related to craniofacial disorders and dental anomalies have been
cloned.  Although much has been accomplished, much work remains to be
done.  Exciting opportunities exist for the continued accumulation of
important information on developmental disorders of genetic origin
affecting human craniofacial structures.  Thus, the purpose of this RFA
is to maintain the impetus provided for multidisciplinary research in
the genetic aspects of craniofacial development and disorders.

Goals of the Centers

The primary goal of the Craniofacial Anomalies Research Centers program
is to support research that capitalizes on the advances in
developmental biology and molecular genetics by multidisciplinary teams
that address yet unsolved problems of normal and abnormal human
craniofacial development.  The following research areas and approaches
may be appropriate for inclusion in applications for support.  These
are intended as examples only, no priorities are implied, and the
examples should not constrain applicants from proposing other research
topics on the molecular biology and genetic aspects of human
craniofacial development or on the etiology of congenital craniofacial

o  Conduct population based molecular genetic epidemiologic studies
using gene mapping techniques to locate genes responsible for specific
craniofacial anomalies.

o  Establish normal DNA variation through linkage analysis using
restriction fragment length polymorphisms (RFLPs) and polymorphisms
defined by repeated DNA segments or variable number of tandem repeats
(VNTRs), for various craniofacial clinical entities.

o  Develop physical maps of genes involved in craniofacial development
using either chromosomal analysis or DNA methodologies, such as in situ
hybridization and somatic cell hybridization.

o  Determine the genetic and biochemical control of morphogenesis of
the skull, face and oral structures.  The genes responsible for
determining craniofacial form are often analogous to the homeotic

o  Correlate phenotypes with genotypes by studying mutations of
identified genes involved in craniofacial disorders.

o  Investigate the involvement of specific genes in craniofacial and
oral anomalies through expression studies using animal models,
including transgenic mice.

o Investigate genetic factors in multifactorial craniofacial disorders.

o  Determine the importance of genetic and biochemical factors in
cellular differentiation, migration and interactions during
craniofacial development.

o  Develop methods for cloning single genes involved in craniofacial

o  Develop DNA probes and monoclonal antibodies that can be used as
clinical diagnostic screening devices for craniofacial disorders .

o  Investigate gene therapy for specific craniofacial disorders.

It is likely that some of the information gained will ultimately lead
to improvements in clinical treatment.  However, it is not intended
that center resources will be used to support research on surgical
treatment or clinical management and rehabilitation of patients with
craniofacial anomalies.  The NIDR is already directing considerable
resources to those aspects of research through existing programs.

Center Characteristics

Each research center will be an identifiable unit within a larger
institution already committed to some aspects of molecular biology,
genetics or craniofacial development research.  The center will consist
of a cluster of related research projects, some of which may be
fundamental and others may involve epidemiological studies.  These
projects should not constitute a collection of individual, unrelated
investigations more appropriately supported by individual research
project or small grants.  The multidisciplinary research necessary to
achieve the center objectives will require collaborations among cell
and molecular biologists, biochemists, classical and molecular
geneticists, clinicians, embryologists, epidemiologists, morphologists
and teratologists.

Core resources, such as animal facilities, computer services and shared
equipment will be provided, although budgetary constraints preclude
expenditures for very expensive items of equipment or major

The center director will provide strong and effective scientific and
administrative leadership.  A committee consisting of staff members and
other expert consultants not members of the center staff and an
external committee that includes members who are not associated with
the applicant institution will advise the director on the merits of new
projects and the progress of existing investigations.

Some funds, not to exceed $25,000 per year in direct costs, may be used
to support pilot projects.  Scientists who wish to broaden their range
of activities during the award period will be expected to obtain
additional research support from sources other than the center grant.
Center grant funds may not be used to provide 100 percent of the salary
support for investigators.  Funding for a five-year project period,
with a possibility of renewal, should provide a more stable environment
than is usually encountered when investigators are supported entirely
by individual research project grants.

Site visits to review the performance of the centers and provide
guidance to the director may be conducted periodically by NIDR staff
and nongovernment expert consultants.  In addition, NIDR staff may
organize periodic meetings of the various center directors to promote
collaboration among the centers.  Such meetings may be held in
conjunction with the annual meetings of the American Association for
Dental Research.  Expenses for these meetings are the responsibility of
the centers.



NIH policy states that applicants for clinical research grants and
cooperative agreements are required to include minorities and women in
study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder, or condition under study;
special emphasis must be placed on the need for inclusion of minorities
and women in studies of diseases, disorders and conditions which
disproportionately affect them.  This policy is intended to apply to
males and females of all ages.  If women or minorities are excluded or
inadequately represented in clinical research, particularly in proposed
population based studies, a clear compelling rationale must be

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group. In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample site appropriate for the scientific objectives of the
study.  This information must be included in form PHS 398 (rev. 9/91)
in items l-4 of the Research Plan and summarized in item 5, Human
Subjects. Applicants are urged to carefully assess the feasibility of
including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all such projects to include representation of the full array of United
states racial, ethnic minority populations (i.e., Native Americans
[including American Indians or Alaskan Natives], Asian/Pacific
Islanders, Blacks, Hispanics).  The rationale for studies on single
minority population groups should also be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully.
Since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed or the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.

All applications for clinical research submitted to the NIH are
required to address these policies.  NIH funding components will not
award grants or cooperative agreements that do not comply with these


Prospective applicants are asked to submit a letter of intent by
September 24, 1993 that includes a descriptive title of the proposed or
existing center, the name, address and telephone number of the center
director, the identities of other key personnel and the participating
institution(s) and a descriptive title of each sub-project, and the
number and title of the RFA in response to which the application may be

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 to the NIDR staff in planning for timely
review of applications. It allows NIDR staff to estimate the potential
workload and to avoid possible conflict of interest in review.

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


Prospective applicants are advised to communicate with program and
grants management staff of the NIDR Extramural Program as early as
possible in the planning phase of application preparation.  NIDR staff
is available to assist applicants to ensure that the objectives,
structure, and the budget format for the proposed center are

Applications are to be prepared on form PHS 398 (rev. 9/91), that may
be obtained from the Office of Grants Inquiries, Division of Research
Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449,
Bethesda, MD 20892, telephone 301-710-0267; and from the program
official named below.  To identify the application as a response to
this RFA, check "yes" on item 2a of the face page of the application
and enter "RFA:  DE-93-03, Craniofacial Anomalies Research Centers."
The RFA label available in the form PHS 398 must be affixed to the
bottom of the face page of the original application.  Failure to use
this label could result in delayed processing of an application such
that it may not reach the review committee in time for review.

The instructions accompanying form PHS 398 must be followed as
completely as possible, but some modifications will be necessary.  For
example, a new Table of Contents should be prepared giving page numbers
for all items in the application.  Pagination must be consecutive
throughout the application.  Each subproject should be identified by
number and investigator.  Separate detailed budgets for each year for
the entire center, core resources, and sub-projects and pilot projects
should be prepared.  A consolidated budget for the center for all years
of support should be included (use pages DD-EE, PHS 398).  Direct and
indirect cost estimates must be provided.  Funds may be requested for
professional, technical, and administrative personnel, core resources,
equipment, supplies, minor renovations, consultant services, travel,
publication costs, and patient costs directly related to the research.
Detailed justification of the budget requests will be required.

Provide a summary of financial support from non-NIDR sources for
studies that will complement and expand the program supported by the
NIDR.  Explain how these studies will further the goals of the center
and make it more cost effective. Awardees will be expected to update
this information on an annual basis.

Under Research Plan, describe the goals of the center and discuss  the
background and significance of the topics being addressed.  Explain how
each project will contribute to achieving those goals.  Describe the
administrative structure, the responsibilities of the center director,
individual investigators, advisory groups and the proposed mechanisms
for monitoring scientific progress.  Describe the relationship of all
existing and pending institutional research projects that may be
relevant to the center regardless of funding source.

Throughout the application, provide sufficient but concise information
to facilitate an effective evaluation.  Brevity and clarity in the
presentation of the research plans and in the description of the
organizational structure, including the cores, may be considered a
reflection of the applicant's ability to achieve the objectives of the
center.  Each research project should be presented as in a research
project grant application.  That is, the instruction on pages 19-24 of
form PHS 398 must be followed.  Each project must be described within
the 25-page limitation that applies to research project grant
applications and each pilot project must be presented in no more than
10 pages.  Describe each core in no more than 25 pages and explain how
it will relate to the projects that will utilize its resources.
Abstracts (page BB, form PHS 398) must be completed for the core
resources, each subproject, pilot  project, and for the entire

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 must be sent to:

George Hausch, Ph.D.
Scientific Review Office
National Institute of Dental Research
Westwood Building, Room 525
Bethesda, MD  20892

Applications must be received by October 21, 1993.  If an application
is received after that date, it will be returned to the applicant
without review.


Applications will be evaluated initially for scientific and technical
merit by a special review committee convened by the NIDR Scientific
Review Office.  Prior to the initial review, a triage mechanism may be
employed to screen out applications that are noncompetitive or
nonresponsive to the RFA.  An applicant interview or site visit may be
included.  Secondary review will be conducted by the National Advisory
Dental Research Council.  Non-competitive or nonresponsive applications
and those received after October 21, 1993, or that exceed the first
year budget limit of $500,000 in direct costs will be returned to the
applicant.  Waivers of the receipt deadline and budget limitation will
not be granted.

Major factors to be considered in the evaluation of applications will

o  The extent to which the center will promote advances in knowledge of
the etiology of craniofacial anomalies that could not be achieved, or
that would be achieved more slowly, if the component projects were
funded separately.

o  The institutional environment, its commitment to research on the
molecular biology and genetics of craniofacial development and evidence
of an organizational structure, that will promote multidisciplinary,
collaborative research.

o  The scientific merit of each subproject, including its originality
and feasibility, the soundness of the methodology proposed, and the
competence of the investigators.  The expertise and familiarity of the
investigators with recently developed techniques of molecular biology
and genetics. Availability of statistical and data analysis resources
and evidence of their use in developing research protocols.

o  The technical merit and justification for core resources requested.

o  The adequacy of laboratory and clinical facilities, the availability
of appropriate populations.

o  The scientific and administrative qualifications, experience and
commitment of the director and his/her ability to provide effective

o  The plans for establishing and developing the center, for monitoring
research, and for reviewing changes in research directions.

o  The appropriateness of the period and budget requested for each
project, core, pilot project and the entire center.

o  For competitive renewal applications, the extent to which the goals
and specific aims of the previous application have been achieved.  The
inclusion of projects that are deemed to have little or no scientific
merit or that are deemed peripheral to the center's objective may be
considered a reflection of the Director's judgment and may adversely
affect the rating.  Component projects without significant and
substantial merit will not be recommended for further consideration.
If such projects are not deemed essential to the success of the center,
they will be recommended for deletion.


The earliest anticipated date of award is September 20, 1994.
Applicants should be aware that in addition to scientific merit,
program priorities, and program balance, the total cost of the
Craniofacial Anomalies Research Centers to the NIDR will be considered
by the NIDR staff and Council in making funding recommendations.  An
additional consideration will be the extent to which complementary
projects, supported from non-NlDR funds, will contribute to the
cost-effectiveness of the proposed center.

Once funded, the Center may undergo an interim review by NlDR to
evaluate progress.  The funding for subsequent years may be contingent
on a successful outcome of this review.

Amended Applications

In the past it has been common practice for applicants responding to
RFAs issued by the NIDR for specialized research centers grants (P50)
to amend unfunded applications and submit them as unsolicited program
project grant (P01) applications.  Alternatively, sub-projects from
unfunded P50 grant applications have been amended and submitted as
applications for other support mechanisms such as research project
grants (R01) or small grants (R03).

Applicants responding to the current RFA should be aware that, because
of fiscal constraints, it is unlikely that the NIDR will be able to
fund P01 grant applications resulting from the amendment of unfunded
applications.  Thus, submission of program project applications with
goals similar to those included in this RFA is discouraged.  However,
applicants are encouraged to amend promising sub-projects from unfunded
P50 applications and apply for support under other grant mechanisms.


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 issues to:

Mohandas Bhat, M.D.S., Dr.P.H
Craniofacial Development and Disorders 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
Grants Management Office
National Institute of Dental Research
Westwood Building, Room 510
Bethesda, MD  20892
Telephone:  (301) 594-7629


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.


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