This Program Announcement expires on June 30, 2004, unless reissued.

NEW APPROACHES TO THE PATHOGENESIS AND TREATMENT OF OROFACIAL PAIN

Release Date:  June 6, 2001

PA NUMBER:  PA-01-108

National Institute of Dental and Craniofacial Research
Office of Research on Women’s Health

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT 
INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS 
THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE

The National Institute of Dental and Craniofacial Research (NIDCR) and 
the Office of Research on Women’s Health (ORWH) invite research grant 
applications for innovative basic research investigations to study the 
pathogenesis of orofacial pain, in particular temporomandibular 
disorders (TMDs). A broad range of research proposals on pathogenic 
mechanisms, new animal models, and interventions to halt and reverse 
disease processes is encouraged.  

The NIDCR and the ORWH encourage collaborative projects that bring 
together investigators from all relevant scientific disciplines 
including molecular and cellular biology, immunology, endocrinology, 
biochemistry, pathology, and chemistry interested in studying this 
problem. Applications that include collaboration with foreign scientists 
conducting unique research on this topic are also encouraged.
 
HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a 
PHS-led national activity for setting priority areas.  This PA addresses 
the priority areas of dental, oral and craniofacial health.  Potential 
applicants may obtain a copy of "Healthy People 2010" (Full Report: 
Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) 
through the Superintendent of Documents, Government Printing Office, 
Washington, DC 20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and 
non-profit organizations, public and private, such as universities, 
colleges, hospitals, laboratories, units of State or local governments, 
and eligible agencies of the Federal government. The total requested 
project period for an application submitted in response to the PA may 
not exceed five years.  Domestic applications may include international 
components but these components.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as 
Principal Investigators.

MECHANISM OF SUPPORT

The mechanism of support for this PA is the National Institutes of 
Health (NIH) research project grant (R01) award mechanism.  
Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant.  New 
investigators without prior R29 or R01 support are strongly encouraged 
to apply.  They should identify their status on the cover page for the 
application.  In addition, the research topics in bioengineering that 
are of special interest to the NIDCR are identified in the NIH Omnibus 
Solicitation for SBIR/STTR Grant Applications found at: 
http://grants.nih.gov/grants/funding/sbir.htm - sbir

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the 
NIH. Complete and detailed instructions and information on Modular Grant 
Applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm
Applications requesting less than $250,000 per year in direct costs must 
use the modular format, with funds requested in $25,000 direct cost 
modules.  A feature of the modular grant is that no escalation is 
provided for future years, and all anticipated expenses for all years of 
the project must be included within the number of modules being 
requested. Only limited budget information is required and any budget 
adjustments made by the Initial Review Group will be in modules of 
$25,000.  Applications that request more than $250,000 in any year must 
use the standard PHS 398 (rev 4/98) application instructions.

RESEARCH OBJECTIVES

Orofacial pain, in particular disorders of the TMJ, represent a group of 
conditions that affect at least 10 million people, primarily women, in 
the United States.  These disorders are therefore an important national 
health problem, affecting many people to the point that many normal 
occupational and social activities are precluded.  The major clinical 
manifestations of TMDs are orofacial pain and tenderness localized (at 
least initially) to the masticatory muscles and/or the TMJ.  The vast 
majority of attempts to treat TMDs have focused on dental approaches to 
the problem, with relatively few studies utilizing state-of-the-art 
approaches to the pharmacological or non-pharmacological management of 
joint or muscle pain.

The appropriate treatment of chronic pain has received much attention; 
with practice guidelines published by the World Health Organization, 
U.S. Agency for Health Care Policy and Research, and more recently the 
Joint Commission on Accreditation of Healthcare Organizations.  Despite 
this, there is considerable evidence that patients with all forms of 
chronic pain are under treated, and are typically given inappropriate 
regimens of pain-relieving drugs.  TMDs are no exception to this, with 
few published studies examining appropriate pharmacological “ladders” of 
agents.  One of the dangerous consequences of a failure to effectively 
treat acute pain is that it can evolve into chronic pain that may have a 
central origin.  This is thought to be due to the induction of 
neuroplastic changes in central nervous system structures induced by a 
continuous afferent barrage.

Basic research in models of pain is revealing molecular and cellular 
mechanisms that may provide a basis for the continued perception of 
pain, even when the initiating insult has resolved.  These effects 
appear to result in the maintenance of functional changes in central 
nervous system neuronal hyperexcitability.  For example, recent studies 
of neurochemical mechanisms in pain models that produce hyperalgesia 
suggest that suppression of nor-adrenergic activity is associated with 
this effect.  This is consistent with clinical findings that central 
administration of alpha-adrenergic agents is effective in the treatment 
of opioid resistant pain.

Summary
 
Areas of research responsive to the PA include physiological and 
molecular mechanisms relevant to pain in the orofacial region, as well 
as pharmacological approaches to the treatment of orofacial pain, 
especially TMDs.  The list below is not meant to be exhaustive, 
exclusive, or delimiting, rather these merely represent illustrations of 
projects that would be considered relevant to this PA.  Examples of 
specific research topics include:

o animal models of specific pathophysiologic conditions that produce 
orofacial pain, in particular ones that induce temporomandibular 
dysfunction;
 
o genetic predisposition as a factor in differential responses to 
insults that produce orofacial pain and TMDs;

o defining unique molecular or physiological differences in the 
components of the orofacial region that may be relevant to orofacial 
pain syndromes;

o development and use of biological markers and surrogate end points to 
objectively classify types of orofacial pain, and for use in the 
development of new therapeutic strategies;
 
o peripheral and central sensitization of nociceptors, in particular as 
it relates to stimuli or lesions known to induce orofacial pain; 

o state of the art analgesic approaches for alleviation of orofacial 
pain; 

o the design and development of controlled release delivery systems 
for delivery of both conventional and new drugs at targeted 
specific sites of the TMJ to alleviate pain and inflammation;

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 sub-populations must be included in all NIH-supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification are provided 
indicating 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 UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for Grants 
and Contracts on August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a 
complete copy of the updated Guidelines are available at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to provide a 
description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable; and b) all investigators to report accrual, and 
to conduct and report analyses, as appropriate, by sex/gender and/or 
racial/ethnic group differences.

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

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age 
of 21) must be included in all human subjects research, conducted or 
supported by the NIH, unless there are scientific and ethical reasons 
not to include them.  This policy applies to all initial (Type 1) 
applications submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects" that was published in 
the NIH Guide for Grants and Contracts, March 6, 1998, and is available 
at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html

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

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained 
within specified page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no 
obligation to view the Internet sites.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an Internet 
site.

APPLICATION PROCEDURES

Applications are to be submitted on grant application form PHS 398 (rev. 
4/98). and will be accepted at the standard application deadlines as 
indicated in the application kit. Application kits are available at most 
institutional offices of sponsored research and may be obtained from the 
Division of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 
20892-7910, Phone (301) 435-0714, Email:  GRANTSINFO@NIH.GOV. 
Applications are also available on the internet at 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any 
amended/revised version of the preceding grant application types 
requesting $500,000 or more in direct costs for any year are advised 
that they must contact the Institute or Center (IC) program staff before 
submitting the application, i.e., as plans for the study are being 
developed. Furthermore, applicants must obtain agreement from the IC 
staff that the IC will accept the application for consideration for 
award. Finally, applicants must identify, in a cover letter sent with 
the application, the staff member and Institute or Center who agreed to 
accept assignment of the application.

This policy requires applicants to obtain agreement for acceptance of 
both any such application and any such subsequent amendment. Refer to 
the NIH Guide for Grants and Contracts, March 20, 1998 at:  
http://grants.nih.gov/grants/guide/notice-files/not98-030.html

The program announcement title and number must be typed on line 2 of the 
face page of the application form and the YES box must be marked.
Submit a signed, typewritten, original of the application, including the 
checklist and five signed photocopies in one package to:

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

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

Modular Grant applications will request direct costs in $25,000 modules, 
up to a total direct cost request of $250,000 per year. (Applications 
that request more than $250,000 in direct costs in any year must follow 
the traditional PHS 398 application instructions).  The total direct 
costs must be requested in accordance with the program guidelines and 
the modifications made to the standard PHS 398 application instructions 
described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct 
Costs (in $25,000 increments up to a maximum of $250,000) and Total 
Costs [Total Direct plus Facilities and Administrative (F&A) costs] 
for the initial budget period.  Items 8a and 8b should be completed 
indicating the Direct and Total Costs for the entire proposed period 
of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD – For applications 
requesting less than $250,000 in Direct Costs per year, do not 
complete Form Page 4 of the PHS 398. It is not required and will not 
be accepted with the application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - For applications 
requesting less than $250,000 in Direct Costs per year, do not 
complete the categorical budget table on Form Page 5 of the PHS 398. 
It is not required and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION – If you are using the modular budget 
format, prepare a Modular Grant Budget Narrative page (See 
http://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages.) At the top of the page, enter the total direct costs 
requested for each year. This is not a Form page.  All other 
applications follow the standard PHS 398 instructions.

o UNDER PERSONNEL, List all project personnel, including their names, 
percent of effort, and roles on the project. No individual salary 
information should be provided. However, the applicant should use the 
NIH appropriation language salary cap and the NIH policy for graduate 
student compensation in developing the budget request.

o FOR CONSORTIUM/CONTRACTUAL COSTS, provide an estimate of total costs 
(direct plus facilities and administrative) for each year, each 
rounded to the nearest $1,000. List the individuals/organizations 
with whom consortium or contractual arrangements have been made, the 
percent effort of all personnel, and the role on the project. 
Indicate whether the collaborating institution is foreign or 
domestic. The total cost for a consortium/contractual arrangement is 
included in the overall requested modular direct cost amount.  
Include the Letter of Intent to establish a consortium.

o Provide an additional narrative budget justification for any 
variation in the number of modules requested.

BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used 
by reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the 
overall qualifications of the research team. A biographical sketch is 
required for all key personnel, following the instructions below. No 
more than three pages may be used for each person. A sample biographical 
sketch may be viewed at: 
http://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o CHECKLIST - This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate 
the type of agreement and the date. All appropriate exclusions must 
be applied in the calculation of the F&A costs for the initial budget 
period and all future budget years.

o The applicant should provide the name and phone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review.

REVIEW CONSIDERATIONS

Upon receipt, the NIH Center for Scientific Review (CSR) will review 
applications for completeness. An appropriate peer review group convened 
in accordance with NIH peer review procedures will evaluate applications 
that are complete for scientific and technical merit.  As part of the 
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 would be discussed, assigned a priority score, 
and receive a second level review by an appropriate advisory council.  

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
In the written comments, reviewers will be asked to discuss the 
following of the application in order to judge the likelihood that the 
proposed of these criteria will be addressed and considered in assigning 
the overall score, weighting them as appropriate for each application.  
Note that the application does not need to be strong in all categories 
to be judged likely to have major scientific impact and thus deserve a 
high priority score.  For example, an investigator may propose to carry 
out important work that by its nature is not innovative but is essential 
to move a field forward.

Significance. 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 and methods adequately 
developed, well integrated, and appropriate to the aims of the project?  
Does applicant acknowledge potential problem areas and consider 
alternative tactics?  

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

Investigators.  Are the investigators 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 
partners?

Environment.  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed 
collaborative arrangements take advantage of unique features of the 
scientific environment?  Is there evidence of collaborative 
institutional support?

The initial review group will also examine: the appropriateness of 
proposed project budget and duration; the provisions for the protection 
of human and animal subjects; and the safety of the research 
environment.

AWARD CRITERIA

Factors that will be used to make award decisions are as follows: 

o Scientific and technical merit of the proposed project as determined 
by peer review; 

o Cost effectiveness of the proposed strategy; 

o Promise of the proposed program to accomplish the goals of this PA 
and address the needs of the participating Institute and Center as 
regards their interest in pain research;

o Program priorities and program balance; 

o Availability of funds. 

INQUIRIES

Written, email and telephone inquiries are encouraged early in the 
development of the application.  The opportunity to clarify any issues 
or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Kenneth A. Gruber
Chief, Chronic Diseases Branch
Division of Extramural Research
National Institute of Dental and Craniofacial Research
Natcher Building, Room 4AN-18C
Bethesda, MD  20892-6402
Telephone:  (301) 594-4836
FAX:  (301) 480-8318
Email:  Kenneth.Gruber@nih.gov

Dr. Lisa Begg.
Director of Research Programs,
Office of Research on Women’s Health
National Institutes of Health
Building 1, Room 201
Bethesda, MD 20892
Telephone: (301) 402-1770
FAX: (301) 402-1770
Email: :beggl@od.nih.gov 
Direct inquiries regarding fiscal matters to:

Mr. Martin Rubinstein
Office of Grants Management
National Institute of Dental and Craniofacial Research
Natcher Building, Room 4AN-44A
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
FAX:  (301) 480-8301
Email:  Martin.Rubinstein@nih.gov

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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