PA-01-121: RESEARCH ON FLUORIDES TO IMPROVE ORAL HEALTH

Department of Health
and Human Services (HHS)

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This Program Announcement expires on July 31, 2004, unless reissued. RESEARCH ON FLUORIDES TO IMPROVE ORAL HEALTH Release Date: July 27, 2001 PA NUMBER: PA-01-121 National Institute of Dental and Craniofacial Research (http://www.nidcr.nih.gov) THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS UP TO $250,000 PER YEAR. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE The National Institute of Dental and Craniofacial Research (NIDCR) invites research grant applications to support research leading to an increase in knowledge about the use of fluorides for improving oral health. Special emphasis is sought in the areas of the overall metabolism of fluoride, effects of fluoride on bone and teeth, the development of gold standard methods for fluoride analysis of a wide variety of sample types, the influence of environmental factors on the effectiveness of fluoride, including temperature, altitude, food components, nutrients, and food additives, and the development of biomarkers for monitoring body fluoride burden and noninvasive methods to quantify fluorosis in vivo. In relation to the first of these areas, a comprehensive approach is intended in order to address bioavailability, intake and excretion and the influence of environment, genetics, nutrition, physiology and socio-economic and cultural diversity on the uptake, metabolism and biological and cosmetic effects of fluoride. The second area includes recognition of the need for practical epidemiologic studies of the current impact of water fluoridation and other fluoride modalities on dental caries and dental fluorosis. 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 Program Announcement, RESEARCH ON FLUORIDES TO IMPROVE ORAL HEALTH, is related to several priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. 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 and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. Domestic applications may include international components. The NIDCR encourages applications that include investigators who are racial/ethnic minority individuals, women and persons with disabilities. Although an application must be submitted from a single institution, collaborative arrangements with other institutions are strongly encouraged. Also, applications are not restricted to traditional dental, oral and craniofacial research settings. MECHANISM OF SUPPORT The mechanism of support will be the individual research project grant (R01) or the exploratory/developmental grant (R21). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The objective of the exploratory/developmental mechanism (R21) is to encourage applications to explore the feasibility of an innovative research question or approach, which may not be justifiable through extant research, or competitive as a standard research project grant (R01). These are short-term awards (up to two years) with limited funding (up to $100,000 per year for direct costs). RESEARCH OBJECTIVES Background Fluoride has been recognized as the central component in strategies to prevent dental caries, a disease that has had major health, economic and social effects on communities worldwide. The use of fluorides in the prevention of dental caries has been demonstrated to be one of the most successful public health promotion measures in history. Dramatic reductions in dental caries in children have been experienced where fluoride has been made available through sources such as fluoridated water, salt, toothpastes, topical rinses, gels, and dietary supplements. Savings of approximately $40 billion have been estimated in oral health care delivery in the USA alone in the past 40 years, primarily as a result of the use of fluoride. Although the incidence of caries has dramatically decreased since water fluoridation and fluoride toothpastes have been widely applied as a preventive measure, dental caries remains widespread and severely affects a large segment of the population in the world. Fluoride has shown to be effective as an anti-caries and anti-osteoporosis element. However, the following critical issues related to its action in bone and teeth remain unclear. 1) The minimal effective fluoride level in human body to prevent and control dental caries without increasing the risk of dental fluorosis is still not established. 2) The cellular and molecular mechanism mediating anti-caries and -osteoporosis effects is unclear. 3) The interactions between fluoride and other food components remain undefined, for example, it has been implicated that some food preservatives such as benzoate can potentiate fluoride effects, but its underlying mechanism has not been fully studied. 4) Fluoride monitoring needs more convenient and accurate gold standard measurement of body fluoride burden, which can be used to determine fluoride in environment, foods, and body fluids and tissues. This measurement method is critical for sample analysis, real-time and pharmacokinetic measurements. It is critical to fully understand the mechanisms by which fluoride prevents dental caries and osteoporosis, and to improve routines, materials and schemes of fluoride administration. Therefore, further investigation of these issues is of great significance. In 1999, the NIDCR held two workshops to bring together fluoride researchers from various fields including biochemistry, nutrition, environment, epidemiology and behavioral science, to discuss the current scientific knowledge and to propose direction for future fluoride research. On February 1, 1999, a group of experts was convened to develop a research agenda related to recent fluoridation interventions that have been introduced within the U.S. A second workshop identified research needs for international collaborative research on fluoride. This workshop was co-sponsored with 10 partners, including other NIH components, the Centers for Disease Control and Prevention (CDC), private corporations, and the International Association for Dental Research. Research recommendations from both workshops form the basis of this announcement. Scope The purpose of this PA is to encourage research leading to an increase in knowledge about the use of fluorides for improving oral health. Appropriate topics for investigation under this PA include, but are not limited to studies: 1. To elucidate the molecular mechanisms of the action of fluoride on tooth and bone cells. These investigations might include the effects of fluoride on: o Expression of genes that play a critical role in tooth and bone development and mineralization, o Proteins and other factors participating in tooth and bone development and mineralization, o Intracellular signaling systems regulating tooth and bone mineralization. 2. To determine the relative contribution of pre-eruptive and post- eruptive effects of fluoride on prevention of dental caries. 3. To determine the target concentration of fluoride in the oral environment to optimize the local action of fluoride for caries prevention. 4. To develop new generations of fluoride therapeutics, local delivery systems or devices to produce long-lasting and appropriate concentration of active fluoride compounds which provide better efficacies, better cost-effectiveness, and an improved safety profile. These new therapeutics will be specific for target tissues, and present in low levels in non-target tissues. 5. To investigate the interactions between fluorides and food components, nutrients and additives, and to develop methods to enhance the beneficial effect of fluoride. 6. To investigate the influence of environmental factors including temperature and altitude on the effectiveness of fluoride. 7. To develop simple global gold standard measurements, which are more accurate, rapid and convenient analyses for monitoring of fluoride levels such as screening, pharmacokinetics, time course determination, and other purposes in body fluids and other specimens including blood, saliva, urine and hair. 8. To ascertain the relative contribution of currently available fluoride modalities on dental caries prevention and control and on dental fluorosis in populations. 9. To investigate skeletal fluorosis and other fluoride effects on bone in areas with high concentrations of natural fluoride, including identification of environmental, cultural and social factors associated with excessive fluoride exposure, the pathogenesis of skeletal fluorosis, and development of valid and noninvasive methods to quantify fluorosis in vivo and to identify risk indicators or markers for dental fluorosis. 10. To measure the public health cosmetic significance of enamel opacities/fluorosis across cultures, and to explore preventive and therapeutic interventions for both enamel and skeletal fluorosis. 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, Vol. 23, No. 11, March 18, 1994 available on the web at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not94-100.html 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 these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the policy that was published in the NIH Guide for Grants an Contracts, June 5, 2000 (Revised August 25, 2000), available at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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 The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in applying for these grants and will be accepted at the standard application deadlines (http://grants.nih.gov/grants/dates.htm) as indicated in the application kit. This version of the PHS 398 is available in an interactive, searchable PDF format. Although applicants are encouraged to begin using the 5/2001 revision of the PHS 398 as soon as possible, the NIH will continue to accept applications prepared using the 4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, the NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. 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 he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant 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 an applicant to obtain agreement for acceptance of the original application as well as any subsequent revisions. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. Applicants are permitted, however, to use the 4/1998 revision of the PHS 398 for scheduled application receipt dates until January 9, 2002. If you are preparing an application using the 4/1998 version, please refer to the step-by-step instructions for Modular Grants available at http://grants.nih.gov/grants/funding/modular/modular.htm. Additional information about Modular Grants is also available on this site. The title and number of the program announcement 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. 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 aspects of the application 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 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. (1) 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? (2) 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? (3) 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? (4) 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)? (5) 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities. Applications will compete for available funds with all other favorably recommended applications. For those applications assigned to NIDCR, 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 NIDCR staff and the National Advisory Dental Research Council in making funding recommendations. In addition, the NIDCR values complementary funding from other public and private sources including foundations and industrial concerns. In circumstances in which applications have similar scientific merit, but vary in cost-competitiveness, the NIDCR is likely to select the more cost-competitive application for funding. INQUIRIES Written, email and telephone inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Guo H. Zhang, Ph.D., M.Sc. Program Director Chronic Diseases Branch Division of Extramural Research, National Institute of Dental Research National Institutes of Health Building 45 (Natcher), Room 4An.18B Bethesda, MD 20892-6402 Telephone: 301 594-0618 Fax: 301 480-8318 Email: guo.zhang@nih.gov Direct inquiries regarding grants management issues to: Mr. Martin R. Rubinstein Chief, Grants Management Section Division of Extramural Research National Institute of Dental Research National Institutes of Health Building 45 (Natcher), Room 4AN-44A Bethesda, MD 20892-6402 Telephone: 301-594-4800 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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