Part I Overview Information


Department of Health and Human Services

Issuing Organization
National Institute of Dental and Craniofacial Research (NIDCR), (http://www.nidcr.nih.gov)

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Institute of Dental and Craniofacial Research (NIDCR), (http://www.nidcr.nih.gov)

Title: Pharmacogenetics of Fluoride (R21)

Announcement Type
New

Update: The following update relating to this announcement has been issued:

Looking ahead: As part of the Department of Health and Human Services' implementation of e-Government, during FY 2006 the NIH will gradually transition each research grant mechanism to electronic submission through Grants.gov and the use of the SF 424 Research and Related (R&R) forms. Therefore, once the transition is made for a specific grant mechanism, investigators and institutions will be required to submit applications electronically using Grants.gov. For more information and an initial timeline, see http://era.nih.gov/ElectronicReceipt/. NIH will announce each grant mechanism change in the NIH Guide to Grants and Contracts (http://grants.nih.gov/grants/guide/index.html). Specific funding opportunity announcements will also clearly indicate if Grants.gov submission and the use of the SF424 (R&R) is required. Investigators should consult the NIH Forms and Applications Web site (http://grants.nih.gov/grants/forms.htm) for the most current information when preparing a grant application.

Program Announcement (PA) Number: PAR-06-215

Catalog of Federal Domestic Assistance Number(s)
93.121

Key Dates
Release Date: March 3, 2006
Letters of Intent Receipt Dates: April 17, 2006, 2007, 2008; August 17, 2006, 2007, 2008; December 17, 2006, 2007, 2008
Application Receipt Dates: May 15, 2006, 2007, 2008; September 15, 2006, 2007, 2008; January 15, 2007, 2008, 2009  (Note: R21 applications must be submitted electronically for receipt dates after June 1, 2006. This Funding Opportunity Announcement (FOA) will be reissued after May 15, 2006 to include electronic SF424 (R&R) submission information)
Peer Review Dates: October-November 2006, 2007, 2008; February-March 2007, 2008, 2009; June-July 2007, 2008, 2009
Council Review Dates: January 2007, 2008, 2009; May 2007, 2008, 2009; September 2007, 2008, 2009
Earliest Anticipated Start Dates: April 2007, 2008, 2009; July 2007, 2008, 2009; December 2007, 2008, 2009
Additional Information To Be Available Date (Url Activation Date): Not applicable
Expiration Date: May 16, 2006

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

The National Institute of Dental and Craniofacial Research (NIDCR) invites applications for research projects focusing on the genetic basis underlying individual responses to ingested fluoride in tooth mineralized tissues and other physiological processes.   Projects should aim to identify and characterize fluoride-responsive genetic variations in humans or animal models.  Applicants should specifically address how pharmacogenetics data will be interpreted and translated into risk assessment for public health. 

Table of Contents


Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
  1. Research Objectives

Section II. Award Information
  1. Mechanism(s) of Support
  2. Funds Available

Section III. Eligibility Information
  1. Eligible Applicants
    A. Eligible Institutions
    B. Eligible Individuals
  2.Cost Sharing or Matching
  3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
  1. Address to Request Application Information
  2. Content and Form of Application Submission
  3. Submission Dates and Times
    A. Receipt and Review and Anticipated Start Dates
      1. Letter of Intent
    B. Sending an Application to the NIH
    C. Application Processing
  4. Intergovernmental Review
  5. Funding Restrictions
  6. Other Submission Requirements

Section V. Application Review Information
  1. Criteria
  2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Sharing Research Data
    D. Sharing Research Resources
  3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
  1. Award Notices
  2. Administrative and National Policy Requirements
  3. Reporting

Section VII. Agency Contact(s)
  1. Scientific/Research Contact(s)
  2. Peer Review Contact(s)
  3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement


Section I. Funding Opportunity Description


1. Research Objectives

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to stimulate research on the genetic basis underlying individual responses to ingested fluoride.  Although there is a volume of literature describing the effects of fluoride on both mineralized and non-mineralized tissues, the genetic determinants of our physiological responses to fluoride is an unexplored research area.  Recent advances in genetic and genomic sciences provide unique opportunities to apply pharmacogenetic approaches to fluoride research; how genetic variations determine heterogeneous physiological responses to fluoride.

Projects should aim to identify and characterize fluoride-responsive genetic variations, e.g. polymorphisms,  in humans and animal models.  Functional analyses of these variants will be necessary in determining their contribution to differential phenotypes in tooth mineralized tissues or other physiological processes in response to fluoride.  Projects may test candidate genetic variants, or search for genetic variants that are accountable for well characterized fluoride-responsive phenotypes.  Projects should explicitly state whether a causal relationship between fluoride-responsive genotype and phenotype will be studied, and how this relationship will be established with appropriate controls.  Applicants should specifically address how pharmacogenetics data will be interpreted and translated into public health risk assessment.  The predicted relevance to human conditions of data generated through animal studies should be addressed.  Study design should include fluoride exposure levels that are relevant and typical of human exposures. Gene expression profiling studies are not responsive to this FOA unless there are data to suggest that changes in gene expression level in response to fluoride are due to polymorphisms or epigenetic modifications in the gene of interest. 

Background

Since the introduction of fluoride in community drinking water in 1945, there has been a steady decline in the prevalence and severity of dental caries among Americans living in fluoridated communities.  In fact, water fluoridation was touted by the Center for Disease Control and Prevention as one of the top ten public health achievements of the twentieth century.  However, with this decline in caries prevalence, there has been an increase in dental fluorosis among children living in fluoridated communities.  It has been estimated that between 20-80% of these children have mild fluorosis and 4% have moderate to severe fluorosis.  A recent analysis of the NHANES datasets indicated that the prevalence of fluorosis among 6-19 year old children increased by 9% since 1987.  This increase is thought to be due, in part, to the increase in fluoride intake from sources other than drinking water including fluoridated beverages, supplements and topical fluoride-containing dental products that may be ingested.  Factors such as nutrition have been implicated in an increase in an individual’s susceptibility to fluorosis but probably do not fully account for the prevalence observed in the population.  On the other hand, although the proper use of fluoride generally reduces dental caries, the extent of its effectiveness varies among different communities.

Ingested fluoride is rapidly and efficiently absorbed through the gastrointestinal system and approximately 35-70% is eventually cleared by the renal system.  Most of the fluoride retained in the body is incorporated into bones and teeth.  The majority of fluoride related research efforts have focused on tooth enamel.  Enamel development begins with the secretion of a set of enamel matrix proteins by ameloblasts that nucleates minerals.  Matrix proteins continue to interact with minerals and guide crystal growth.  Crystals are aligned in parallel arrays, which further orient themselves to form an interwoven superstructure of hydroxyapatite.  Matrix proteins are degraded by proteolytic enzymes and removed leaving enamel that contains 98% minerals.  Fluoride is anticariogenic at low concentration.  Studies have shown that, during enamel mineralization, fluoride can be intercalated into the enamel crystal structure as fluoroapatite which is more resistant to dissolution than hydroxyapatite.  However, excess fluoride results in dental fluorosis characterized by changes in enamel that vary from barely discernible fine white striations to pitted brown lesions.  Some studies suggest that fluoride interferes with the activities of enamel matrix protein processing enzymes resulting in a delay in the clearance of matrix proteins during the maturation phase of amelogenesis and incomplete mineralization.  Fluoride may also interfere with the maturation and differentiation of ameloblasts.

In regard to its effects on bone, fluoride is considered anabolic in that it stimulates osteoblast proliferation and mineral deposition.  However, excessive fluoride can result in an increase in bone density which can compromise bone quality and strength such that fluorotic bones have increased fracture rates and delayed fracture repair. 

Fluoride might also affect the physiological processes of non-mineralized tissues.  Human and animal studies of acute lethal or toxic levels of fluoride show that it affects the gastrointestinal, cardiovascular, renal, reproductive, and neuroendocrine systems.  It has also been proposed that fluoride might increase the incidence of osteosarcomas in young males. Most of these studies have been inconclusive and inconsistent.  Animal experiments have used relatively high levels of fluoride, whereas well controlled studies using relevant ranges that reflect more typical levels of human exposure are lacking.   

The involvement of genetic determinants in fluoride responsiveness has been implicated in several studies.  A number of ecological studies of populations around the world living in areas with naturally high levels of fluoride in the water suggest that there is considerable variation in fluorosis among and within these populations.  Responsiveness to fluoride cannot be correlated with the total bioburden of fluoride as assayed in urine samples.  Heterogeneous responses to fluoride have also been observed in different mouse strains with certain strains exhibiting fluorosis while other strains are unaffected.  Several fluoride-responsive genes have been identified but how these genes and their gene products determine physiological responses to fluoride has not been clarified.  Nevertheless, these studies strongly suggest that there is a genetic basis underlying the effects of fluoride.

With the completion of the Human Genome Project and rapid advancement of the International HapMap Project, genomic science can begin to be translated into genomic medicine.  On the forefront of this progress is the emerging field of pharmacogenetics; an interdisciplinary study of genetic variations that determine heterogeneous responses to drugs and other chemical compounds.  Global and high throughput map-based or sequence-based approaches, gene expression profiling and proteomic studies can be utilized to ascertain functionally significant genetic variations in drug responses and to identify polygenic interactions that determine complex drug responses.  Genetically engineered animals such as recombinant congenic strains of mice are available to accelerate genetic dissection of complex traits. It is timely to apply these state-of-the-art approaches to fluoride research and to attract new investigators and investigators with diverse expertise to this area.   

Scope and Objectives

This FOA encourages human and animal studies on: 1) whole genome approaches such as linkage and mapping studies to identify fluoride-responsive genetic variations; 2) candidate gene strategies based on existing knowledge of the mechanisms of fluoride action to identify and characterize functional genetic variants; 3) the development of animal models with clearly defined differential physiological responses to ingested fluoride at levels relevant to normal human exposures and the association of these phenotypes with genotypes; 4) the development and validation of relevant fluoride-responsive genetic variants into predictive genetic standards for an individual’s physiological responses to fluoride; and 5) gene-gene and gene-environment interactions that modify the function of fluoride-responsive genetic variants.  Applicants are also encouraged to consider the Nutritional Data System for Research with Fluoride (http://www.ncc.umn.edu/), a software program designed to assess total fluoride exposure, to augment their research design when applicable.

This FOA focuses on capturing emerging scientific opportunities and technologies to provide the genetic and molecular basis for the physiological outcome of ingested fluoride.  These studies will pave the way for the identification of specific populations or individuals that will benefit from fluoride supplement and/or exhibit other physiological consequences due to the action of fluoride.  The knowledge gained from these studies will serve as the basis for individualized recommendations for total fluoride intake.  This information will also elucidate fundamental mechanisms by which fluoride influences biomineralization.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information


1. Mechanism(s) of Support

This funding opportunity will use the NIH Exploratory/Developmental Research Grant (R21) award mechanism.

As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

This funding opportunity uses just-in-time concepts. It also uses the modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/modular/modular.htm).

2. Funds Available

The NIDCR has not set aside funds for this Program Announcement.  The number of awards will be dependent on their scientific merit.

The total project period for an application submitted in response to this funding opportunity may not exceed 2 years. Direct costs are limited to $275,000 over the two years of the R21 award, with no more than $200,000 in direct costs allowed in any single year. Applicants may request direct costs in $25,000 modules, up to the total direct costs limitation of $275,000 for the combined two-year award period. The request should be tailored to the needs of the project. 

NIH grants policies as described in the NOT-OD-05-004.  

Section III. Eligibility Information


1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.

2. Cost Sharing or Matching

Cost sharing is not required.

The most current Grants Policy Statement can be found at: http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#matching_or_cost_sharing

3. Other-Special Eligibility Criteria

Exploratory/developmental (R21) grant support is for new projects only; competing continuation applications will not be accepted.   Two revisions of a previously reviewed exploratory/developmental (R21) grant application may be submitted as defined in NIH Policy at http://grants.nih.gov/grants/policy/amendedapps.htm

Section IV. Application and Submission Information


1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Proposed research should provide a unique research opportunity not available in the U.S.

3. Submission Dates and Times

See Section IV.3.A for details.

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Dates: April 17, 2006, 2007, 2008; August 17, 2006, 2007, 2008; December 17, 2006, 2007, 2008
Application Receipt Dates: May 15, 2006, 2007, 2008; September 15, 2006, 2007, 2008; January 15, 2007, 2008, 2009
Peer Review Dates: October-November 2006, 2007, 2008; February-March 2007, 2008, 2009; June-July 2007, 2008, 2009
Council Review Dates: January 2007, 2008, 2009; May 2007, 2008, 2009; September 2007, 2008, 2009
Earliest Anticipated Start Dates: April 2007, 2008, 2009; July 2007, 2008, 2009; December 2007, 2008, 2009

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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 allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Lillian Shum, PhD
Director, Mineralized Tissue and Salivary Gland Physiology Program
Center for Integrative Biology and Infectious Diseases
National Institute of Dental and Craniofacial Research
45 Center Drive
Building 45, Room 4AN-18B
Bethesda, MD 20892-6402
Telephone: (301) 594-0618
Fax: (301) 480-8319
Email: ShumL@nidcr.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant application forms found in the PHS 398 instructions for preparing a research grant application. 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 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

3.C. Application Processing

Applications must be received on or before the application receipt/submission date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review.

Upon receipt applications will be evaluated for completeness by CSR. Incomplete applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.

6. Other Submission Requirements

The NIDCR uses the Exploratory/Developmental Grant (R21) mechanism to provide support for innovative, high risk/high impact research requiring preliminary testing or development; exploration of the use of approaches and concepts new to a particular substantive area; research and development of new technologies, techniques or methods; or initial research and development of data upon which significant future research may be built.  Applications submitted under this mechanism should be exploratory and novel.  These studies should break new ground or extend previous discoveries toward new directions or applications.  Although preliminary data are not required for an R21 application, they may be included.  Items 2-5 of the Research Plan of the R21 application may not exceed 15 pages, including tables and figures.  R21 appendix materials should be limited, as is consistent with the exploratory nature of the R21 mechanism, and should not be used to circumvent the page limit for the research plan.  The following materials may be included in the appendix: up to five publications, including manuscripts (submitted or accepted for publication), abstracts, patents, photos, or other printed materials directly relevant to the project, surveys, questionnaires, data collection instruments, and clinical protocols; these documents may be stapled as sets.

Specific Instructions for Modular Grant applications.

Applications requesting up to $250,000 per year in direct costs must be submitted in a modular budget format. The modular budget format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular budgets. Applicants must use the currently approved version of the PHS 398. Additional information on modular budgets is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information


1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications submitted for this funding opportunity will be assigned to the ICs on the basis of established PHS referral guidelines.

Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit.

As part of the initial merit review, all applications will:

The following will be considered in making funding decisions:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria 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 an 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: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Are fluoride exposure levels in the study design relevant and typical of human exposures?  Will the study inform a causal or associative relationship between fluoride-responsive genotype and phenotype?  Are there appropriate controls in the study design to demonstrate the specificity of the fluoride response?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

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? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

Relevance to Public Health: Does the project have a clearly defined and acceptable standard on how pharmacogenetics data will be interpreted and translated into public health risk assessment?  If animal studies were proposed, does the project discuss the predictive relevance to human conditions of the data generated?  Will the study generate interpretable and useful information relevant to public health?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates
Not applicable

Section VI. Award Administration Information


1. Award Notices

After the peer review of the application is completed, the PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts


We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Lillian Shum, PhD
Director, Mineralized Tissue and Salivary Gland Physiology Program
Center for Integrative Biology and Infectious Diseases
National Institute of Dental and Craniofacial Research
45 Center Drive
Building 45, Room 4AN-18B
Bethesda, MD 20892-6402
Telephone: (301) 594-0618
Fax: (301) 480-8319
Email: ShumL@nidcr.nih.gov

2. Peer Review Contacts:
Not applicable

3. Financial or Grants Management Contacts:

Mary Daley, Chief Grants Management Officer
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN 44B
45 Center Drive 
Bethesda, MD 20892-6402
Telephone: (301) 594-4808
FAX: (301) 480-3562
Email: daleym@mail.nih.gov

Section VIII. Other Information


Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

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 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 funding opportunity 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.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
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 clinical research projects unless a clear and compelling justification is 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 clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

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 (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov/). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov/) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

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 is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance (CFDA# 93.121) at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov/.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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