It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Enamel formation occurs through the process of amelogenesis, during which ameloblasts form and secrete the extracellular matrix which eventually matures into the outer hydroxyapatite layer of the tooth crown. Any perturbation in this complex process, such as accumulation of excess amounts of proteins normally targeted for degradation in the extracellular enamel matrix, or inadequate calcium and ion transport, can lead to hypomineralized or malformed enamel. These enamel defects subject the whole tooth to wear and/or caries, typically leading to subsequent failure of the tooth and decreased quality of life. In genetic conditions such as amelogenesis imperfecta (AI), in which certain enamel proteins are mutated, teeth are weak and often require repeated and increasingly extensive restorations to regain partial function. AI can manifest clinically in many forms from hypoplastic to hypomineralized enamel, and not only requires substantial clinical care, but also has psychosocial sequelae for the patient. AI is a challenge to study because it is a genetically and clinically diverse group of conditions. Another hypomineralized enamel condition, molar-incisor hypomineralization (MIH) which affects a specific subset of teeth, has a range of prevalence of up to 44% among children according to a 2015 literature review. Another report examining 70 studies across the world accentuates the lack of information on MIH in the United States. Its etiology is currently unknown, but associations have been made with environmental exposure. Studies are needed to understand and prevent MIH in the US. Enamel diseases, both newly recognized in the field and those that are long-established, manifest themselves early in development and are mostly irreversible after teeth have been formed and erupted.

Over the past decades, models of enamel disorders have been generated to study different aspects of the developmental pathways involved. Genetic manipulation and proteomic tools have revealed many of the major players in amelogenesis, and both animal models and cell lines have proven useful. Although studies employing cells derived from these models have produced a wealth of important basic science knowledge, these models have limitations and are compounded by the fact that results from different laboratories do not always reconcile well with each other. The next frontier for accelerating research in enamel formation and restoration lies in developing new innovative models and identifying optimal conditions and factors necessary to recapitulate amelogenesis reliably and reproducibly. Importantly, to meet this need, and to facilitate translation of laboratory findings to the clinic, these models need to be physiologically relevant to enamel development in humans.

Advances in developmental and stem cell biology, bioengineering, microfabrication, and three-dimensional (3D) in vitro systems-based technologies may prove useful in fulfilling current needs for advanced model systems to study enamel development and maturation. For example, organoid and 3D tissue culture systems incorporating multiple interacting tissue types (also known as Microphysiological Systems or Tissue Chips) are being developed and utilized to mimic complex tissues and organs. Incorporating ameloblasts into such bioengineered in vitro platforms could be highly beneficial, given their polarized nature, requirement for positional cues, and high metabolic rates. It has been demonstrated that 3D co-cultures can closely mimic the native tissue environment and can incorporate biological and mechanical cues not present in traditional flat-plate culture systems; such sophisticated 3D cultures hold significant promise for adaptation to enamel research.

Additional opportunities are also available in the field of cellular reprogramming and controlled differentiation of induced pluripotent stem cells (iPSCs) towards the ameloblast lineage. While certain advances have been made in generation of tooth-like structures from iPSCs, additional work is needed to elucidate the mechanistic aspects of these processes and to understand their relevance to normal enamel development and morphogenesis. Gene editing techniques such as clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated nuclease 9 (Cas9) are allowing unprecedented ease of manipulating specific genetic targets. The CRISPR-Cas9 system is now being widely used to introduce specific genetic changes to develop new cell lines and animal models. Moreover, the ability to knock-in or knock-out multiple genes simultaneously has the potential to recapitulate complex diseases and conditions, ultimately contributing to our understanding of normal physiology and disease pathogenesis.

The objectives of this FOA are to 1) generate new and improved models that closely mimic physiological enamel development and maturation to enable studies of amelogenesis, and 2) validate those models to ensure they are robust and accurately reflect human physiology and pathology. These efforts may include generating animal models or establishing 3D co-cultures or organoids composed of different cell types and incorporating biological signals necessary for differentiation, maintenance, and function of ameloblasts. As such, tools and approaches to establish and validate these models will be needed. It is expected that scientists from multiple disciplines will collaborate to develop these models, and that this work will accelerate understanding of multiscale processes of enamel formation and inform strategies to mitigate diseases affecting enamel and associated structures, as well as to restore enamel.

This initiative is intended to encourage enamel researchers to examine the needs of the community in developing novel or improving existing models. Applicants should describe how their model will advance research in the field and overcome existing limitations of models that are currently available. Projects may begin with any stage of amelogenesis, and more than one model may be developed in one application provided they are distinct and can all be completed within the constraints of the project period and budget. Collaborations between researchers and clinicians are particularly encouraged, with clinicians on the teams defining clinical needs for mitigating diseases and conditions affecting enamel.

In order to be useful to researchers, models must be transferable to other laboratories and must consistently produce the anticipated results, endpoints, and outcomes, as measured by well-defined assays. Consistent with the effort on NIH’s policy on Rigor and Reproducibility, there is a need to validate these models so they can be widely used by researchers in the enamel field. It is expected that the groups funded through this program will cross-validate each other's models.

This FOA uses the Phased Award Cooperative Agreement (UG3/UH3) mechanism, which requires that milestones be met in the first phase of the award (UG3) in order to proceed to the second phase (UH3). Milestones for the UG3 first phase must be outlined in the Appendix of the application, as detailed below, and will be negotiated and agreed upon with NIH Program Staff prior to any award. Programmatic assessment of accomplished milestones achieved during the UG3 will guide the decision to allow advancement to the UH3 second phase. It is recommended that potential applicants discuss research plans in advance with NIDCR Program Staff.

Examples of topics include, but are not limited to those listed below:

• Developing novel genetic animal models of human diseases and conditions affecting enamel development and maturation
• Developing models that allow assessment of factors associated with human disease (e.g., fluoride, lifestyle variables, environmental toxins)
• Developing 3D co-cultures that include multiple cell/tissue types, along with platforms, instrumentation, advanced biomaterials, or media, to recapitulate ameloblastogenesis and/or enamel maturation
• Determining chemical, biological, and mechanical variables that can maintain undifferentiated pre-ameloblasts, as well as induce controlled differentiation of pluripotent cells into different ameloblast stages
• Isolating and/or generating ameloblasts at various stages of enamel formation that will allow for detailed mechanistic studies. These cells must maintain normal karyotype within the duration of the study

Projects which will be considered non-responsive include:

• Further characterizing cells already in use by the research community
• Studies focusing on synthesis of chemical substitutes of enamel
• Developing materials/devices without associated biological components as defined by the goals of this FOA
• Deriving and utilizing transformed and/or tumor-derived cell lines for above-referenced studies
• Genetically modifying human embryonic stem cells

This phase must be focused on final validation and cross-validation of the newly-developed or improved models resulting from the UG3 phase of the project. The validation phase will show physiological relevance of the model. Specifically, cellular models should closely mimic structure, function, phenotype, and physiology of the ameloblasts and their extracellular microenvironment; and diseased animal models should mimic a disease or condition that is clinically significant. The work during this phase will sufficiently validate the models to enable seamless utilization of the models by other users in accordance with requirements of the Authentication of Key Biological and/or Chemical Resources section in NIH applications. Validation should include appropriate functional readouts or endpoints to enable quantitative evaluation. In addition, as part of this cooperative agreement mechanism, PD(s)/PI(s) of the awarded grants are expected to cross-validate each other's models in the UH3 phase.

Examples of appropriate goals for the UH3 phase include, but are not limited to:

• Validating function such as secretion, molecular transport, structural integrity, supporting architecture, etc.
• If the model is designed to study secretory processes, ensuring that:
• Proper movement of inorganic and organic molecules and macromolecules occurs
• Expected changes in cell/tissue morphology corresponding to physiologic function are displayed (e.g., Tomes processes, ruffled and smooth borders)
• If the model is designed to study the mineralization process, ensuring that:
  • Consistency of organic and inorganic mineral content corresponding to appropriate amelogenesis stages can be demonstrated
  • Orientation, spacing, and physical/mechanical properties of enamel extracellular matrix and crystals to mimic those in native enamel can be demonstrated
• If the model is designed to study developmental processes ensuring that:
  • Appropriate biomarkers are available to identify the developmental and functional stage of the model
  • Appropriate cell migration and cell-cell interactions take place as verified using high-resolution cell tracking/imaging methodologies
• Carrying out quantitative comparisons between the model and human disease
• Implementing plans for quantitative comparisons and cross-validation between similar models
• Updating resources and repositories in which data and the model were deposited

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization 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 support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Dr. Yasaman Shirazi
Telephone: 301-594-5593
Fax: 301-480-8303
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Intellectual Property (IP)

Applications must include an Intellectual property (IP) strategy, if appropriate. Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials. This section should describe a dissemination plan that involves patent protection and commercialization.

Applicants should describe the IP landscape surrounding their model system. Applicants should describe any known constraints that could impede sharing of their model system (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar model systems that are under patent protection and/or on the market, etc.) and how these issues could be addressed with achieving the goals of this program.

Applicants should include a letter (see letter of support) from any entity who has ownership of the IP indicating whether they will provide the technology, if there are any limitations on the studies that can be performed with that technology, agreement about public disclosure of results (including negative results), and whether there is an agreement already in place.

If patents pertinent to the technology being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated US Patent and Trademark Office links, if applicable.

Applicants should discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions. Applicants should clarify how IP will be shared or otherwise managed if multiple PD/PIs and institutions are involved, consistent with achieving the goals of the program.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: Include a brief overview of the context and overall rationale for the proposed set of studies, emphasizing how the model being developed will significantly contribute to the studies of amelogenesis and how this knowledge can translate to the clinic. In addition, present a separate objective for the UG3 and UH3 phases along with the technical questions to be answered to determine the feasibility and validity of the model.

Research Strategy: The Research Strategy should include the following sections:

• Rationale and Unmet Need
• Preliminary data to support and justify the proposed hypothesis, rationale, or development plan should be included. Data that demonstrate technical capacity of the model should be included for assessing the feasibility of the proposed study. However, preliminary data are not strictly required for the UG3/UH3 application.
• Whenever possible, investigators are encouraged to describe the model’s translational potential and the advantages of the model over currently available ones.
• For study of a disease, applicants should describe the value of the model in predicting the course and progression of a human disease.
• Approach
• The Approach must contain separately labeled sections that describe the specific aims for the UG3 and UH3 phases. Research design and methods could be presented as needed for either of the phases, however, it is not necessary to repeat information or details in the UH3 section that are described in the UG3 section.
• Plans for internal replication of model
• This section should include plans of how the model will be tested in the UG3 phase to ensure successful replication of the model. The PDs/PIs should include criteria that will be established at the beginning of the study.
• Internal reproducibility is expected in the originating laboratory as a part of reaching the corresponding milestones.
• Plans for validation of the model
• PD/PIs of the awarded UG3/UH3 in this program are expected to cross-validate models of the other PD/PIs in this program.
• Validation should be based upon how the model represents the developmental stage of ameloblastogenesis and enamel maturation as determined by criteria established at the beginning of the study. Mechanical readouts and endpoints are expected. If the model represents a disease state, applicants should indicate how the model can recapitulate aspects of the disease phenotype and etiology.
• Appropriate statistical methodologies and analyses must be described in sufficient detail. For additional information, see: https://grants.nih.gov/reproducibility/index.htm.
• Timeline
• A timeline must be included demonstrating feasibility of model generation, data collection, and analysis within the budget and time constraints for both phases.
• The proposed timeline should be clearly delineated and indicate when anticipated components of the UG3 and UH3 phases, including milestones of the project, will be completed. Be sure to allocate time (but not necessarily budget) for material transfer agreements and related activities, especially those associated with shipping/quarantine of animals at other institutions. The timeline should appear as the last element of the Research Strategy Section.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Description must include what resource/data/protocol will be initially stored but not shared, what resource/data/protocol will be immediately and freely accessible to the public, and what resource/data/protocol will require prior approval before sharing. Indicate how these processes will occur. Be sure to describe plans for how data will be Findable, Accessible, Interoperable, and Reusable (FAIR) during and beyond the project period of the grant. Include timeframes of when the open access resource will be operational, and how requests for information or data will be handled and granted. If the open access resource will be created solely for this project, plans for continued support of that resource after the funding period of this FOA has ended must be included. If plans involve using an existing open access resource, such as www.FaceBase.org, details of how the resource/data/protocol will be incorporated must be included.

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. with the following modifications

Milestones for UG3 Transition to UH3 must be included in the Appendix

• The application must include milestones that are expected to be achieved by the end of the UG3 phase. Reaching these milestones is required for transition from the UG3 to UH3 phase. Milestones should be clearly defined, quantifiable, and scientifically justified to allow the investigator and NIH Program Staff to assess progress in the UG3 phase. Milestones should not be a restatement of the specific aims for the UG3 phase. A discussion of the milestones relative to the progress of the UG3 phase and the implications of successful completion of the milestones for the execution of the UH3 phase should be included.

All applications must include the following milestones at a minimum in the Appendix:

• Attainment of prototype/animal/cell model that is verified and quantified by appropriate assays (e.g., sequencing, gene expression, immunohistochemistry, imaging, mechanical testing, etc.)
• Successful implementation of protocols and best practices for generating the model (provide quantitative targets demonstrating model retains the genotype/phenotype/karyotype/functionality for the duration of the study)
• Verification of internal, within laboratory reproducibility in generating the model (provide definitions of the targeted levels for evaluating and ensuring reproducibility, robustness, viability of the cellular components, and integrity)
• Deposition of protocols and data describing properties and manipulating/handling of the model in an open access resource such as www.Facebase.org that facilitates storing and sharing

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

All applications must include the following:

• Specific aims for the UG3 Developmental Phase
• Clear milestones for UG3 transition to UH3 that allow for go/no-go decisions
• Separate specific aims for the UH3 Validation Phase (to include description of how model validation will be accomplished)
• Timeline demonstrating feasibility of model generation, data collection, and analysis within the budget and time constraints for both phases
• Description of how the model and/or data will be made accessible to the scientific community (model organism, resource, and data sharing plans must be sufficiently detailed with timeframes, and request and transfer processes) as appropriate and consistent with achieving the goals of the program, and any Intellectual Property Strategy where applicable (see Other Project Information under Section IV of this FOA)
• Letters of support from all collaborating laboratories describing communication plans throughout the life of the grant

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does the model have the potential to demonstrate physiological relevance to humans to facilitate transfer from the laboratory to the clinic? Does the model have the potential to recapitulate aspects of a disease phenotype and etiology, as applicable? Is there a demonstrated unmet need the model can fill? Is it likely the model will advance research in the field and overcome limitations of existing models?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Are the investigators knowledgeable and experienced about the biological target and/or disease biology? Do the PD(s)/PI(s) involve collaborators commensurate with the multidisciplinary nature of the project? Are the roles of each collaborator carefully defined in the research plan? Does the investigative team have relevant experience to develop or generate the model, and evaluate robustness and validity of the model?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Does the model constitute significant improvement/enhancement of currently available models in enamel research? Does the model have the potential to overcome hurdles currently preventing progress in the field?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects? Are there separate specific aims for the UG3 and UH3? Are plans sufficient to adequately assess the models and ensure their robustness? Are there plans for replication and verification of the model? Is there a description of how to validate the model including readouts or endpoints? Are there plans to cross-validate with other groups? Will the proposed validation process clearly establish that the model represents specific developmental stage(s) or functions? Are quantitative comparisons planned between the model and human disease or between similar models? Are appropriate statistical methods and analyses included in sufficient detail?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Milestones and Timelines

Are milestones associated with clear, quantitative criteria for success that allow go/no-go decisions? If a criterion is not to be used for go/no-go decisions, is it justifiable? Are there additional key experiments that need to have milestones designated? Do the milestones allow for the evaluation of progress in the UG3 phase and will successful completion of these milestones provide confidence that the PD(s)/PI(s) will be able to successfully implement the UH3 phase?

Are the measures for model verification and quantification appropriate and adequate to determine the model has been attained? Does the model successfully demonstrate the genotype/phenotype/karyotype/functionality will be retained for the duration of the study as implemented with the protocols and best practices? Are the definitions for internal reproducibility quantitative and adequate to ascertain reproducibility, robustness, viability of cellular components, and integrity of the model?

Can the model be generated/fabricated, and data collected and analyzed within the timeframe and budget constraints of the respective phases? Are the timelines realistic for achieving the milestones? Does the timeline include anticipated dates for completing essential components of the UH3 phase?

Intellectual Property

If applicable, is the IP Strategy adequate? Does it include the applicable components listed in Section IV "SF424(R&R) Other Project Information" (i.e., letters from IP owners, information about patents filed or to be filed) of this FOA? Does it address issues that may affect sharing of the model? Is the dissemination plan that involves patent protection and commercialization acceptable?

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Not Applicable

Not Applicable

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Letters of support

Reviewers will assess whether letters of support from each of the collaborating laboratories are included. PD(s)/PI(s) are not required to provide evidence of prior collaborative relationships, however, a plan should be included describing how findings will be communicated with each other throughout the life of the grant.

Not Applicable

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS). Reviewers will also assess whether the description for what types of data/resource/model properties/protocols will be stored, openly shared, not shared initially, or selectively shared on a prior approval basis is included and whether these processes are Findable, Accessible, Interoperable, and Reusable, and operational within the time frame of the two phases.

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIDCR's Scientific Review Branch, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Dental and Craniofacial Research Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. 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.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Prior to funding an application, NIH Program Staff may contact the applicant to discuss the proposed milestones and any changes suggested by the review panel. A final set of approved milestones will be specified in the Notice of Award.

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 and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• The NIDCR Program Official will be responsible for negotiating before award a set of clearly defined and quantitative milestones, based on those proposed in the application as well as from comments from the review panel. At the end of the UG3 phase, the NIDCR Program Official will be responsible for evaluating whether the milestones have been met in order to transition to the UH3 phase. Cross-validation in the UH3 phase will be facilitated by the Program Official. Additionally, an agency Program Official and/or Project Scientist will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

• PD(s)/PI(s) of projects which have successfully transitioned to the UH3 phase are expected to cross-validate models of the other PD(s)/PI(s). All other responsibilities are divided between awardees and NIH staff as described above.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. The Dispute Resolution Panel will have three members (with one vote each): a designee of the award governing body chosen without NIH staff input, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two Panel members. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Jason Wan, PHD
National Institute for Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-9898
Email: [email protected]

Yasaman Shirazi, PHD
National Institute for Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-5593
Email: [email protected]

Diana Rutberg, MBA
National Institute for Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

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 Part 52 and 45 CFR Part 75.