Required Application Instructions

It is critical that applicants follow the 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

Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response, and epigenetic regulation of gene expression. Mitochondria play a central role in these pathways, not only through energetics and ATP production, but also through activities of metabolites generated in the tricarboxylic acid (TCA) cycle, and mitochondrial-nuclear signaling related to mitochondrial morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation. Mitochondrial processes can affect epigenetic regulation of nuclear-encoded genes through generation of TCA metabolites, including acetyl CoA, ATP, NAD+, and α-ketoglutarate, which are required for the activities of proteins involved in histone modifications (e.g., acetylation and methylation) and DNA methylation proteins (e.g., TET enzymes).

Recent studies suggest that both endogenous and exogenous stressors (e.g., toxic metals, pesticides and air pollution components) can induce altered epigenetic patterns including histone modifications and altered DNA methylation of nuclear-encoded genes, possibly through mitochondria-mediated responses to changes in energetics and/or ROS signaling. Mitochondria are also tightly integrated with cellular responses to DNA damage to both mtDNA and nuclear DNA, and are clearly involved in sensing and responding to ROS and oxygen levels in the cell. A deeper understanding of signaling (cross-talk) between the mitochondria and the nucleus or other cellular response pathways will lead to a more comprehensive understanding of how cells sense and respond to environmental stress, forming a more solid basis for developing early biomarkers for environmentally-related diseases.

Current approaches are often limited by the lack of precise measures of specific ROS/reactive nitrogen species (RNS), probes for mitochondrial metabolites, or experimental systems to characterize mitochondrial-cell signaling pathways, including signaling between the mitochondria and nucleus with respect to epigenetic regulation, response to changes in ROS, or DNA damage response. Therefore, this FOA supports the development of technologies and experimental models that will enable a more comprehensive understanding of mitochondrial-cell signaling in response to environmental stressors.

This FOA uses the R21/R33 Phased Innovation Award mechanism to support the development and application of technologies and experimental models that will enable the detection of mitochondrial-cellular signaling pathways in response to environmental stressors. Improved detection technologies and enhanced experimental models are needed to more effectively explore mitochondrial-cellular cross-talk and signaling. For example, characterizing the role of small molecules that mediate this cross-talk will require development and application of tools to measure metabolites and individual ROS or RNS with increased sensitivity and specificity. Development and application of enhanced experimental models, including in vitro systems and model organisms will also be needed to identify cross-talk and signaling under baseline and environmental stress conditions. Although mitochondrial toxicants, electron transport chain (ETC) complex inhibitors, or genetic knock-down of mitochondrial genes may be used to induce mitochondrial dysfunction leading to altered signaling, applications to this FOA must use at least one environmental toxicant in the development, and application of these technologies. Examples of environmental toxicants include, but are not limited to, pesticides, air pollution components, industrial chemicals, toxic metals, endocrine-disrupting compounds, ultraviolet light and ionizing radiation, and toxins produced by pathogenic organisms. However, pathogens themselves are not considered environmental stressors; use of pathogens in the development of these technologies is not responsive to this FOA. Effects of signaling in response to environmental stressors can include altered epigenetic regulation (e.g., changes in transcriptional programs from altered DNA methylation or histone modifications), activation of DNA damage response pathways (including DNA repair and apoptosis pathways), changes in global expression or post-translational modifications to the mitochondrial proteome, or mitochondrial-cellular signaling in other stress response pathways involving ROS/RNS, nutrient stress, or endoplasmic reticulum stress. Mitochondrial functions and signaling pathways will vary by cell type; projects developing technologies or approaches for elucidating mitochondrial-cell signaling in specific cell types or comparing signaling between cell types are appropriate for this FOA.

R21 Phase

The initial activity is a two-year exploratory research project focused on developing and demonstrating the performance of the technology or experimental model at the pilot scale using at least one environmental toxicant.  This includes demonstration of sensitivity and specificity of probes or reagents used to detect individual ROS/RNS, mitochondrial metabolites, or other small molecules that mediate mitochondrial-cell signaling. Improved or enhanced in vitro or in vivo experimental models should focus on mitochondrial-cell signaling pathways that are highly conserved between these model organisms and humans. Applicants must develop a set of appropriate milestones that must be adequately demonstrated by the completion of the R21 phase to transition into the second application and validation phase. For example, sensitivity and specificity for reagents for ROS/RNS or probes for mitochondrial metabolites should be clearly demonstrated in the R21 phase. For experimental models, R21 milestones should include demonstration of functional changes in transgenic, knock-down models with respect to altered mitochondrial endpoints or other cellular pathways. Final milestones will be negotiated with program staff as a term and condition of the award. 

Examples of technology development include but are not limited to:

• Improved reagents for sensitive detection of individual ROS and RNS, or probes for imaging or tracking mitochondrial metabolites including real time, in vivo detection capabilities.
  
  
• Expanded metabolic flux analysis capabilities, that may include new approaches for labeling metabolites, improved computational methods, or application of existing flux analysis approaches to mitochondrial metabolites (e.g., citrate, acetyl-coA, α-ketoglutarate, or NAD+/NADH) in different cell types.

Examples of improved experimental models include:

• in vitro studies using either embryonic stem (ES) cells or induced pluripotent stem (iPS) cells to characterize signaling and cross-talk in different cell types. For example, iPS cells from patients with inherited mitochondrial defects differentiated into specific cell types could be used to evaluate altered sensitivity to mitochondrial toxicants compared to unaffected individuals.
  
  
• application of lower organism models including yeast, C. elegans, D. melanogaster, or zebrafish to probe signaling under environmental stress conditions, including the effects of environmental stressors on mitochondrial-cellular signaling during critical windows in development.
  
  
• mouse models or other appropriate experimental models that incorporate effects of genetic diversity can be used to probe signaling networks.

R33 Phase

Following an administrative review of progress in the R21 phase, each awarded application will have the potential to progress into the R33 phase. This stage will allow the applicant to now focus on larger scale application and testing of the technology or approach, pending the availability of funds.  The intent of the R33 phase is to apply novel technologies or experimental models to a focused study of bi-directional communication between mitochondria and other cellular pathways under normal and environmental stress conditions. This will be up to a three-year study based on the needs of the research aims and progress made in the R21 phase.

Areas of research could include:

• expanding the elucidation of mitochondrial-cellular signaling with single environmental toxicants, particularly signaling between the mitochondria and nucleus, to the effects from a range of diverse environmental stressors. Traditional environmental toxicants can be used in combination with mitochondria-specific toxicants (e.g., complex inhibitors, or uncoupling agents) or genetic knockdown of mitochondrial genes to alter normal mitochondrial function and examine the effects of environmental stressors on epigenetic regulation, DNA damage response, ROS signaling, or other cellular response pathways.
  
  
• conducting limited omics studies, including flux analysis, metabolomics, global DNA methylation or chromatin modifications, global expression of mitochondrial proteins, or post-translational modifications of mitochondrial proteins (including acetylation).
  
  
• applying new probes, reagents, or experimental models to characterize differences in mitochondrial-cellular signaling in different cell types.
  
  
• integrating changing metabolite profiles or kinetics (flux) with other signaling endpoints (epigenetic patterns, protein expression or post-translational modifications) under environmental stress conditions.
  
  
• evaluating the effects of altered cellular response programs on mitochondrial functions including, altered mitochondrial respiration and energetics, mitochondrial dynamics and trafficking, fission and fusion, biogenesis or mitophagy.
  
  
• limited application of mitochondrial-cellular signaling studies to human population studies, e.g., pilot studies to demonstrate the feasibility of detecting signaling networks in human samples

Phase Transition

Transition to the R33 is not automatic, and not all R21s awarded will result in an R33 award. The materials in the transition package will be reviewed by NIEHS Program staff on the basis of:

• Success in completion of milestones
• Programmatic priority
• Availability of funds

Applications that do not include a traditional environmental toxicant in both the R21 and R33 phases will be deemed non-responsive. Examples of environmental toxicants include, but are not limited to pesticides, air pollution components, industrial chemicals, toxic metals, endocrine-disrupting compounds, ultraviolet light and ionizing radiation, and toxins produced by pathogenic organisms. However, the pathogens themselves are not considered environmental stressors; use of pathogens in the development of these technologies is not responsive to this FOA. Dietary factors may be used in conjunction with environmental toxicants, but in this FOA are not considered environmental stressors themselves. Likewise, failure to include detailed plans for both pilot evaluation in the R21 phase, application and validation in the R33 phase and appropriate milestones will result in the application being deemed incomplete. If there are questions about whether exposures or stressors are responsive to the FOA, please contact the Scientific/Research contact listed in this announcement.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are 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).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows.  The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the 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:

Leroy Worth, PHD
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
PO BOX 12233, MD K3-03
Research Triangle Park, NC 27709-2233
Telephone: 919-541-0670
Email: worth@niehs.nih.gov

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

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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.

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

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

R21 grant awardees will be required to meet toward the end of the grant period to review progress, and share information on the R21 milestones and before submitting the transition package for review and consideration for the R33 award. This workshop will be planned by NIEHS Program Administrator. Applicants should request travel funds in their budgets.

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: The R21 and R33 phases should have distinct and clearly enumerated specific aims; both phases should be included in a single specific aims section.

Research Strategy: This should contain a single background section which gives detailed justification for the development of approaches to identify mitochondrial-cell signaling with environmental stress, the need for detection technologies or experimental models, and a detailed description how these approaches will developed and tested. 

The Research Strategy should also include a dedicated section detailing plans for the R21 phase including discussion of the feasibility of the proposed approach to better characterize mitochondrial-cellular signaling.  This section must also include quantitative milestones, when applicable or demonstration of functional changes in experimental models (e.g., transgenic or knock-down models) with respect to altered mitochondrial endpoints or other cellular pathways to be achieved by the completion of the R21 phase and a Gantt chart timeline.  Milestones should not be a restatement of the R21 specific aims.

The Research Strategy will also include a detailed description of the R33 Phase. The R33 Phase must describe the effort apply and/or expand technologies or experimental models to studies of bi-directional communication between mitochondria and other cellular pathways under normal and environmental stress conditions.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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 by the Center for Scientific Review and responsiveness by National Institute of Environmental Health Sciences, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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?

Innovation

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?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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? 

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?

Environment

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.

Protections for Human Subjects

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.

Inclusion of Women, Minorities, and Children 

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.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

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.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

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).

Resource Sharing Plans

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) Genome Wide Association Studies (GWAS).

Budget and Period of Support

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 the National Institute of Environmental Health Sciences, 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 Environmental Health Sciences 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. 

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.

Transition packages should include a detailed description of progress in completing milestones from the R21 phase, including quantitative results when applicable, and any changes proposed in R33 aims based on results from the R21 research. If at the completion of the R21 phase the investigators do not feel that adequate progress towards milestones has been achieved, they may request up to one year of no-cost extension.  At any point during that year they may submit an R33 transition package as described above.  Only in unusual circumstances will a second no-cost period be granted for the R21 phase.  A no-cost extension will not count against the five year time limit of the study.

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 the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

A final progress report, 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.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
TTY: 301-451-5939
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

Daniel Shaughnessy, PhD
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-2506
Email: shaughn1@niehs.nih.gov

Leroy Worth. PhD
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-0670
Email: worth@niehs.nih.gov

Wanda Boggs
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-316-4638
Email: boggsw@niehs.nih.gov

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 Parts 74 and 92.