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

Environmental exposure induced perturbations of epigenomic marks are correlated with multiple aspects of disease pathogenesis. In 2012, the National Institute of Environmental Health Sciences established the multi-phased Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET) Program to further address the role of the environment in disease susceptibility as a function of changes to the epigenome. The first phase of this program, TaRGET I (RFA-ES-12-008, TaRGET I: Chromatin Structure, Genomics, and Transcriptional Responses to the Environment), solicited and funded applications that support environmental health scientists' pursuit of research objectives aimed at understanding the environmental control of epigenetic mechanisms. These grants consider the impact of environmental toxicants on the following processes: nucleosome positioning, chromatin accessibility, chromatin remodeling and the role of non-coding RNAs. However, identifying exposure-induced changes in tissues/cells affected by disease is not always feasible in humans. The purpose of this Funding Opportunity Announcement is to establish the TaRGET II Consortium which will assess the utility of surrogate tissue epigenomic analysis as a means to examine the role of environmental exposures on epigenomic marks in target tissues. The goals are: to enhance our understanding of the relationship between exposure-induced perturbations of epigenetic marks in target versus surrogate tissues; determine conditions where these studies will be valid; and aid in the interpretation of the results of such studies. Applications submitted in response to this FOA must propose aims that focus on disease relevant environmental exposures and evaluate epigenomic changes or patterns of changes in surrogates that may serve as potential biomarkers of exposure associated pathologies. This FOA is published in parallel with a companion FOA, RFA ES-015-002, TaRGET II: Environmental Epigenomics Data Coordination Center (U24). Projects funded by these FOAs will collectively form the TaRGET II Consortium (T2C) and will develop a publically accessible database that provides data to the broader scientific community on the conservation of environmental exposure induced epigenomic changes in target tissues and cells and selected surrogates.

Different cell types have distinctive patterns of epigenetic regulatory marks, such as DNA methylation and post-translational histone modifications that are associated with specific transcriptional programs. Exposure to environmental toxicants/chemicals can lead to changes in these normal epigenetic patterns, and may be associated with the development of environmentally-induced disease. For example, exposure to heavy metals such as arsenic and nickel is associated with epigenetic changes that may underlie the development of diseases known to be associated with these exposures, such as cancer, cardiovascular disease, neurological disorders and autoimmune disease.

One of the challenges in making direct connections between exposure-induced epigenetic changes and health outcomes in human populations is that it is not always easy to obtain the tissues that are directly involved in disease pathogenesis. Increasingly, researchers rely on tissues indirectly implicated with disease pathogenesis to conduct analyses, such as those found in peripheral blood, buccal cells, or skin cells. For the purposes of this announcement, we will refer to these cells/tissues as surrogate tissues . We use the term 'target tissues' to refer to cells/tissues in which the environmental exposure induces changes directly correlated with disease progression.

Furthermore, it is not clear whether the epigenetic changes that may have contributed to the development of the disease are conserved in surrogate tissues. Conversely, if an epigenetic change is observed in a surrogate tissue, what is the likelihood that the same or similar changes or pattern of changes will also be found in the target tissue? It is anticipated that in some cases, modifications of epigenomic marks will be conserved across target and surrogate tissues and in other cases, conservation may not occur or be so straightforward as modifications and/or conservation of modifications may depend on timing/dose of exposure and/or other variables. Determining the utility of surrogate tissue epigenomic analyses in a tractable model system will enable more effective use of population-based studies to make connections between exposure, epigenetic changes, and the development of disease. The TaRGET II program is being developed to address this research gap, as well as to gain additional insight into the nature of epigenetic changes induced by exposure. The purpose of this program is to characterize the epigenetic changes that are induced by environmental exposures in a variety of tissues and cell types, to investigate the factors, such as the timing of exposure, that influence whether induced changes are conserved across tissues, and to assess the utility of surrogate cell types for epigenetic analyses in environmental health research.

This FOA and its companion (RFA-ES-15-002) will support the epigenetic analysis of selected tissues/cells from mouse models that have been exposed to environmental toxicants and utilize epigenomic analyses of surrogate tissue/cells to predict locus specific and/or genome-wide epigenetic modifications. The goal of these two FOAs is to form a consortium that studies the conservation of exposure induced epigenetic perturbations in surrogate tissues and their relationship to environmental perturbations in target tissues. A key challenge for the consortium will be to develop conceptual frameworks that identify how the degree of conservation of epigenomic marks or signatures depends on key experimental factors (e.g., diseases, timing of exposures). Applications should demonstrate capacity to perform high throughput epigenomic analyses and have appropriate toxicological expertise as part of their investigative teams. Applicants are advised that specific exposures they propose may not be the exposures they actually perform as final determination of exposures and tissue selection as well as tissue sharing procedures will be determined collaboratively post award and involve the members of the T2C Steering Committee. The T2C will be constituted by the TaRGET II investigators, TaRGET Environmental Epigenomics Data Coordinating Center investigators and NIEHS program staff.

The objectives of the T2C are to:

• Produce comprehensive, high resolution, experimental data depicting the impact of select environmental exposures on epigenetic marks in specific target and surrogate tissue/cell types.
• Collaborate within/across the membership of the T2C to deliver appropriate environmental epigenomic data sets to the broader scientific community;
• Facilitate additional data analyses to integrate data from Consortium members from specific target: surrogate pairs for different epigenetic marks;
• Conduct ancillary studies to develop limited data on functional aspects of epigenetic control of gene activity.

Applications must propose use of mouse models of environmentally relevant diseases to assess epigenomic modifications in selected tissues and surrogates. The objective should be to collect from both exposed and unexposed animals target cells from the affected organ involved in a disease, with the assumption that this would generally be a challenge because of the poor accessibility of these organs. Epigenome wide studies may ask whether there are exposure induced epigenetic changes that differentiate target tissues in exposed animals from target tissues in unexposed animals, and which, if any, of these patterns are conserved in the surrogate tissues. Questions may be posed to address whether epigenetic perturbation associated with exposure is present in multiple tissues, whether it occurs at the same or different loci, and to what degree.

Examples of surrogate tissues may include but are not limited to:

• Airway epithelial cells and the more readily accessible nasal epithelial cells in studies of respiratory diseases.
• Pulmonary and nasal microphages
• Buccal epithelial cells
• Peripheral blood leukocytes
• Skin cells
• Exfoliated cells from GI tract, uterus, kidney, bladder or other organs
• Cerebrospinal fluid cells

Examples of target tissues include but are not limited to cell populations or sub-regions of the following:

• Brain
• Liver
• Heart
• Lung
• Uterus
• Pancreas
• Kidney

A range of toxicants or a range of target tissues may be proposed and selection of target tissues should be relevant to disease outcomes associated with exposures to the selected toxicant(s). These may include but are not limited to:

• Metals, e.g., As, Cd, Pb, Ni, Hg
• Endocrine disrupting chemicals e.g., BPA, genestein, phthalates, tributyl tin, brominated flame retardants
• Pesticides
• PAHs
• Airborne particulates
• Environmental tobacco smoke

Applications that use psychosocial stressors, dietary exposures, or mixtures will not be considered responsive to the FOA and will not be reviewed. If there are questions about whether exposures or stressors are responsive to the FOA, please contact the Scientific/Research contact listed in this announcement.

There are multiple factors that may influence or contribute to variability in epigenomic marks and complicate the interpretation of studies. Applications should address potential sources of variability including but not limited to:

• The age of animals and timing of exposure should be key components of applications as it relates to exposing developing animals during certain windows of susceptibility considering gestational age, perinatal, neonatal, juvenile periods or in adult animals, as the timing of exposure(s) may be critical to disease susceptibility, perturbation of epigenomic marks and/or conservation of epigenomic signature perturbations across target and surrogate tissues.
• Intra-individual epigenetic variability as different cell types and tissues from the same individual will have different epigenomic patterns that are cell type specific
• Tissue heterogeneity which may lead to diluted epigenomic signals from target tissues, so applicants are encouraged to use purified cell populations if possible or otherwise describe how they will address the heterogeneity issue.
• Underlying genetic sequence/diversity may contribute to variability in response to environmental stressor induced changes in epigenomic marks in target and surrogate tissues. Thus applicants are encouraged that utilize different mouse strains or represent genetic diversity such as Collaborative Cross or Diversity Outbred mouse models, or other appropriate genetic models of environmentally relevant diseases in mice.
• Sex
• Software packages to be utilized for data analysis

Proposed studies investigating DNA methylation, histone modification, chromatin accessibility, nucleosome position, chromatin remodeling, microRNAs or long ncRNA interactions with chromatin are of the highest scientific priority. Applicants are encouraged to propose use of high throughput next generation sequencing technologies e.g., reduced representation bi-sulfite sequencing(RRBS), whole genome bisulfite sequencing platforms, ChIP-seq, RNA-seq, NOME-seq, ATAC-seq, etc.

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).

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, including Supplemental Grant Application Instructions 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
National Institute of Environmental Health Sciences
PO BOX 12233, MD K3-03
Research Triangle Park, NC 27709-2233
Telephone: 919-541-0670
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.

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

All instructions in the SF424 (R&R) Application Guide must be followed. Applicants are required to allocate budget for annual grantee meetings to be convened on the NIEHS campus in Research Triangle Park, NC for each of the four award years.

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:

Research Strategy

• The post award selection and assignment of specific toxicant exposures and tissues to individual Consortium members is a critical function of the T2C Steering Committee and applicants should indicate in their applications their flexibility and capacity in cooperating with the goals of the Consortium.
• Applicants must indicate in their willingness to participate as a member of the T2C which will require coordination of which specific environmental exposures are used, sharing of tissues between investigators and regular submission of data and supporting documentation to the Data Coordinating Center.

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:

• All applications should address a Data Sharing Plan.
• Applications must include descriptions of data analysis and data sharing that are consistent with the NIH Genomic Data Sharing Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html). Applications without this information will be considered incomplete. Applicants should provide a specific proposal for release of production data in the application, and are encouraged to address the issue of the release of data analyses.Applicants should indicate their willingness to participate in the development of the T2 Steering Committee data release final plan anda commitment to abide by it.

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. 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.

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 the NIEHS, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the NIEHS Referral Office by email at mailto: [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

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.

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?

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? Has the investigative team demonstrated expertise in disease relevant environmental exposures as well as expertise in high throughput next generation sequencing technologies and appropriate expertise in data analysis and informatics?

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?

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? Does the application clearly articulate the investigators' flexibility and capacity to adapt to the objectives and goals that will be defined by the T2C? Does the application include descriptions of data analysis and data sharing that are consistent with the NIH Genomic Data Sharing Policy?

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.

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 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.

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.

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.

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 Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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 initial review, NIEHS program staff will be responsible for any additional administrative review of the plan for sharing data and may negotiate modifications of the data sharing plan with the prospective awardee before recommending funding of an application. The adequacy of the negotiated data sharing plan will be considered by program staff when making funding recommendations. The final negotiated version of the data sharing plan will become a term and condition of the award of the cooperative agreement. After all of the awards have been made, the T2C Steering Committee, of which all awardees will be members, will develop a final, common data release plan as appropriate for the Project that will address the interests of the data producers and analysts, as well as the users of the TaRGET II catalogs. The effectiveness of data sharing will be evaluated as part of the administrative review.

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.

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.

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

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS 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:

The PD/PI (or multiple PDs/PIs, if applicable) will have primary authority and responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of projects conducted. The PD/PI assumes responsibility and accountability to the applicant organization officials and to the NIH for the performance and proper conduct of TaRGET II research in accordance with terms and conditions of the award.

All Program Directors/Principal Investigator(s) of the T2C will have the primary responsibility for:

• Overseeing the budget and activities of the award, as detailed, above.
• Cooperating with other TaRGET II investigators and NIH Staff, as appropriate, in the design and conduct of protocols, analysis of data, and reporting of results of research undertaken by the T2C. This includes, but is not limited to:
  • Providing goals and estimated costs for procedures and protocols.
  • Sharing data, protocols and other research resources generated through the TaRGET II award.
  • Promoting and coordinating cross-TaRGET II scientific collaboration.
  • Ensuring training of study site personnel as needed for standardization of collaborative protocols across sites and for accurate and timely data entry.
• Facilitating the formation of and participating in appropriate Working Groups to promote the exchange of preliminary findings, experiences, protocols, and ideas across the T2C.
• Interacting and complying with requests for information from the T2C Steering Committee and other sub-committees as appropriate.
• Participating in the annual PD/PI scientific meetings, and monthly committee calls organized by the TaRGET II Data Coordination Center, as relevant.
• Cooperating in the program evaluation activities.
• ccepting and implementing all scientific, practical, and policy decisions approved by the TaRGET II Steering Committee to the extent consistent with applicable grant regulations.
• Serving on the T2C Steering Committee (for details, see "Areas of Joint Responsibility" below).
• Providing information to the NIH Program Directors and Project Scientists concerning progress by submitting annual progress reports in a standard format.
• Complying with federal regulatory requirements, including but not limited to those relating to human subjects protections, informed consent, and reporting of adverse events.

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

One or more NIEHS Program Directors will be substantially involved in the T2C as NIH Project Scientists. NIH Project Scientists will have substantial scientific and programmatic involvement that is above and beyond the normal stewardship role in awards. NIEHS Project Scientist(s) will have the following responsibilities to all TaRGET II Consortium awardees:

• Have substantial involvement to guide, coordinate, and participate in the conduct of the T2C activities.
• Attend and participate in all Steering Committee and subcommittee meetings of the T2C.
• Coordinate and facilitate the interactions among the awardees under this U01 cooperative agreement.
• Serve as a liaison between the Steering Committee, the T2C, the NIH and other federal agencies as needed.
• Facilitate and coordinate the exchange of information and interactions between Consortium awardees to support collaborative efforts.
• Participate in organizing and coordinating TaRGET II Scientific meetings as required.
• Advise on the design of research activities, availability of resources, and/or management and technical performance of projects, as appropriate.
• Participate as collaborators to the TaRGET II investigators in some shared activities, if appropriate.
• Assist in avoiding unwarranted duplications of effort across the T2C.
• Evaluate the adherence of TaRGET II awardees to any approved data sharing plans or intellectual property plans.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The NIH reserves the right to adjust funding, withhold, suspend, or terminate the support to those TaRGET II awardee institutions that are unable to meet the performance requirements set forth in these Terms and Conditions of Award, or significantly change the level of performance. The NIH Program Official will be responsible for monitoring the level of performance and making recommendations for any corrective actions.

Areas of Joint Responsibility include:

A Steering Committee will serve as the governing board for the T2C.

• The T2C Steering Committee will have primary responsibility for:
• Overseeing the overall organization of the TaRGET II initiative and for reviewing its research goals. Evaluating the adherence of TaRGET II awardees to any approved data sharing plans or intellectual property plans.
• Developing the appropriate structure of Working Groups to promote the exchange of experiences, protocols, novel research findings, etc. across the TaRGET II Consortium.
• Establishing advisory committees and subcommittees, as necessary, to serve the T2CI Steering Committee and the TaRGET II awardees.
• Making recommendations for re-directing the Consortium's focus in order to accommodate new scientific opportunities and directions.
• Sharing and reviewing annual progress among the components of the TaRGET II Consortium.
• The Steering Committee will be comprised of the following voting members:
  • A research investigator from each individual TaRGET II (RFA ES-15-001), who will have one vote.
  • A research investigator from the TaRGET Environmental Epigenomics Data Coordinating Center (RFA ES-15-002)
  • One NIEHS project scientist, who will have one vote.
• Other NIH staff members may participate in Steering Committee meetings as non-voting members.
• A Steering Committee Chair will be elected every twelve months from amongst the Steering Committee members by the committee. An individual may continue serving as Chair for more than one year if all committee members agree. NIH staff cannot serve as Steering Committee Chair.
• In the event that PDs/PIs cannot agree on critical aspects of the Consortium, such as common protocols, then the Steering Committee, in consultation with NIH Program Staff, will vote on a recommendation for how to proceed. NIEHS Staff will have final authority to implement proposed recommendations. All activities must comply with NIH, DHHS, and Federal Guidelines.
• Other guidelines for the Steering Committee, such as a quorum and frequency and type of meetings (in-person, remote), will be determined at its initial meeting. It is anticipated that the Steering Committee will meet at least once per month by teleconference.

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 will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. 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 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.

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Frederick L. Tyson, PhD
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-0176
Email: [email protected]

Leroy Worth, PhD
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-0670
Email: [email protected]

Michelle Victalino
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-316-4666
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.