NIH’s new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically; paper applications will not be accepted. ASSIST replaces the Grants.gov downloadable forms currently used with most NIH opportunities and provides many features to enable electronic multi-project application submission and improve data quality, including: pre-population of organization and PD/PI data, pre-submission validation of many agency business rules and the generation of data summaries in the application image used for review.

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) and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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

It has been more than a decade since the human genome was completely sequenced. Despite vastly improved technologies and many important foundational discoveries, our understanding of how genomic information specifies proper execution of spatial and temporal gene expression programs remains to be fully elucidated. This knowledge is essential for understanding how cells divide or respond to their environment, for identifying the regulatory mechanisms that control development and are dysregulated in disease, and for studying phenotypic variations among human populations. It is now clear that while mammalian genomes encode genetic information in their linear sequence, the appropriate cell type specific expression of their genes depends on higher order nuclear organization, from the folding of chromosomes into three-dimensional structures, to chromatin loops that connect genes and transcriptional regulatory complexes, to larger chromosomal domains and nuclear compartments. Defining chromatin interactions and the ways in which nuclear architecture constrains/enables interactions, and describing the relationships of genomic regions to transcription, RNA processing and chromatin regulatory machineries, are likely to reveal how individual cells access, read and interpret genetic information. Because this spatial organization of genomes is dynamic, we also need to understand how it changes in response to environmental challenges and cellular processes such as cell cycle, differentiation, or neoplastic transformation. A comprehensive understanding of the contribution of the structural and functional organization of the mammalian genome to development and disease in both space (3D Nucleome) and time (4D Nucleome) will require major efforts.

The Four-Dimensional Nucleome (4DN) was selected by the NIH Leadership as the focus for a Common Fund Program following a series of discussions with panels of scientific experts and stakeholders, and with input from the broad community solicited via a Request for Information early in 2014 (NOT-RM-14-010). The impetus for its selection as a Common Fund program was the growing awareness that understanding the architecture of the cell nucleus may have widespread and profound implications for human health and disease, but our current ability to study nuclear organization is hindered by a number of outstanding technological and conceptual challenges.

Experts from the research community identified the following scientific priorities as areas that represent challenges and opportunities for investment by the NIH: 1) next-generation, high-resolution and high-throughput tools to explore the relationships between nuclear organization and the regulation of gene expression programs, including with single cell resolution; 2) computational tools to integrate existing data sets, and to manage, analyze, and visualize the datasets generated by a community effort; 3) predictive models of nuclear structure/function relationships in the context of various cellular states or transitions (differentiation, reprogramming, cell cycle, responses to external stimuli, disease development); 4) next-generation tools to explore nuclear dynamics through controlled disruption of nuclear conformation, and imaging in live cells and tissues; and 5) pilot maps (using in-development technologies) and reference maps (using robust and validated technologies) of the 3D architecture of the interphase nucleus for a variety of eukaryotic cells and tissues.

The Common Fund 4DN Program has been developed to address these critical issues. The overarching goals of the 4DN Program are to understand the principles that guide the spatial and temporal organization of the nucleus, the role of this organization in orchestrating the transcriptional complexity in individual cells and tissues, and the way in which changes in nuclear organization affect development and disease processes. The Program consists of 6 initiatives, of which this FOA is one. Specifically, the initiatives are:

RFA-RM-14-006 Nuclear Organization and Function Interdisciplinary Consortium (U54)

RFA-RM-14-007 Nucleomics Tools (U01)

RFA-RM-14-008 Study of Nuclear Bodies and Compartments (U01)

RFA-RM-14-009 4D Nucleome Imaging Tools (U01)

RFA-RM-14-010 4D Nucleome Network Organizational Hub (U01)

RFA-RM-14-011 4D Nucleome Network Data Coordination & Integration Center (U01)

Awards funded under these FOAs are anticipated to pursue research activities conducted by multidisciplinary teams of investigators. In addition, all awardees from all 6 initiatives will form the 4DN Network, with the overarching goal of determining the fundamental principles of nuclear organization. Validation and comparisons across studies will be essential to establish these cross-cutting principles so investigators must be willing to work collaboratively as part of the Network.

This initiative is funded through the NIH Common Fund, which supports crosscutting programs that are expected to have exceptionally high impact. All Common Fund initiatives invite applicants to develop bold, innovative, and often-risky approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for rapid progress.

The organization of the three dimensional genome exhibits multiple layers of complexity including chromosomal territories, megabase-long chromatin domains, DNA looping between enhancers and promoters, or protein- and/or RNA-DNA interactions at transcriptionally active or repressive sites, all of which contribute to regulating gene expression. Accordingly, the organization of the genome is highly dynamic and variable among individual cells, making a comprehensive description of genome structure/function relationships an extremely important but complex technical challenge. A comprehensive understanding of the structure-function conundrums of nuclear architecture will require major efforts to map the structural organization of the nucleus in space and time, including positional changes of endogenous loci and chromosome territories and their interactions with nuclear bodies and machineries involved in regulated nuclear functions such as transcription, co-transcriptional splicing, or DNA/chromatin replication and repair. It will require an integrated effort of genome and epigenome research, nuclear biochemistry and biophysics, high-content imaging, and computational modeling, with an emphasis on both structural and functional research.

Recent years have seen the emergence of biochemical approaches (such as 3C, 5C, HiC and ChIA-PET) that can measure physical interactions among chromatin elements in a genome-wide fashion. These methods, which enable high-throughput and systematic mapping of some aspects of the three dimensional organization of mammalian genomes, have provided new insight into nuclear architecture. However, currently available technologies which largely rely on chemical cross-linking, DNA-DNA proximity ligation and restriction enzyme digestion are by their nature limited to static ensemble measurements. In addition, important features of genome organization and function cannot be measured by current technologies, including higher-order nuclear organization and dynamics at the chromosomal level, or genome-wide measurements of functional interactions between genomic DNA and key regulators of genome organization and function such as ncRNAs or promoter/enhancer protein complexes. Finally, the early models of genome structure/function relationships derived from the use of existing mapping methods have not always been convincingly validated for biological relevance.

While current mapping technologies have provided important insight into the nuclear architecture of genomes, improvement and validation of existing technologies, and the development of complementary mapping approaches need to take place prior to the generation of reliable high-definition reference maps of the 3D organization of mammalian genomes. These improvements will require an interplay between the production of large physical interaction datasets and the development of computational models, leading to new paradigms of nuclear structure and function that can be tested or manipulated in the context of a specific biological system. As the number of technologies and investigators applying them increases, it will be critical to develop community-accepted standards for mapping chromatin interactions.

This FOA seeks to establish technology-development and data-production centers to develop experimental approaches that can measure and model various aspects of genome organization within the mammalian cell nucleus. Successful U54 centers will constitute the Nuclear Organization and Function Interdisciplinary Consortium (NOFIC) whose mission will be to benchmark, standardize, and validate the next generation of high-throughput technologies that can produce dynamic three dimensional physical and functional maps of mammalian genomes. NOFIC investigators will also develop predictive models of mammalian genome structure-function relationships, and test the relevance of new nuclear organizational principles within the context of specific biological paradigms and systems. The overarching goal of this initiative is to obtain, by the end of the 5-year funding period, a set of complementary mapping strategies that can be combined to build comprehensive, whole-genome, and high-definition reference maps of the physical and functional organization of mammalian nuclear genomes.

NOFIC will be composed of 5-8 multidisciplinary U54 teams of experts in relevant areas of chromatin biology and nuclear organization, biophysics, chemistry, and computational modeling. The NOFIC teams will be expected to work together on the shared objective of developing and benchmarking the next generation of high-throughput technologies that could produce genome-wide maps of biologically-relevant physical genomic interactions, functional interactomes regulating gene expression programs, and/or other aspects of genome nuclear organization and function. While the development of mapping technologies may require an initial focus on only a fraction of the genome, or an order of magnitude improvement of genome-wide approaches with low spatial resolution, it is expected that the NOFIC "pilot mapping" effort will bring the NOFIC technology toolbox to a point where it can be used for the generation of reliable, high-resolution reference maps of nuclear organization in mammalian cells by the end of the funding period.

While all NOFIC teams will need to include investigators with complementary expertise, U54 projects could vary significantly in size and scope. At a minimum, all U54 applications will need to include the following three elements:

1) Mapping Technology Development: develop a new method, or greatly improve on an existing technology, to study critical aspects of genome organization and/or function in a systematic and high-throughput manner. All proposed methods should have the potential to produce reliable and biologically-relevant datasets, to be scaled-up for genome-wide analysis and "pilot mapping" in mammalian cells, and to be combined with other mapping technologies to contribute to the generation of comprehensive three dimensional physical and/or functional maps of mammalian genomes;

2) Data Analysis and Computational Modeling: propose novel principles of physical and/or functional organization of the mammalian nuclear genome, and formulate predictive models of genome structure/function relationships, based on the analysis of the data collected with the new/improved mapping technology;

3) Biological Validation: validate these novel principles of nuclear organization and predictive computational models of structure/function relationships using biological read-outs such as genome-wide transcriptomics, nuclear imaging or measurement of key aspects of cell function. The validation of new organizational principles or predictive models could be achieved through controlled manipulation of defined organizational elements, the study of their evolutionary conservation, or by measuring in a non-disruptive manner the establishment, maintenance, and dynamic changes of organizational determinants in live cells in the context of processes such as mitosis, cell differentiation, or cell reprogramming.

In addition to addressing the three minimum requirements stated above, larger U54 projects could propose additional tool development or data generation efforts to further explore genome structure/function relationships in a variety of cellular contexts, or integrate new principles of nuclear organization with well-documented and defining characteristics of human genome organization such as genetic or epigenetic determinants. Technology-development and research efforts that could be proposed in addition to the three minimum requirements stated above include, but are not limited to:

• Develop strategies for the controlled manipulations of nuclear architecture, or high-performance imaging tools to validate predictive models of structure/function relationships;

• Develop computational tools to: improve the sensitivity, efficiency and/or reliability of existing mapping technologies; integrate datasets generated using distinct but complementary technologies, such as chromatin interaction measurements, genome-wide transcriptomics and/or nuclear imaging data, into coherent models of genome organization;

• Combine novel mapping measurements and principles of nuclear organization with known determinants of mammalian genome organization and function, such as epigenomic information and genomic regulatory elements (Roadmap Epigenomic Program and ENCODE), or disease-associated risk loci (GWAS), in order to validate or refine novel principles of nuclear organization;

• Develop approaches to measure chromatin structure dynamics with a time resolution that allows measurements of genome-wide re-organization during events such as the cell cycle or changes in cell fate;

• Develop technologies that allow the production of single-cell maps of nuclear organization, or can report on single-cell genome organization and function with high-resolution, dynamically in live cells, tissues or model organisms.

To be responsive to this FOA, investigators must develop a mapping approach for which the primary means of measurement does not rely on imaging technologies, although imaging studies can be used to help with the development or validation of the new mapping technology. For the development of primarily imaging-based technologies to better understand mammalian genome structure and function, the applicant is directed to RFA-RM-14-009. Applicants proposing to develop a single method for studying the organization of the nuclear genome in relationship to the topography of nuclear bodies and nuclear compartments should apply to RFA-RM-14-008. Applicants proposing to develop an original chemical or biochemical approach to measure an important aspect of genome organization that cannot be adequately measured with existing technologies, but are not expecting that this new technology can be scaled-up within the current funding period to become a validated high-throughput, genome-wide mapping technology, should consider applying to RFA-RM-14-007.

NOFIC investigators, as a group, are expected to agree on practical ways to minimize scientific and strategic redundancies between the various U54 projects, and to put in place through the NOFIC Steering Committee a collaborative framework in which new mapping technologies can be developed and combined in a coordinated fashion. In order to develop standard protocols for the field and to compare the performance of various mapping approaches when used by different laboratories, the NOFIC Steering Committee will be asked to identify a small number of common cell types and/or biological systems to be used by all NOFIC investigators for pilot mapping and validation efforts, in addition to the biological platforms originally proposed in the individual NOFIC applications. The NOFIC Steering Committee will update NIH Staff regularly on the level of performance of the various NOFIC-supported mapping technologies, data analysis tools and computational modeling tools, to include metrics and measurements of reproducibility, accuracy, biological relevance and cost-effectiveness, and work closely with the 4DN Network Data Coordination & Integration Center (4DN-DCIC, see RFA-RM-14-011) to develop standards and data analysis tools to be used by the broader scientific community. Once a set of mapping technologies is deemed sufficiently robust and reliable by the NOFIC Steering Committee and the NIH staff, NOFIC investigators may be encouraged to start producing a small set of reference maps in specific cell types and/or tissues that will be chosen as a result of consensus deliberations.

4DN Cooperative Agreement

This FOA uses the U54 Cooperative Agreement mechanism. Successful applicants will become members of the larger 4D Nucleome Network composed of investigators who have been funded in response to at least one of the six related 4DN Network FOAs. In addition to completing the research goals outlined in their applications, successful applicants will be expected to work collaboratively with all members of the 4D Nucleome Network, including the 4DN Network Organizational Hub (RFA-RM-14-010) and the 4DN Network Data Coordination & Integration Center (RFA-RM-14-011), to help develop common standards, metrics for data generation and storage, and data analysis and visualization tools that can be used by the broader scientific community. The 4DN Network will encourage the initiation of new collaborative research projects across the entire network. Some of these interactions could be facilitated by an Opportunity Pool of funds that will be managed by the 4DN Organizational Hub and NIH Program Staff.

A key aspect of this program is the formation of a consortium-type partnership amongst all 4DN Network awardees. Shared responsibilities derived from the use of the cooperative agreement mechanism are described later in this FOA, and will be further articulated during the kickoff meeting of the 4DN Network that will take place a few months after awards are made. All 4DN Network investigators will be required to attend this initial 4DN Kickoff meeting, as well as annual 4DN investigator meetings and regular teleconferences with Network members and NIH Staff for the duration of the funding cycle.

All applicants are strongly encouraged to contact NIH Staff to discuss the alignment of their proposed work with the goals of this FOA, and the 4DN Program. A Technical Assistance teleconference will be held for potential applicants. NIH staff will be available to answer questions related to this FOA. Time, date, and dial in information for the call will be announced in an NIH Guide Notice and will be posted on the 4DN website: http://commonfund.nih.gov/4Dnucleome/index.

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 including the NIH Intramural Program

• 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).

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 can access 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.

Most applicants will use NIH’s ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

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 and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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:

Olivier Blondel, Ph.D. (on behalf of the NIH Common Fund 4D Nucleome Working Group)
Program Director, Endocrine Systems Biology Program
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
6707 Democracy Boulevard, Room 796
Bethesda, MD 20892-5460
Phone: 301-451-7334
Email: [email protected]

Component Types Available in ASSIST	Research Strategy/Program Plan Page Limits
Overall	6
Mapping Tech Dvpmt (use for Mapping Technology Development)	6
Data Analysis (use for Data Analysis and Modeling)	6
Biological Valid (Use for Biological Validation Development)	6
Tool Dvpmt-Data Gen (use for Additional Tool Development or Data Generation)	6

Additional page limits 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 a multi-component application.

The application should consist of the following components:

Overall: required

• Mapping Technology Development: required

• Data Analysis and Modeling: required

Biological Validation Development: required

Additional Tool Development or Data Generation: optional

When preparing your application in ASSIST, use Component Type Overall .

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

SF424 (R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Research & Related Other Project Information (Overall)

Follow standard instructions.

Project/Performance Site Location(s) (Overall)

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Research & Related Senior/Key Person Profile (Overall)

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

In addition to stating their relevant expertise, applicants should describe when applicable any prior experience in working as part of a research consortium, developing consensus approaches for data sharing and other research-related topics, or any other significant collaborative activities.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

Budget (Overall)

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

PHS 398 Research Plan (Overall)

Specific Aims: The Specific Aims for the Overall Component should describe the overall vision for the U54 Center. These Specific Aims should not be the same as the specific aims of the other components, but should be overarching and at a higher level. Applicants should describe how their combined proposed efforts will meet the Research Objectives stated in this FOA. It should include general plan for collaborations between the U54 team and other components of the 4DN Network such as the 4DN-OH, 4DN-DCIC, NOFIC investigators and non-NOFIC 4DN Network investigators.

Research Strategy: The Overall Component should provide a concise vision and proposed plan for the Center. What scientific challenges are being addressed, what approaches, methods, software, and tools will be generated, and how will the Center be useful? The Overall Component should also include a concise description of the structure of the Center and how individual components of the Center including key personnel will interact. Clearly explain the guiding principles of the interaction, particularly between the three main components of mapping technology development and data production, data analysis and data modeling, and biological data validation. As NOFIC projects will be developing significant tools and new data, a proactive outreach to other components of the 4DN Research Network and to the larger scientific community will accelerate their use and adoption.

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, with the following modification:

Applicants should describe how they plan to interact with other members of the consortium to facilitate the development of common standards for the field, and facilitate the timely sharing of data, reagents and protocols generated by NOFIC investigators. The resource sharing plan for the Overall Component should cover all the activities of the Center. Program Staff may negotiate modifications to these plans prior to funding. The Sharing Plan for the Overall Component should address at least the following three components:

• Data Release Principles and Standards: All applications, regardless of the amount of direct costs requested for any one year, should include a Data Sharing Plan. Data from this FOA are expected to be shared in an easily accessible, machine readable format in order to increase the value of the significant public investment. Consistent with achieving the goals of this program, the NIH expects that information such as data syntheses, study protocols, bioinformatics tools, and any other metadata collected will be widely shared with the scientific community for research and made publicly available through the 4DN data portal and other data repositories.

Applicants should indicate their willingness to cooperate with the 4DN Program, 4DN Network Steering Committee (4DN-SC), NIH staff, and other stakeholders in the development and implementation of research and standardization methods, data standards and formats, metadata requirements, and quality control metrics for this resource.

• Data sharing: All controlled access data generated through this FOA are expected to be deposited into dbGaP (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap) or other NIH Trusted Partners databases. All data without privacy concerns are expected to be deposited in appropriate public databases and also made available via the 4DN Network Virtual Resource Repository (4DN-VRR) that will be built by the 4DN Network Organizational Hub (4DN-OH) to collect, curate, and disseminate information regarding data, critical tools, and reagents being developed by the 4DN Network. The 4DN-VRR will be accessible through the 4DN Network Portal. Applicants should indicate their willingness to abide by all data deposition and release policies defined by 4DN-SC and approved by NIH staff. In general, rapid deposition of data into repositories will be expected to maximize utility to the scientific community. The applicant's milestones should reflect the expected broad and rapid data sharing as outlined in the new NIH data sharing policy (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-111.html . Additionally, applicants are expected to adhere to future changes to NIH-wide data sharing policies. Applicants should provide a specific proposal for release of data, and are encouraged to address the issue of frequency of the release, based on practical considerations or previous experience and the recommendations above. Applicants should address whether they anticipate any of their data requiring controlled access. The reasonableness of the proposed data sharing plan will be assessed by the reviewers.

• Protocol, tool and reagent sharing: The applicant should discuss plans for sharing and distribution of non-data resources that will be generated by the proposed project, including models, protocols, computational tools, biomaterials, and reagents. As one of the essential goals of this program, NIH intends that tools and reagents generated by the 4DN Network be broadly available and distributed at minimal cost, and without undue intellectual property constraints, so that they can be as widely used as possible, thus enabling downstream applications for the reagents by the larger scientific community. The 4DN-OH will work with all 4DN Network investigators to collect, curate, and disseminate information regarding critical tools and reagents being developed by the 4DN Network through the 4DN-VRR. 4DN Network investigators and the 4DN-OH will develop solutions to facilitate the request and distribution of 4DN Network-generated tools and reagents within and outside of the 4DN Network community. Whether tools and reagents are distributed by individual investigators or through public repositories, the 4DN-VRR is expected to serve as a "one-stop shop" for all 4DN Network-generated tools and reagents. Applicants should also be familiar with the NIH statements regarding intellectual property of resources developed with Federal funds (NIH Research Tools Policy (http://grants.nih.gov/grants/intell-property_64FR72090.pdf) and other related NIH sharing policies at http://sharing.nih.gov).

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 preparing your application in ASSIST, use Component Type Mapping Tech Dvpmt.

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

SF424 (R&R) Cover (Mapping Technology Development)

Complete only the following fields:

• Applicant Information

• Type of Applicant (optional)

• Descriptive Title of Applicant’s Project

• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Mapping Technology Development)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Mapping Technology Development)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Mapping Technology Development)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Mapping Technology Development)

In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.

• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.

• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.

• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Mapping Technology Development)

Budget forms appropriate for the specific component will be included in the application package. Budget requests must include costs for the PD/PI to attend the initial in-person 4DN Network kick-off meeting, and for the PD/PI and up to five other members of the project team to attend the annual 4DN Network Investigator's meetings.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Mapping Technology Development)

Specific Aims: Applicants must describe all of the following: the expected performance goals for their technology, including throughput, sensitivity, scalability, capacity for single-cell versus ensemble measurements, and ability to measure dynamic changes in mammalian genome organization; how the proposed method can produce new, reliable and biologically-relevant datasets; how it improves upon or adds to existing mapping technologies; how it can be scaled-up for genome-wide analysis and "pilot mapping" in mammalian cells; and how it can be combined with other mapping technologies to contribute to the generation of comprehensive, three dimensional physical and/or functional maps of mammalian genomes..

Research Strategy: As part of the Research Strategy, applicants are asked to address the following points:

1) Significance: Applications to develop high-risk, high-impact, broadly applicable technologies and analytical techniques allowing genome-wide measurements not currently possible are strongly encouraged. Explain the importance of the problem or critical barrier to progress in the field that the new/improved technology will address, and how the new/improved technology will contribute to a solution. Explain how the proposed project will improve scientific knowledge and technical capability by providing new tools and experimental approaches to users. Describe how the current concepts, methods, or technologies in the field will be changed if the Specific Aims are achieved. Critically evaluate existing knowledge and approaches that have been or are being applied in the area and specifically describe how the proposed approach will advance the field.

2) Innovation: Innovation for this FOA is measured by the ability to deliver emerging or new capabilities to end-users, including through integration and automation of proven approaches that recognize their resources, workflow, and skills. For example, and for the purpose of this component, it might be considered innovative to develop a genome-wide mapping technology that solves a recognized unmet need in our ability to study the physical and functional nuclear organization of mammalian genomes. Innovation in this case might also be heightened by the development of a technology that can be easily adopted into routine practice and will give users, for example biomedical researchers, new understanding not available from existing technologies. Identify the nature of innovations involved and explain their importance to the success and potential impact of the application. Describe how the performance of the proposed mapping technology compares to the current state of the art. To the extent relevant, explain how the application challenges and seeks to shift current research paradigms. Explain any refinements, improvements, or new applications of theoretical concepts, approaches or methodologies, system integration, combinations, scale-up, instrumentation, or interventions.

3) Approach: Technical feasibility for the approach should be clearly established by preliminary results so that any risks present can be mitigated and alternative approaches discussed. Comparison of performance specifications with current practices is expected, such as sensitivity, specificity, reproducibility, reliability, portability, throughput, and operability by other biological researchers. Describe the overall strategy, methodology, and analyses to be used to accomplish the specific aims of the project. Discuss potential problems, alternative strategies, and benchmarks for success anticipated to achieve the aims. If the project is in the early stages of development, describe any strategy to establish feasibility, and address the management of any high risk aspects of the proposed work. An integrative systems approach or a design-driven approach and their appropriateness for the proposed project should be described, including plans for collecting, analyzing, interpreting, and archiving data. Details for making the performance of technologies sufficiently selective, sensitive, or otherwise appropriate for the identified problem should be supported with quantitative benchmarks. Potential technical challenges and possible alternative approaches to achieve the aims of the project should be discussed. The robustness and reproducibility of preliminary results should be described along with independent validation or replication of results if available. Alternative interpretations of preliminary data, including relevant literature in support of or disagreement with the results, should be described.

4) Outreach and Education: as NOFIC projects will be developing significant tools and new data, a proactive outreach to other components units of the 4DN Research Network and to the larger scientific community is required to accelerate their use and adoption. Applicants should provide a plan that describes how this outreach will be conducted, particularly in areas such as: development of community standards for data production and data analysis; relationship and integration of the data being generated to other data types or existing datasets relevant to the structure/function of mammalian genomes; education outreach to the scientific community to facilitate the use and adoption of the new mapping technology.

Project Timeline: A timeline (Gantt chart) including milestones is required. Milestones are intermediate steps towards the completion of concrete goals, that create go/no-go decision points in the project and must include clear and quantitative criteria for success. Yearly quantitative milestones are required in order to provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of non-competing award years. Milestones and the timeline must be provided in a separate heading at the end of the Approach section.

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, with the following modification:

The Resource Sharing Plan for the entire U54 application should be included in the Overall Component of the application.

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..

Planned Enrollment Report (Mapping Technology Development)

Not Applicable

PHS 398 Cumulative Inclusion Enrollment Report (Mapping Technology Development)

Not Applicable

When preparing your application in ASSIST, use Component Type Data Analysis.

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

SF424 (R&R) Cover (Data Analysis and Modeling)

Complete only the following fields:

• Applicant Information

• Type of Applicant (optional)

• Descriptive Title of Applicant’s Project

• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Data Analysis and Modeling)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Data Analysis and Modeling)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Data Analysis and Modeling)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Data Analysis and Modeling)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.

• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.

• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.

• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Data Analysis and Modeling)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Data Analysis and Modeling)

Specific Aims: Applicants should describe how the proposed data analysis and computational tools will lead to robust predictive models of genome structure/function relationships using the datasets generated with the new/improved mapping technology.

Research Strategy: As part of the Research Strategy, applicants are asked to address the following points:

1) Significance: Explain the importance of the proposed data analysis and predictive modeling strategy in the context of the development and use of the new/improved mapping technology. Explain how the proposed approach will lead to robust principles/models of nuclear organization derived from the use of the new/improved mapping technology, so that this technology can be adopted with confidence by the research community. Critically evaluate existing knowledge and approaches that have been or are being applied to analyze comparable datasets and lead to predictive models of genome organization, and specifically describe how the proposed analytical and modeling tools will advance the field.

2) Innovation: Innovation for this FOA is measured by the ability to deliver emerging or new capabilities to end-users, including through integration and automation of proven approaches that recognize their resources, workflow, and skills. For the purpose of this component, it might be considered innovative to develop computational tools for data analysis and predictive modeling that perform significantly better than existing tools, can be convincingly validated for their biological relevance, and/or can lead to the predictive modeling of aspects of mammalian genome structure/function relationships that simply cannot be achieved with existing analytical tools. Innovation in this case might also be heightened by the development of tools that can be easily shared and adopted by the community. Identify the nature of innovations involved in the data analysis and computational modeling strategy, and explain their importance to the success and potential impact of the overall application.

3) Approach: Feasibility for the approach should be clearly established by preliminary results, or by the documented previous development of similar analytical tools, so that any risks present can be mitigated and alternative approaches discussed. Comparison of performance specifications with existing and comparable analytical tools is expected, such as sensitivity, specificity, reproducibility, reliability and operability by other biological researchers. Describe the overall strategy, methodology, and analyses to be used to accomplish the specific aims of the project. Discuss potential problems, alternative strategies, and benchmarks for success anticipated to achieve the aims. If the project is in the early stages of development, describe any strategy to establish feasibility, and address the management of any high risk aspects of the proposed work. Details for making the performance of data analysis and modeling tools sufficiently appropriate for the identified problem should be supported with quantitative benchmarks. Potential technical challenges and possible alternative approaches to achieve the aims of the project should be discussed. The robustness and reproducibility of preliminary results should be described along with independent validation or replication of results if available. Alternative interpretations of preliminary data, including relevant literature in support or disagreement with the results, should be described.

4) Outreach and Education: as NOFIC projects will be developing significant new analytical tools related to the development of new mapping technologies and to the interpretation of the resulting data, a proactive outreach to other units of the 4DN Research Network and to the larger scientific community will be required to accelerate their use and adoption. Applicants should provide a plan that describes how this outreach will be conducted, particularly in areas such as: development of community standards for data analysis; relationship and integration of the analytic tools being developed to other data types or existing datasets relevant to the structure/function of mammalian genomes; education outreach to the scientific community to facilitate the use and adoption of the new analytical tools.

Project Timeline: A timeline (Gantt chart) including milestones is required for all studies. Milestones are intermediate steps towards the completion of concrete goals, that create go/no-go decision points in the project and must include clear and quantitative criteria for success. Yearly quantitative milestones are required in order to provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of non-competing award years. Milestones and the timeline must be provided in a separate heading at the end of the Approach section.

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, with the following modification:

The Resource Sharing Plan for the entire U54 application should be included in the Overall Component of the application.

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.

Planned Enrollment Report (Data Analysis and Modeling)

Not Applicable

PHS 398 Cumulative Inclusion Enrollment Report (Data Analysis and Modeling)

Not Applicable

When preparing your application in ASSIST, use Component Type Biological Valid

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

SF424 (R&R) Cover (Biological Validation Development)

Complete only the following fields:

• Applicant Information

• Type of Applicant (optional)

• Descriptive Title of Applicant’s Project

• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Biological Validation Development)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Biological Validation Development )

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Biological Validation Development)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Biological Validation Development)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.

• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.

• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.

• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Biological Validation Development)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Biological Validation Development)

Specific Aims: All projects should propose a detailed plan for the biological validation of the data and principles derived from the new genome-wide mapping methods early in the technology-development process. Applicants should describe the strategy that will be developed to perform the validation of predictive models of genome organization or structure/function relationships derived from the use of the new/improved mapping technology, including cell systems, biological read-outs and/or perturbation experiments to be used. When choosing cell systems or experimental platforms in response to this initiative, applicants have to keep in mind that the most important milestone that needs to be met at the end of the funding period is the development of at least one high-throughput, genome-wide mapping strategy that can quantitatively and reliably describe an important aspect of nuclear organization and/or function in mammalian cells. However, given that the development of a new technology can be facilitated by the use of lower organisms, and that its biological validation can benefit from measurements in whole organisms, the inclusion of non-mammalian cell types or model organisms for the purpose of accelerating technology development or biological validation is an acceptable option.

Research Strategy: As part of the Research Strategy, applicants are asked to address the following points:

1) Significance: Explain the importance of the proposed biological validation strategy in the context of the development of new principles/models of physical and/or functional organization of mammalian nuclear genomes using high-throughput datasets generated with the proposed new/improved mapping technology. Explain how the proposed validation strategy will convincingly establish the biological relevance of the new principles/models of nuclear organization derived from the proposed mapping technology, so that this technology can be adopted with confidence by the research community. Critically evaluate existing knowledge and approaches that have been or are being applied to validate comparable mapping technologies and/or new principles/predictive models of genome organization, and specifically describe how the proposed validation strategy compares to these existing approaches, and will advance the field.

2) Innovation: Innovation for this FOA is measured by the ability to deliver emerging or new capabilities to end-users, including through integration and automation of proven approaches that recognize their resources, workflow, and skills. For the purpose of this component, it might be considered innovative to develop cell-based validation strategies that are more robust and convincing than existing approaches aimed at demonstrating the biological relevance of new principles of genome organization. Innovation might also be heightened by the development of a validation strategy that can be easily adopted into routine practice. Identify the nature of innovations involved in the validation strategy, and explain their importance to the success and potential impact of the overall application.

3) Approach: Technical feasibility for the approach should be clearly established by preliminary results so that any risks present can be mitigated and alternative approaches discussed. Describe the overall strategy, methodology, and analyses to be used to accomplish the specific aims of the project. Discuss potential problems, alternative strategies, and benchmarks for success anticipated to achieve the aims. If the project is in the early stages of development, describe any strategy to establish feasibility, and address the management of any high risk aspects of the proposed work. Details for making the performance of technologies sufficiently selective, sensitive, or otherwise appropriate for the identified problem should be supported with quantitative benchmarks. Potential technical challenges and possible alternative approaches to achieve the aims of the project should be discussed. The robustness and reproducibility of preliminary results should be described along with independent validation or replication of results if available. Alternative interpretations of preliminary data, including relevant literature in support of or disagreement with the results, should be described.

Project Timeline: A timeline (Gantt chart) including milestones is required for all studies. Milestones are intermediate steps towards the completion of concrete goals, that create go/no-go decision points in the project and must include clear and quantitative criteria for success. Yearly quantitative milestones are required in order to provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of non-competing award years. Milestones and the timeline must be provided in a separate heading at the end of the Approach section.

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, with the following modification:

The Resource Sharing Plan for the entire U54 application should be included in the Overall Component of the application.

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.

Planned Enrollment Report (Biological Validation Development)

Not Applicable

PHS 398 Cumulative Inclusion Enrollment Report (Biological Validation Development)

Not Applicable

When preparing your application in ASSIST, use Component Type Tool Dvpmt-Data Gen.

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

SF424 (R&R) Cover (Additional Tool Development or Data Generation)

Complete only the following fields:

• Applicant Information

• Type of Applicant (optional)

• Descriptive Title of Applicant’s Project

• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Additional Tool Development or Data Generation)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Additional Tool Development or Data Generation)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Additional Tool Development or Data Generation)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Additional Tool Development or Data Generation)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.

• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.

• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.

• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Additional Tool Development or Data Generation)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Additional Tool Development or Data Generation)

Specific Aims: The applicant should articulate how the Specific Aims will contribute to a greater understanding of the fundamental principles of the nuclear organization of mammalian genomes.

Research Strategy: As part of the Research Strategy, applicants are asked to address the following points:

1) Significance: Explain the importance of the problem or critical barrier to progress in the field that this component of the grant will address, and how the proposed Specific Aims will contribute to a solution. Explain how the proposed project will improve scientific knowledge and technical capability by providing new tools and experimental approaches to users. Describe how the current concepts, methods, or technologies in the field will be changed if the Specific Aims are achieved. Critically evaluate existing knowledge and approaches that have been or are being applied in the area and specifically describe how the proposed approach will advance the field.

2) Innovation: Innovation for this FOA is measured by the ability to deliver emerging or new capabilities to end-users, including through integration and automation of proven approaches that recognize their resources, workflow, and skills. Innovation in this case might be heightened by the development of a technology, approach or generation of a set of data that can be easily adopted by the scientific community and will give users, for example biomedical researchers, added experimental capabilities or scientific knowledge not available from existing technologies or datasets. Identify the nature of innovations involved and explain their importance to the success and potential impact of the application, as well as relevance to the mission of NOFIC and the 4D Nucleome Research Network. To the extent relevant, explain how the application challenges and seeks to shift current research paradigms. Explain any refinements, improvements, or new applications of theoretical concepts, approaches or methodologies, system integration, combinations, scale-up, instrumentation, or interventions.

3) Approach: Technical feasibility for the approach should be clearly established by preliminary results so that any risks present can be mitigated and alternative approaches discussed. Comparison of performance specifications with current practices is expected, such as sensitivity, specificity, reproducibility, reliability, portability, throughput, and operability by other biological researchers. Describe the overall strategy, methodology, and analyses to be used to accomplish the specific aims of the project. Discuss potential problems, alternative strategies, and benchmarks for success anticipated to achieve the aims. If the project is in the early stages of development, describe any strategy to establish feasibility, and address the management of any high risk aspects of the proposed work. An integrative systems approach or a design-driven approach and their appropriateness for the proposed project should be described, including plans for collecting, analyzing, interpreting, and archiving data. Details for making the performance of technologies sufficiently selective, sensitive, or otherwise appropriate for the identified problem should be supported with quantitative benchmarks. Potential technical challenges and possible alternative approaches to achieve the aims of the project should be discussed. The robustness and reproducibility of preliminary results should be described along with independent validation or replication of results if available. Alternative interpretations of preliminary data, including relevant literature in support or disagreement with the results, should be described.

Project Timeline: A timeline (Gantt chart) including milestones is required for all studies. Milestones are intermediate steps towards the completion of concrete goals, that create go/no-go decision points in the project and must include clear and quantitative criteria for success. Yearly quantitative milestones are required in order to provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of non-competing award years. Milestones and the timeline must be provided in a separate heading at the end of the Approach section.

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, with the following modification:

The Resource Sharing Plan for the entire U54 application should be included in the Overall Component of the application.

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

Planned Enrollment Report (Additional Tool Development or Data Generation)

Not Applicable

PHS 398 Cumulative Inclusion Enrollment Report (Additional Tool Development or Data Generation)

Not Applicable

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) using ASSIST or other electronic submission systems. 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.

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.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

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) and component Project Leads 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.

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 (SAM). 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 components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above. The intramural project should be added as a separate component to the parent 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.

The Overall Center impact score will emphasize a) the overall effectiveness and innovation of the approaches, methods, software, tools, and related resources in generating a mapping technology that can provide validated, biologically relevant datasets and analytical tools leading to a greater understanding of the structural and functional organization of mammalian genomes; b) the scientific merit and likely contribution to the field of the proposed technology, datasets and predictive modeling tools, c) the potential for acceptance of the proposed technology, analytical tools and new principles of genome organization by the research community based on technical criteria such sensitivity, specificity, reproducibility, reliability, portability, throughput, operability and cost-effectiveness, as well as proposed efforts to develop community standards and educational outreach; d) the qualifications of the Center Director and other staff; e) the quality of the plans for management and oversight of the Center; f) the adequacy of plans for the release of data, methods, software, tools, and related dissemination activities; g) the synergy among the components; h) the contribution to the goals and activities of the NOFIC and the 4DN Network. The overall impact score for the NOFIC application may be higher or lower than the average of the individual components based on assessment of whether the whole is greater than the sum of its components

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?

Specific to this FOA: Will the proposed mapping technology or combination of mapping technologies significantly advance our understanding of the spatiotemporal organization and function of the genome in the mammalian cell nucleus? Will the proposed technologies and strategies enable the study of critical aspects of genome organization that cannot be adequately measured with existing technologies, or constitute an order of magnitude improvement on existing approaches in terms of throughput, sensitivity, scalability or cost? Will the project address a problem or critical barrier in understanding the 4D organization or function of the mammalian genome for which there is a scarcity of other solutions? What is the potential for the proposed approach to be widely adopted and easily used by the research community?

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?

Specific to this FOA: Does the project team have appropriate experience with developing, optimizing, and validating the proposed technology and related analytical and modeling tools in mammalian cells during the proposed funding period? Does the project team have a track record of disseminating novel tools and techniques broadly?

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?

Specific to this FOA: Will the proposed approaches or concepts solve current technical limitations or gaps in knowledge in creative ways? Does the application represent an innovative technological solution for measuring important aspect of the nuclear organization of mammalian genomes? Will the project deliver new or significantly more precise quantitative measurements to potentially change our understanding of the physical and/or functional organization of the mammalian nuclear genome?

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?

Specific to this FOA: Are the technology development, analytical and modeling tools, and validation approaches adequately described, well-integrated, and appropriate to the aims of the project? Is the application milestone driven with clear metrics and go/no-go decision points, and are these appropriate? Is a timetable with annual, quantitative research milestones propose, and are the annual milestones quantitative and realistic? Will the proposed technology and the novel principles of nuclear organization that are derived from it receive adequate validation, so that this technology has the potential to be used, at the end of the funding period, for the production of reference maps of nuclear organization in various mammalian cells and tissues?

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?

Specific to this FOA: Are the proposed environment and team-structure likely to foster true multi-disciplinary collaborations in pursuit of developing and validating an innovative technology?

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

Not Applicable

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 Center for Scientific Review, 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 on the basis of established PHS referral guidelines 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 appropriate national Advisory Council or Board. 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.

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 Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement U54, 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. A Memorandum of Understanding (MOU) developed by the NIH Common Fund should serve as a guidance document to provide a framework under which relationships between investigators and NIH Program Staff are established. Templates for Confidential Disclosure Agreements (CDAs) and Collaborative Research Agreements (CRAs) have been developed by the NIH Office of Technology Transfer. 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 will be primarily responsible for the planning and conduct of the operations defined by the terms and conditions of the cooperative agreement award.

• The PD/PI will assume responsibility and accountability to the applicant organization officials and to the NIH for the performance and proper conduct of the research and administrative functions supported under this Funding Opportunity Announcement in accordance with the terms and conditions of award, as well as all pertinent laws, regulations and policies.

• The PD/PI and his/her staff will be required to participate in a cooperative, interactive, and collaborative manner with NIH staff, 4DN Network investigators and one another.

• The PD/PI will become a voting member of the NOFIC Steering Committee (NOFIC-SC) that will be tasked with establishing guidelines and agreements with regard to NOFIC-specific scientific, strategic and administrative issues, including but not limited to the development of common standards, metrics and measurements of reproducibility, accuracy, biological relevance, and cost-effectiveness.

• The PD/PI may also be elected by the NOFIC-SC to represent NOFIC investigators on the 4DN Network Steering Committee (4DN-SC) that will be tasked with establishing agreements that address the following issues: (1) procedures for data sharing among consortium members, data sharing with the scientific community outside of the 4DN Network, and data sharing with industry partners; (2) procedures for safeguarding confidential information, including without limitation, any data generated by the consortium as well as information and/or data received from external collaborators; (3) procedures for addressing ownership of intellectual property that result from aggregate multi-party data; (4) procedures for sharing tools and reagents under an overarching MTA amongst consortium members that operationalizes material transfer in an efficient and expeditious manner; (5) publication policy for the entire 4DN Network, determining timing, authorship and content of co-publications, in order to facilitate collaborations and co-publications by consortium members while protecting each 4DN Network investigator’s primary ownership and authorship of their data and discoveries.

• The PD/PI and his/her staff will maintain the confidentiality of the information developed or handled by the NOFIC and the 4DN Network, including, without limitation, unpublished data, informatics tools, protocols, data analysis, confidential exchanges between members of the 4DN Network, etc. per policies approved by the 4DN-SC, as well as any confidential information received by third party collaborators.

• The PD/PI must facilitate the public release and dissemination of results, data, reagents, technologies and other products generated through this 4DN award in a timely manner via the 4DN Network Virtual Resource Repository (4DN-VRR) that will be built and managed by the 4DN Network Organizational Hub (4DN-OH) to collect, curate and disseminate information regarding data, critical tools and reagents being developed by the 4DN Network. The 4DN-VRR will be accessible through the 4DN Network Portal. The PD/PI is expected to share data and resources generated through this award in accordance with the approved plan for making quality-assured data and materials available to the scientific community and the NIH as written in the final version of the grant application, and consistent with sharing policies and recommendations developed and approved by the NOFIC-SC, the 4DN-SC, NIH sharing policies and the goals of the FOA.

• The PD/PI agrees that any industry collaborations should be governed by a research collaboration agreement (e.g. CTA, RCA, etc) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH policies and procedures and any policies and procedures developed by the 4DN-OH or the 4DN-SC.

• The PD/PI must operate in accordance with processes and goals as delineated in the Funding Opportunity Announcement.

• The PD/PI must operate in accordance with processes, goals, and policies established by the 4DN-SC.

• The PD/PI must attend an initial face-to-face meeting of 4DN Network PDs/PIs soon after all 4DN Network awards have been made, followed by at least one 4DN Network investigator meeting annually.

Adherence to a 4DN Communication Plan:

A consensus 4DN Communication Plan will be drafted by the 4DN-SC during the kickoff meeting of the 4DN Network. This plan will clearly spell out interactive requirements that all 4DN investigators are expected to follow, including:

• Participate on regular conference calls with fellow 4DN colleagues through contribution to various sub-committees and working groups;

• Coordinate efforts with other awardees, in particular through interactions with the Organizational Hub and the Data Coordination & Integration Center;

• Participate and present findings at annual workshops convened by Organizational Hub;

• Jointly publish findings in a timely manner; a consensus guidance document articulating the clearance mechanism for joint publications will need to be developed by the 4DN-SC.

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

• The NIH will designate program staff, including a Program Officer and a Grants Management Specialist to provide stewardship and administrative oversight of the cooperative agreement. The Program Officer and Grants Management Specialist will be named in the Notice of Grant Award.

• A NIH Project Scientist will be substantially involved in the management of the awards resulting from this FOA above and beyond the normal stewardship of an NIH Program Official.

• The NIH Project Scientist and Program Officer will review the scientific progress of 4DN projects, and review the project for compliance with sharing and operating policies developed by the 4DN-SC and the NIH. Based on this review, the Project Scientist in conjunction with the Program Officer may recommend to the NIH to continue funding, or to withhold or restrict support for the grantee for lack of progress or failure to adhere to 4DN Network or NIH policies. Review of progress may include regular communications between the PD/PI and NIH staff, site visits, or fiscal review. The NIH also retains the option of organizing periodic external review of progress of the work supported by the 4DN award.

• The NIH reserves the right to terminate any 4DN award in the event of (1) A substantial shortfall in accomplishing the management goals and responsibilities as stated in the reviewed application, (2) A failure to meet the 4DN Network policies and procedures, (3) Substantive changes in the management of the 4DN award that are not in keeping with the objectives of the FOA and/or (4) failure to make substantial progress towards milestones keeping in mind the agreed upon go/no-go decisions.

Areas of Joint Responsibility include:

4DN Network Steering Committee (4DN-SC)

The awardee agrees to the role and authority of a 4DN Network Steering Committee (4DN-SC) that is responsible for joint governance of 4DN Network activities. The main characteristics and functions of the 4DN-SC are as follows:

• The 4DN-SC will be composed at a minimum of its nine voting members: the 4DN-OH PD/PI, the 4DN-DCIC PD/PI, three elected members of the NOFIC Steering Committee (NOFIC-SC), three peer-elected PDs/PIs representing each one of the three technology-development FOAs (RFA-RM-14-007, RFA-RM-14-008 and RFA-RM-14-009) and one NIH Project Scientist involved in the management of the 4DN Network. The 4DN-OH PD/PI and 4DN-DCIC PD/PI will be permanent members of the 4DN-SC. All other members of the 4DN-SC will be selected by their peers to serve 2-year term on the 4DN-SC. Renewal or continuation of 4DN-SC membership will be decided during the in-person meeting of the 4DN-SC at the 2nd and 4th annual 4DN Network Investigator Meeting. Other designated NIH program staff, 4DN-OH staff, 4DN-DCIC staff or external experts may attend the 4DN-SC meetings on a regular or ad-hoc basis, but will be ex officio (non-voting) members.

• The 4DN-SC will be constituted at the 4DN Network kick-off meeting, and will meet at least quarterly, including at least once in-person during the annual 4DN Network Investigator Meeting.

• The first meeting of the 4DN-SC will be chaired by the NIH representative on the 4DN-SC. Following that initial meeting, a Chairperson for the 4DN-SC will be chosen by the NIH amongst the 4DN-SC to serve a two-year term. The Chairperson is responsible for coordinating the 4DN-SC activities, for preparing meeting agendas and for chairing 4DN-SC meetings. After two years of service, NIH staff may ask the 4DN-SC Chairperson to serve a second 2-year term, or choose a replacement for that role. NIH staff may also choose to replace the 4DN-SC Chair at any time based on poor job performance or failure to follow the relevant procedures and guidelines.

• All major scientific and policy decisions will be determined by voting policies as established by the 4DN-SC. Specific activities of the 4DN-SC will include, but are not limited to: developing collaborative protocols; identifying impediments to success and strategies to overcome them; developing shared tools for disseminating information about the 4DN Network projects; identifying opportunities for sharing techniques, materials, information and tools developed within each individual 4DN Network project; facilitating communication and fostering collaboration across the 4DN Network; reviewing progress of the 4DN Network towards meeting the overall Network goals; developing publication policies to facilitate collaborations and co-publications by consortium members; developing data standards, metadata requirements, data quality standards, and submission and release policies; ensuring the 4DN Network leverages existing NIH resources and programs; making recommendations on the possible use of the opportunity pool of funds, such as topics for initiatives or tool/reagent-development projects that can benefit the 4DN Network activities; reviewing the progress of applications or projects that will use "opportunity pool" funds; helping organize the scientific Agenda for the annual 4DN Network Investigator Meeting.

• Trans-4DN Network subcommittees and working groups may be constituted following recommendations and approval by the 4DN-SC, to help the 4DN-SC with scientific planning activities, development of common 4DN Network standards and policies, etc.

• The 4DN-OH is responsible for providing and maintaining a record of minutes of all 4DN-SC meetings, which will be approved by the 4DN-SC.

• The 4DN-SC activities and decisions will consider the advice of the NOFIC-SC, various trans-4DN Network subcommittees and working groups, and the 4DN-ESP.

• NIH Project Scientists involved with the management of the 4DN Network will help the 4DN-SC develop and draft sharing and operating policies that are in accordance with NIH guidelines. NIH Project Scientists, in concert with the 4DN-SC, will also have the option to redirect activities or operations being pursued within the 4DN-OH and 4DN-DCIC if it is considered beneficial to the overall program.

• The 4DN-OH PD/PI and 4DN-DCIC PD/PI will be responsible for accepting and implementing the goals, priorities, procedures, protocols, and policies agreed upon by the 4DN-SC. The 4DN-OH PI, the 4DN-DCIC PI, and the 4DN-SC Chair will jointly report progress with regard to overall 4DN Network activities and the development of new 4DN Network policies at the annual 4DN Investigator Meeting.

NOFIC Steering Committee (NOFIC-SC)

The main characteristics and functions of the NOFIC-SC are as follows:

• The NOFIC-SC will be composed at a minimum of the following voting members: all NOFIC U54 PDs/PIs, one representative of the 4DN-DCIC and one NIH Project Scientist involved in the management of the NOFIC. A staff member of the 4DN-OH will facilitate NOFIC-SC meetings and teleconferences and generate minutes that will need to be approved by the NOFIC-SC. Other individuals involved with the management of the 4DN Network could participate as Ex Officio (non-voting members) to the NOFIC-SC, in a permanent or ad hoc fashion, as needed and agreed upon by the voting members of the NOFIC-SC. These individuals could include various members of the 4DN-DCIC and the 4DN-OH, non-PI NOFIC investigators, or 4DN Network investigators who are not part of NOFIC. NIH staff and 4DN external experts will always be allowed to attend meetings and teleconferences of the NOFIC-SC as non-voting participants.

• The NOFIC-SC will be constituted at the 4DN Network kick-off meeting, and will meet at least quarterly, including at least once in-person during the annual 4DN Network Investigator Meeting. The first meeting of the NOFIC-SC will be chaired by the NIH representative on the NOFIC-SC. Following that initial meeting, a Chairperson for the NOFIC-SC will be chosen by the NIH amongst NOFIC U54 PDs/PIs to serve a two-year term. The Chairperson is responsible for coordinating the NOFIC-SC activities, for preparing meeting agendas and for chairing NOFIC-SC meetings. After two years of service, NIH staff may ask the NOFIC-SC Chairperson to serve a second 2-year term, or chose a replacement for that role. NIH staff may also choose to replace the NOFIC-SC Chair at any time based on poor job performance or failure to follow the relevant procedures and guidelines. During its initial meeting, the NOFIC-SC will also elect three NOFIC representatives to the 4DN-SC.

• Specific activities of the NOFIC-SC will include, but are not limited to: facilitate communication and foster collaborations across the NOFIC; identify opportunities for sharing techniques, materials, information and tools developed by NOFIC investigators; develop data standards, metadata requirements, data quality standards in close collaboration with the 4DN-DCIC; identify common cell types and/or biological systems to be used by all NOFIC investigators for the development of performance and reproducibility standards, NOFIC-wide pilot mapping efforts using combinations of mapping technologies, or the validation of models of structure/function relationships across NOFIC projects; review progress of the NOFIC towards meeting the overall goal of developing a set of complementary mapping strategies that can be combined to build comprehensive, whole-genome, and high-definition reference maps of the physical and functional organization of mammalian nuclear genomes and update NIH Staff regularly on the level of performance of the various NOFIC-supported mapping technologies, data analysis tools and computational modeling tools, to include metrics and measurements of reproducibility, accuracy, biological relevance and cost-effectiveness; help NIH assess when specific mapping technologies are sufficiently robust, validated and reliable to be used for the building of reference maps of genome organization in mammalian cells, at which point NIH staff may encourage NOFIC investigators to start producing a small set of such reference maps in specific cell types and/or tissues that will be chosen through consensus deliberations by the NOFIC-SC; make recommendations to the 4DN-SC on the possible use of the opportunity pool of funds, by proposing topics for initiatives or tool/reagent-development projects that can benefit NOFIC and 4DN Network activities;

• NOFIC subcommittees and working groups may be constituted following recommendations and approval by the NOFIC-SC, to help the NOFIC-SC with strategic planning activities, development of standards and policies, etc.

• The 4DN-OH is responsible for providing and maintaining a record of minutes of all NOFIC-SC meetings, which will be approved by the NOFIC-SC.

• The NOFIC-SC activities and decisions will consider the advice of the 4DN-SC, various trans-4DN Network subcommittees and working groups, and the 4DN Network External Scientific Panel (4DN-ESP, defined below).

• NIH Project Scientists involved with the management of the NOFIC will help the NOFIC-SC develop and draft sharing and operating policies that are in accordance with NIH guidelines. NIH Project Scientists, in concert with the NOFIC-SC, will also have the option to redirect activities or operations being pursued within the NOFIC and 4DN-DCIC if it is considered beneficial to the overall program.

4DN Network External Scientific Panel (4DN-ESP)

An independent panel of 3-6 External Experts will be appointed by NIH and meet by teleconference with the 4DN-SC at least once a year. The 4DN-ESP will be updated on progress and provide feedback to NIH on adjustments and future directions for the 4DN Network activities. NIH staff will appoint a 4DN-ESP Chair who will attend the annual 4DN Network Investigator Scientific Retreat and be invited to participate ex officio in 4DN-SC meetings. All members of the 4DN-ESP will be given the opportunity to listen to 4DN-SC meetings and to attend the annual 4DN Network Investigator Scientific Retreat. The 4DN-OH will support costs for 4DN-ESP members to participate in the 4DN Network Investigator Annual Meeting.

Dispute Resolution:

Disagreements that may arise in scientific/technical matters, publication/authorship matters or programmatic matters (within the scope of the award) between award recipients, or between award recipients and the NIH, may be brought to arbitration after first attempting to resolve the issue through the 4DN-SC or its subcommittees, as appropriate. An Arbitration Panel composed of three members will be convened. The Panel will be composed of: a designee of the 4DN-SC 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 members; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure in no way affects the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590 or 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.

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
Email: [email protected]

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Contact Center Telephone: 800-518-4726
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Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
Email: [email protected]

Olivier Blondel, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-451-7334
Email: [email protected]

Judy Mietz, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6250
Email: [email protected]

David Balasundaram, Ph.D.
Scientific Review Officer
Center for Scientific Review (CSR)
Telephone: 301-435-1022
Email: [email protected]

Craig E. Bagdon, MPA
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-2115
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 Parts 74 and 92.