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

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

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

The BRAIN Initiative: The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is aimed at revolutionizing our understanding of the human brain. By accelerating the development and application of innovative technologies, researchers will be able to produce a new dynamic picture of the brain that, for the first time, will show how individual cells and complex neural circuits interact in both time and space. It is expected that the application of these new tools and technologies will ultimately lead to new ways to treat and prevent brain disorders.

NIH is one of several federal agencies involved in the BRAIN Initiative. Planning for the NIH component of the BRAIN initiative is guided by the long-term scientific plan, BRAIN 2025: A Scientific Vision, which details seven high-priority research areas and calls for a sustained federal commitment of $4.5 billion over 12 years. This FOA and other FOAs issued in Fiscal Year 2017 are based on careful consideration by the NIH of the recommendations of the BRAIN 2025 Report, and input from the NIH BRAIN Multi-Council Working Group. Videocasts of the NIH BRAIN Multi-council Working Group are available at http://www.braininitiative.nih.gov/about/mcwg.htm.

To enable rapid progress in development of new technologies as well as in theory and data analysis, the BRAIN Initiative encourages collaborations between neurobiologists and scientists from statistics, physics, mathematics, engineering, and computer and information sciences; and NIH welcomes applications from investigators in these disciplines.

NIH encourages BRAIN Initiative applications from investigators that are underrepresented in the biomedical, behavioral, or clinical research workforce (see data at http://www.nsf.gov/statistics/showpub.cfm?TopID=2&SubID=27 and the most recent report on Women, Minorities, and Persons with Disabilities in Science and Engineering). Such individuals include those from underrepresented racial and ethnic groups, those with disabilities, and those from disadvantaged backgrounds.

NIH also encourages businesses to participate in the BRAIN Initiative. It is possible for companies to submit applications directly to BRAIN Initiative program announcements or to collaborate with academic researchers in joint submissions. Small businesses should consider applying to one of the BRAIN Initiative small business FOAs (http://braininitiative.nih.gov/funding/index.htm).

In addition to the National BRAIN initiative, the NIH continues to have a substantial annual investment in neuroscience research. The Institutes and Centers contributing to the NIH BRAIN Initiative (http://braininitiative.nih.gov/) support those research efforts through investigator-initiated applications as well as through specific FOAs. Potential applicants to this FOA are strongly encouraged to contact Scientific/Program staff if they have any questions about the best FOA for their research.

The BRAIN Initiative will require a high level of coordination and sharing between investigators.

This FOA is related to the Recommendations in Section III.1 and 2 of the Final Report (http://braininitiative.nih.gov/2025/index.htm) of the BRAIN working group. Specifically, this FOA solicits applications that will address the recommendations in "Section III.1. Discovering Diversity" and those on meso-scale connectome in "Section III.2. Maps at Multiple Scales".

The mammalian brain contains an astronomical number of cells. There are an estimated 1.13 x 10^8 cells in the mouse brain and an estimated 1.7 x 10^11 cells in the human brain, with each neuron making thousands of synapses with other cells. Since the early work of Ram n y Cajal, beginning with the elegant staining of individual neurons in the brain using the Golgi method, brain cell types have been increasingly defined by their location, morphology, connectivity, neurotransmitter type, physiology, and most recently, their transcriptional profile. Cataloging brain cell types and their connectivity is a prerequisite to understanding how they are organized in circuits, and how they change in brain disorders. In addition, a detailed understanding of cell classes and subclasses will enable the development of novel tools that allow researchers to target specific cell types and manipulate circuits for further study. However, there is not yet a consensus on what a brain cell type is, since a variety of factors including experience, cell interaction, and neuromodulators can diversify the molecular, electrical, and structural properties of similar cells, and cell phenotypes may change over time. Nonetheless, there is general agreement that cell types can be defined provisionally by invariant and generally intrinsic properties, and that this classification can provide a good starting point for a census. A recent workshop co-sponsored by the BRAIN Initiative and the NIH Single Cell Analysis Program shared information on how investigators are currently describing cellular phenotypes and novel approaches to better quantify, evaluate, understand, and communicate the brain cell classification. The consensus is that classification of cell types will be facilitated by a systematic collection and integrative analysis of three data elements at cellular level: (1) molecular signature (e.g., transcriptome, epigenome, proteome, metabolome), (2) anatomy (e.g., location, size, orientation, morphology, and connectivity), and (3) function (e.g., electrophysiology, functional connectivity). Current technological capabilities promise a new era in the call for a brain cell census hallmarked by high dimensionality of molecular information at an unprecedented scale and resolution. Single cell omics analyses (transcriptomics, epigenomics, and proteomics) will likely help define unique cell type markers and unveil the regulatory code that controls cell type formation, maintenance, and transition in health and disease. The new molecular insights gained may thus transform our understanding of cells types by revealing fundamental biological principles with mechanistic underpinnings to define discreet cell classes as well as relevant transition states.

The BRAIN Initiative Cell Census Network (BICCN)

The BRAIN initiative cell census program awarded 10 grants in September, 2014 under RFA-MH-14-215, forming the BRAIN Cell Census Consortium (BICCC) to pilot cell classification strategies for a comprehensive brain cell census (see Census of Cell Types: http://www.braininitiative.nih.gov/funding/fundedAwards.htm for information on these awards). The purpose of these awards was to test various methods in multiple brain regions from different organisms to determine whether approaches were mature enough to allow for the generation of large-scale and comprehensive cell census in the mammalian brain. Advances such as single cell transcriptional profiling, anatomical mapping at cellular resolution, and other approaches have proven ultimately to be powerful and scalable. At this time, the BRAIN initiative cell census program is looking to establish the BICCN for a systematic generation of reference cell census data and relevant tools. This FOA and the companion announcements intend to recompete the BRAIN initiative cell census projects within the network. The overarching goals of the BICCN are to ultimately:

• generate a comprehensive 3D common reference mouse brain cell atlas that integrates molecular, anatomical, and physiological annotations of brain cell types, and
• generate reference atlases of brain cells from human and/or non-human primate brain samples.

The expected outcomes of the BICCN include:

• fundamental knowledge on diverse cell types and their three dimensional organizational logic in the brain;
• an open-access 3D digital brain cell reference atlas with molecular, anatomical, and physiological annotations of brain cell types in mouse;
• a comprehensive neural circuit diagram in mouse brain;
• reagents for cell-specific targeting;
• validated high throughput and low cost approaches to characterizing cell diversity in human and/or non-human primate brain samples.

The BICCN will be composed of a group of Centers and Collaboratories supported via four companion FOAs: Comprehensive (U19) Center(s) supported via RFA-MH-17-225 that will focus on building up a comprehensive mouse brain cell atlas; Specialized (U01) Collaboratory via RFA-MH-17-230 that will contribute cell census data for endpoints in the mouse brain not otherwise covered in the U19 Center(s); Specialized (U01) Collaboratory via RFA-MH-17-210, the FOA being described here, that will begin to collect cell census data from human or non-human primate brains; and finally, the U24 BRAIN Cell Data Center (BCDC) via RFA-MH-17-215 that will integrate, visualize, and disseminate the cell census data generated by the U19 and U01 Centers and Collaboratories as well as create a brain cell knowledge base. The NIH expects that the BICCN will operate as a cooperative network to promote collaboration and coordination with any research entities that have similar goals. It is expected that funded projects in the BICCN will work together to achieve the overall goals. This will include regular meetings and other coordinated activities within the BICCN as well as in the BRAIN Initiative more broadly. Thus, the BICCN will leverage existing atlases and common coordinate systems to facilitate collaborative efforts for the data annotation and 3D spatial mapping.

Common Brain Tissues and Coordinate Systems

A large amount of data concerning brain anatomy and physiology exists, and continues to grow rapidly. With the advent of single cell omics technologies, new biomolecular data are expected to flourish, adding to the existing expansion of data sets. Correspondingly, there is an increasing need to enhance data interoperability and harmonization among data producers and data accessibility to the broad research community, and to reduce unnecessary repetition in data generation. Atlases and common coordinate systems play a fundamental role in gathering, analyzing, communicating, and standardizing data. This FOA embraces the existing effort of the research community (e.g., the International Neuroinformatics Coordination Facility) to collaboratively build up brain atlases with broadly accessible common brain coordinate systems to integrate and disseminate the brain cell census data. Thus this FOA supports the use of common brain samples, and common brain coordinate systems to minimize source variability and maximize resource sharing. Accordingly, the NIH expects that imaging based cell census data will be registered to common coordinate systems, which include in-situ hybridization, immunohistochemistry, cell morphology, and neuronal connectivity mapping. In case non-imaging based approaches are used, applicants should propose how to spatially assign the data to the brain regions as accurately as possible. For example, microdissection and computational tools may help map single cell data onto a reference brain atlas spatially.

Postmortem healthy human brain tissues are available with minimal tissue degradation (e.g., NIH NeuroBioBank; GTEx program, Biopreserv Biobank. 2015 Oct;13(5):311-9). Much progress has been made to develop and implement common coordinate systems for human brain (e.g., BigBrain, BrainSpan, Talairach Coordinate System, MNI Coordinate System) and image segmentation and registration tools (e.g, Insight Segmentation and Registration Toolkit (ITK)) that allow individual labs to integrate their data to the common coordinate systems.

Research Scope of U01 Specialized Collaboratory on Human and Non-Human Primate Brains

As primate brains are several orders of magnitude larger than the mouse brain in size and number of cells, the NIH expects that the U01 Specialized Collaboratory on Human and Non-Human Primate Brains will begin to implement high throughput approaches and to establish experimental feasibility towards the generation of comprehensive reference brain atlases for larger brains at cellular resolution. For example, the Specialized Collaboratory may focus on one or a few select brain regions (e.g., hippocampus, striatum, amygdala, hypothalamus, defined regions of the cortex, cerebellum, etc.) and generate molecular signatures data. The data production goals should be as comprehensive and complete as possible with a broad coverage of multiple different brain structures/regions and adequate depth in characterizing multiple cellular properties. Overall applicants should propose to use methods that have been demonstrated to generate high-quality data, to be cost-effective, and to have the capability to accurately and efficiently define cell types. Scalable and multiplexed approaches are expected to enable a comprehensive cell type survey. In addition, applicants are encouraged to adopt technology platforms that are capable of acquiring multimodal datasets from the same cells with adequate throughput. For example, RNA fluorescence in situ hybridization (FISH) may be combined with immunohistochemistry labeling to monitor both RNA and protein molecules in the same cells.

Examples of responsive activities include but are not limited to the following data and resource production and research themes:

1. Molecular Signatures

Applicants should adopt scalable experimental approaches that will maximize the discovery and classification of all brain cell types. The research objectives may include but are not limited to:

• generating spatially defined single cell transcriptome data to unveil brain cell classes and types based on transcriptome signatures;
• generating immunohistochemistry and immunocytochemistry data using validated protein affinity reagents to identify specific cell types and neurite projections;
• generating spatially defined single cell epigenome data (e.g., chromatin accessibility, DNA methylation) to help define brain cell types;
• determining microenvironment, tissue composition and ratio of various cell types (e.g., neurons, glial cells, vascular cells, immune cells, progenitor cells, synapses, spines, stroma) in the brains.

2. Anatomy

Applicants should leverage existing reference anatomical atlases and adopt scalable experimental approaches that will maximize the discovery and classification of all brain cell types and/or neuronal connections. The research objectives may include but are not limited to:

• generating comprehensive novel data specifying cell spatial location and morphology (e.g., cell size and shape);
• generating novel mesoscale long- and short-distance neuronal connectivity map;
• discovering monosynaptic input and output neurons (e.g., using retrograde and anterograde viral tracings);
• determining microenvironment, tissue composition and ratio of various cell types (e.g., neurons, glial cells, vascular cells, immune cells, progenitor cells, synapses, spines, stroma) in the brains.

3. Functional Measures

Applicants should adopt scalable experimental approaches that will maximize the discovery and classification of all brain cell types. The research objectives may include but are not limited to:

• generating electrophysiological and cell morphological data from neuron types with defined spatial location;
• generating functional connectivity data (e.g. synaptic input field, network modules) from neuron types with defined spatial location and cell morphology using advanced microscopic imaging methods.

4. Advanced Approaches and Tools

Technology improvements will play an important role in increasing the data production efficiency. As appropriate, applicants may propose to adapt and improve advanced approaches and tools to enhance data production and data quality goals. Applications should address limitations and gaps of the current technologies and tools as a benchmark against which the improvements or competitive advantages of the proposed ones will be measured. The improvements include throughput, sensitivity, selectivity, scalability, spatiotemporal resolution and reproducibility in cell census analyses.

The cell census data and tools t generated by the BICCN will be an important and unique resource for use by the broad research community, and thus the following issues related to the large-scale production are paramount to the success of the program.

Data Quality. Two of the cornerstones of science advancement are rigor in designing and performing scientific research and the ability to reproduce biomedical research findings. (http://grants.nih.gov/reproducibility/index.htm). The BICCN is expected to establish stringent data quality standards and quality control and quality assurance processes for the experimental and statistical approaches, so that the data generated will be broadly referenced and used by the research community.

Data Comprehensiveness & Completeness. The data production goals should be as comprehensive and complete as possible with a broad coverage of different brain structures/regions and adequate depth in characterizing multiple cellular properties. In practice, achieving a comprehensive and complete census of brain cells that include neurons, glia cells, and other cell types will require careful planning of workflow, strategic allocation of resources, and optimal lineup of complementary technologies. To ensure comprehensive coverage of cell diversity and avoid overcommitting resources to a limited number of brain regions and cell types, the NIH program staff may consider portfolio balance when making funding decisions and negotiating the milestones. The purpose is to establish a Network with complementary capabilities and capacities toward generating a comprehensive and complete brain cell atlas.

Data Utility. The ultimate utility of cell census data for the broad research community may reside in an effective integration of different cell census data elements including molecular content, cell anatomy, and physiology to define a cell type. Each element of data may be limited in its own value, but combined the data collected by individual projects should inform and cross validate each other to arrive at an integrative description closer to nature. Rapid data exchange and integration are critical for defining a cell type and unveiling the organizational rules behind cellular makeup and neural circuits. The BICCN Collaboratories are expected to abide by the agreed data sharing policy and process to ensure unhindered data exchange and sharing.

Production Workflow. As the ultimate long-term goal is to establish comprehensive reference brain cell atlases, the BICCN should attain a high level of production at an affordable cost by adopting scalable technology platforms and streamlined workflows. As with other large-scale data generation efforts, the BICCN Collaboratories are expected to have the capability to operate at scale at the inception of the project, establish adequate process control with quantitative quality metrics at key points in the production workflow, and have plans to improve production workflow and cost efficiency.

Each U01 Collaboratory must include data management and analysis activities to provide central data storage, data management and information security services to all researchers within the collaboratory, and will be responsible for ensuring the timely submission of data and data analyses to the BCDC. In addition, the Collaboratory should have bioinformatics expertise to support data integration and analysis according to the Collaboratory’s research objectives, including mining and integrating existing data and information, and assisting study design. As appropriate, the Collaboratory may perform statistical analysis of single cell omics data to identify and classify cell types, discover unique cell type markers, predict spatiotemporal relations, and infer gene expression regulatory mechanisms underlying cell type formation, maintenance, and transitional states. The Collaboratory’s data expert(s) will represent the Collaboratory in a cross-BICCN data sub-committee that will operate under the Steering Committee to promote coordination and collaboration among all BICCN Centers and Collaboratories including data sharing, data harmonization, refinement of data standards, data analysis and integration, data mapping to common brain coordinate systems, and data visualization.

Each U01 Collaboratory must also include administrative activities to coordinate the Collaboratory activities and facilitate its integration into the broader BICCN, as well as include mechanisms that will foster effective interactions with other BICCN network Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) and institutions to promote synergistic research efforts. The effective management of a production collaboratory requires a significant commitment by the PD/PI. A program manager may in addition strengthen the collaboratory administration. The Collaboratory administration will be responsible for organization, management, decision-making, and periodic evaluations of individual groups within the Collaboratory, involvement of institutional and other resources, and shared publications.

Milestones: The success of BICCN will be facilitated by the adoption of clear, quantitative milestones by each of the participating Centers and Collaboratories. Applications lacking milestones will be deemed incomplete and will not be reviewed (See Section IV.2).

Activities that are not responsive: The following research areas are considered outside the research scope of this FOA, and such applications will be considered non-responsive and will not be reviewed:

• studies of neural circuit diagrams at macroscale and/or microscale using magnetic resonance imaging (MRI)- and/or electron microscopy (EM)-based methods;
• studies of cultured cells, isolated cell samples and/or stem cell lines that are maintained under culture conditions;
• early stage technology development. Note: Applications for the early stage technology development may be submitted to a separate BRAIN FOA (RFA-MH-17-220 and its reissues) that supports development and validation of novel tools to analyze cell-specific and circuit-specific processes in the brain.

Program Technical Assistance Note: On November 18 (Friday), 1 pm Eastern Time, an interactive technical assistance webinar will be held for investigators who are interested in information about the structure of collaborations, topics of interest or programmatic requirements of the FOA. Potential applicants are strongly advised to solicit Program feedback from the NIMH Scientific/Research Contact (BICCN Technical Assistance) well in advance of the application due date to determine whether their proposed studies align with the FOA purpose.

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

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

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

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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

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

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

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

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

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

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

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

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

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

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

The letter of intent should be sent to:
Email: [email protected]

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

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

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

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

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

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

The Collaboratory PD/PI funded under this FOA should devote at least 25% effort (3 person months) to the Collaboratory project for the duration of the award.

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

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

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

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

Specific Aims: Describe overall research aims and strategy of the Collaboratory. State in priority order the aims of the proposed project.

Research Strategy:

The Collaboratory is expected to perform the following activities aligned with the research objectives: (1) data and resource generation, (2) data management and analysis, (3) administrative, and if appropriate, (4) improvement of tools and technologies. In addition to the information requested in the application guide, the applicant should also address the following four parts.

(1)The data and resource generation part is expected to:

• describe the data and resource production and research theme(s);
• describe the brain samples and structures/regions to be analyzed;
• describe currently existing data and tool generation effort and the state-of-the art approaches used;
• state the issues (general and specific), gaps, and challenges in the relevant cell census research;
• propose experimental design to ensure the data generated are rich in content and spatially annotated on a common brain atlas for the dissemination and use by the broad research community;
• describe scalable methods with preliminary data and case studies to support their feasibility of generating high-quality data in cost-effective manner;
• provide current estimates of data quality and plans for how data quality will be evaluated during the course of the project;
• describe how to optimize experimental procedures to reduce technical noise and enhance data quality;
• define comprehensiveness and completeness or breadth and depth for the proposed project, describing how close to that target the proposed project will get in a five-year timeframe for each data element being investigated;
• describe production workflow including throughput as well as rate-limiting steps, and provide plans for assessing and improving the pipeline;
• describe quality control/quality assurance measures and decision making process;
• describe costs at the beginning of the project and then describe anticipated cost reductions during the project period with a cost model incorporating a standardized cost structure including a useful unit (e.g., per experiment or per cell characterized) and identify large-cost items that dominate the cost model;
• describe innovative aspects of the Collaboratory including the generation of novel datasets and/or tools.

(2)The data management and analysis part is expected to:

• describe database infrastructure, information management and monitoring, management of complex multimodality data, statistical analysis and inference of biological mechanisms, data integration and registration to a common brain coordinate system, and computational modeling if appropriate;
• propose and justify data/metadata standards and formats to be used while demonstrating flexibility for adopting different ones once the BICCN is formed;
• propose data analysis methods and procedures for the Collaboratory including analysis algorithms and data hierarchy;
• provide statistical rationale about data quality and informatics analysis about data novelty;
• list and define the data/metadata to be shared with the funded U24 BCDC (companion announcement) and other BICCN Centers and Collaboratories to ensure seamless and efficient operation;
• For shared data, propose when it will be made available, where it will be stored, how it will be maintained, and how others will be able to find, access, and reuse it. Note that funded Collaboratories will be required to share data in accordance with agreed-upon standards for the BICCN as appropriate and consistent with achieving the goals of the program.

(3) The administrative part is expected to:

• describe plans for ensuring the Collaboratory is meeting the performance objectives and milestones;
• describe organizational structure and staff of the Collaboratory and individual responsibilities (Note: No steps need to be taken to include an external advisory board in the applications as a BICCN-wide External Scientific Panel will be established by the NIH BRAIN Project Team after awards are made);
• describe how to manage all aspects of the production of brain cell census data and tools, data management and analyses, and how resources will be prioritized, allocated, and managed;
• describe plans for: developing and implementing standard operating procedures (SOPs); maintaining fidelity to research procedures and fiscal accountability; ensuring quality control (QC) for data and/or tools generation; timely submission of data to BCDC;
• describe how to enhance the collaborative effort and ensure efficient cooperation, communication and coordination, and resource sharing among the BICCN entities, and how the proposed Collaboratory will create an integrated entity capable of performing the functions specified in the FOA. (4) As appropriate, the tool and technology part is expected to explain how the improvements of tools and technologies will serve the proposed Collaboratory. For example, describe limitations and gaps of the current technologies and tools in throughput, sensitivity, selectivity, scalability, spatiotemporal resolution and reproducibility in cell census analyses; propose improvements in technologies and tools that will address the current limitations and gaps, and how, as a result, the improved technologies and tools will enhance the goals of the Collaboratory as well as the overarching goals to generate a brain cell reference atlas.

Milestones. Applications to this FOA must define a clear set of overall goals that are aligned with the expected BICCN’s outcomes, and must include annual milestones with metrics that will document progress towards the achievement of the overall goals. Applications lacking milestones will be considered incomplete and will not be reviewed. For each approach, clear, quantitative outcomes should be set and described. Annual milestones should reflect the current ability to produce data from the beginning of the project, and include plans for critically evaluating and revising these milestones on a regular basis. Specific items in milestones include but are not limited to:

• number of attempted experiments (Define experiment as it relates to the proposed method(s) including informatics);
• number of verified experiments (A practical definition for verification is when a dataset has been demonstrated to be of sufficient quality to merit follow-up experiments and for public release);
• number of cells, brain regions, samples, and/or experimental conditions tested,
• number of antibodies tested (if applicable);
• number of tools generated (if applicable),
• product (data or tool) quality as measured by characterization experiments and use of relevant data or tool standards;
• production efficiency and cost effectiveness as measured by throughput and cost per experiment, including informatics.

Letters of Support: Include letters of support/agreement for any collaborative/cooperative arrangements, subcontracts, or consultants. Letters of support should indicate the specific activities the individual or organization will perform in pursuit of the Collaboratory goals; letters of support from individuals or organizations without a specific role in the Collaboratory should not be included.

The applications are expected to include written statements from the officials responsible for intellectual property issues at all of the applicant institutions (including subcontractors) to the effect that the institution supports and agrees to abide by the resource sharing plans put forth in the application if applicable. Such letters would be clear expressions of commitment. A separate letter should be sent by each participating organization including each subcontractor. Please note that institutional sign-off on the grant application signifies that all relevant components of the institution, including the relevant office handling intellectual property matters have reviewed and approved the document.

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

A central goal of this FOA is to build up a comprehensive brain cell census data resource that will be widely used throughout the research community. It will take the combined resources of researchers in the public and private sectors many years to catalog and characterize the biology of brain cells, neuronal connectivity of interest, to understand brain function, and then to use that information to improve public health. The open sharing of the brain census data, research tools, and resources will not only lead more rapidly to their broad use by the research community, but also encourage scientific rigor in data production and analysis, with resulting benefits to public health. In order to reap the maximum value from this program, all molecular, anatomical, and physiological data, experimental protocols, tools generated are expected to be made publicly available. Applications must include a detailed plan for sharing data and resources and include the following key elements:

• Project management of data and resource sharing;
• Description of what specific data and resources will be shared (e.g., single cell transcriptome data, immunohistochemistry data, cell morphology data, neuronal connectivity data, electrophysiological data, functional connectivity data, software, model organisms, reagents, completed tools or repurposed components);
• Schedule/timeline for availability of data and resources to other users.

Data Sharing. Applicants must provide a specific proposal for data sharing in the application, and address the issues related to the public release of data and data analyses (see the rationale for FAIR (Findability, Accessibility, Interoperability, and Reusability) Data Principles). After the initial review, the BRAIN program staff will be responsible for any additional administrative review of the plan for sharing data and may negotiate modifications of the data sharing plan with the prospective awardee prior to award. The final negotiated version of the data sharing plan will become a term and condition of the award of the cooperative agreement. After all of the awards have been made, the BICCN Steering Committee, of which all awardees will be members, will develop a final, common data release plan as appropriate for the project that will address the interests of the data producers and analysts, as well as the users of the BICCN brain cell census atlases. Applicants should indicate their willingness to participate in the development of such a final plan and to accept it. The NIH expects that verified raw data will be submitted in real time or other agreed-upon timeframe depending on the data types and verification requirements to long-term publicly accessible archives such as GEO or others as appropriate. Applicants should address whether they anticipate any of their data will require controlled access. Agreement to abide by that policy is a requirement for anyone to join the Network.

Resource Sharing. As the BICCN is generating a community resource, in addition to data, resources generated by the BICCN projects should be made rapidly available to the research community. Rapid dissemination of these resources would accelerate scientific exploration and avoid duplicative resource development effort. The applicant should provide specific plans for resource sharing and distribution in the application. After the initial review, the BRAIN program staff will be responsible for any additional administrative review of the plan for sharing resources and may negotiate modifications of the resource sharing plan with the prospective awardee prior to award. The final negotiated version of the resource sharing plan will become a term and condition of the award of the cooperative agreement.

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

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

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

In order to expedite review, applicants are requested to notify the NIMH Referral Office by email at

[email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

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 may 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 the 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.

Applicants are required to follow our Post Submission Application Materials policy.

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

For this particular announcement, note the following:

Since this FOA specifically seeks applications to systematically generate brain cell census data and possibly related tools, the NIH expects that some applications may propose mature and well-established approaches that may not be innovative per se to produce robust high quality datasets for broad use by the research community. In their evaluation of Innovation reviewers will be asked to weigh the potential of the applications to generate novel cell census data and/or tools that may lead to transformative, paradigm-shifting advances.

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

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

Does the Collaboratory address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Do the proposed aims and scientific questions align well with the overarching goals and the expected outcomes of the BICCN? Are the expected results likely to provide significant data related to the identification and classification of brain cell types?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Are the PD/PI and other key personnel devoting sufficient time/effort to achieve the goals? Has adequate leadership for day-to-day project management activities been described?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Does the application describe evidence that demonstrates the novelty of cell census data and tools to be generated? Will the novel data and/or tools lead to transformative, paradigm-shifting advances of the field?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Does the application adequately describe and discuss experimental designs to ensure the data quality, comprehensiveness & completeness? Are potential pitfalls clearly discussed and minimized accordingly? Does the application adequately provide a rationale and supporting data on the adequacy of the cell sampling? Will experimental designs ensure novel, high-quality cell census data will be generated? Does the application adequately address issues related to the data mapping to a common brain coordinate system?

Does the application demonstrate the capability to operate at scale as proposed? Does the application provide evidence of how production goals are set and can be attained? Does the application present sufficient preliminary data to support feasibility of the proposed scalable methods and adequate throughput? Are rate-limiting steps identified and appropriately addressed? Are plans included for improving the pipeline adequate?

Does the application adequately demonstrate an effective workflow? Does the application describe workflow assessments and proposed improvements? Does the application provide current estimates of data quality and plans for how data quality will be evaluated during the course of the project?

Is the data management and analysis plan appropriate to facilitate attainment of the objectives of the proposed Collaboratory project? Does the application adequately describe data management, integration, and analysis? Is the plan for data registration to a brain atlas and/or common brain coordinate system adequate? Does the application propose and justify standards and formats of the data/metadata, data analysis methods? Are there appropriate data infrastructure(s) and pipeline(s) to support data sharing?

Is the administrative plan appropriate to ensure the Collaboratory will meet the performance objectives and milestones? Does the application adequately describe the organizational structure and individual responsibilities? Does the application adequately describe administrative plans for: developing and implementing standard operating procedures (SOPs); maintaining fidelity to research procedures and fiscal accountability; ensuring quality control (QC) for data and/or tools generation; timely submission of data to BCDC? Does the application adequately propose how to enhance the collaborative effort among the BICCN entities to ensure efficient cooperation, communication and coordination, and resource sharing?

Does the application describe limitations and gaps of the current technologies and tools in throughput, sensitivity, selectivity, scalability, spatiotemporal resolution and reproducibility in cell census analyses? If proposed, does the application adequately describe improvements to tools and technologies? Will proposed improvements in technologies and tools address the current limitations and gaps, and enhance the goals of the Collaboratory and the overall outcomes of the BICCN?

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

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

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

Milestones and Timeline

Are clear, quantitative, and actionable, milestones and timelines proposed? Do the milestones establish feasibility for all aspects of the proposed research? Does the application include plans for critically evaluating and revising milestones on a regular basis? Are there additional key experiments that need to have milestones? Will the overall milestones provide adequate information to evaluate yearly progress of the Collaboratory project as a whole? Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps?

Overall Coordination

Is there a clear and sound plan for communication and coordination within the Collaboratory and across BICCN demonstrating an integrated Collaboratory project capable of performing the functions specified in the FOA?

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

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

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

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

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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not Applicable

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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

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

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

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

Does the application adequately address the issues related to the public release of data and data analyses (see the rationale for FAIR (Findability, Accessibility, Interoperability, and Reusability) Data Principles)? Does the application adequately describe for shared data, when it will be made available, where it will be stored, how it will be maintained, and how others will be able to find, access, and reuse it? Does the application adequately describe specific plans for resource sharing and distribution in the application?

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

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

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

As part of the scientific peer review, all applications:

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

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

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the 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.
• Programmatic balance. The purpose is to develop a network with complementary capabilities towards generating a comprehensive brain cell atlas. Therefore, decisions about awards will consider the mix of capabilities offered by the proposed collaboratories.

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

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

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

Prior to funding an application, the program staff will contact the applicant to discuss the proposed milestones. The program staff and the applicant will negotiate and agree on a final set of milestones as the basis for judging the success of the project. The milestones will be reviewed annually (and at other times, if necessary), and new milestones will be re-negotiated with the NIH as described in the terms and conditions of a Cooperative Agreement in section VI.2.

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.

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

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

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR 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, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibilities as described below:

• Define the details for the project within the guidelines of this FOA.
• Oversee and perform the scientific activities.
• Administratively manage the Collaboratory grant.
• Accept close coordination, cooperation, and participation of NIH BRAIN program staff in the scientific, technical, and administrative management of the BICCN. Inform the NIH program official of all major interactions with other members of the Steering Group.
• Provide milestones and cost for the Collaboratory operation to the NIH BRAIN program staff as requested (usually at the outset of the award and annually thereafter, but also at other times as requested by the program staff).
• Use common brain samples, common coordinate systems, and standard nomenclature to generate and integrate the data, metadata, and knowledge.
• Demonstrate capability and flexibility for modifying brain regions of study, data formats and metadata.
• Ensure that the products of the production effort meet the quality standards.
• Share data and resources according to the data release and resource sharing policies developed for and by this project as appropriate and consistent with achieving the goals of the program.
• Fully disclose algorithms, software source code to the other members of the Network for the purpose of scientific evaluation.
• Not disclose confidential information obtained from other members of the Network.
• Submit data for quality assessment and/or validation in any manner specified by the Steering Group, the External Scientific Panel, and/or the NIH BRAIN program to ensure scientific rigor;
• Adhere to NIH policies regarding intellectual property and other policies that might be established during the course of this activity. Awardees will retain custody of and have primary rights to the data and resources developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
• Participate in BICCN activities, including periodic meetings to report the Collaboratory’s progress, and coordinate publication of research results.
• Coordinate and collaborate with other U.S. and international groups that may be generating relevant cell census datasets;
• Serve as a member of the BICCN Steering Committee.
• Submit periodic progress reports as agreed upon by the Steering Committee.
• Accept and implement the common guidelines and procedures approved by the Steering Committee, External Scientific Panel, and NIH.

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

• A Program Officer will be assigned to this award. The Program Officer will be responsible for normal scientific and programmatic stewardship and guidance for the overall project within the NIMH and will ensure that the generation of cell census datasets and resources are relevant to the diverse research community served by the NIH Institutes and Centers. The Program Officer will be responsible for milestone negotiations to ensure that the milestones are achieved and goals are being met. In addition, the NIH Program Officer is responsible for monitoring and implementing the Data Sharing Plan (http://grants.nih.gov/grants/policy/data_sharing/index.htm). The NIH Program Officer may attend Steering Group meetings as a non-voting participant. The NIH Program Officer will be named in the award notice.
• One or more extramural NIH program staff member will be assigned as the Project Scientist(s) for this award. The same person may serve as the Project Scientist for multiple BRAIN Initiative awards. The Project Scientist(s) will interact scientifically with the PDs/PIs and other named personnel of that award, as a partner in the research, including providing technical assistance, advice, and coordination for the BICCN and its component parts. However, the role of NIH staff will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the BICCN Steering Committee and that NIH staff will be given the opportunity to offer input to this process. One NIH Project Scientist will participate as a member of the Steering Committee and will have one vote.
• An NIH BRAIN Project Team will be composed of Program Officials and other relevant extramural staff from NIH Institutes and Centers and the Project Scientist(s). Its primary role is to ensure that the datasets and resources generated represent the diverse interests of the participating NIH Institutes and Centers, advise on brain cell census activities relevant to their individual Institute/Center mission, monitor overall progress, attend Steering Group meetings as required, and report back to their Institute/Center.
• The NIH BRAIN Project Team will establish an External Scientific Panel (ESP) to help evaluate the progress of the BICCN.
• NIH intramural scientists involved in the BICCN will have the same rights and responsibilities as the comparable extramural scientists involved in the BICCN. An intramural scientist may not receive salary, equipment supplies, or other remuneration from awards resulting from this FOA. The intramural scientist must obtain written approval of his/her NIH Institute Scientific Director for the amount of resources that may be allocated to the project. The approval must also specify that the conduct of the project will comply with the DHHS regulations for research involving human subjects (if applicable) and with the PHS policy on vertebrate animal research. The participation of an intramural scientist is independent of and unrelated to the role of the NIH Project Scientist(s). The involvement of intramural scientists needs to be consistent with NIH Policy. http://sourcebook.od.nih.gov/ethic-conduct/ethical-conduct-toc.htm

Areas of Joint Responsibility include:

BRAIN Cell Census Network (BICCN) Steering Committee:

The Steering Committee will be composed of the PD(s)/PI(s), Project Scientist(s) and External Scientific Panel members (experts to be named after award). The Steering Committee will be established to help monitor progress, encourage improvements, and coordinate the production of brain cell census datasets and resources through the BICCN. It is anticipated that additional coordination mechanisms will be set up with other U.S. and international groups that may join this effort. The BICCN Steering Committee members will meet periodically to plan and design activities, review and discuss progress, and establish priorities and policies. A chair will be designated on a rotating basis as needed. Each PD(s)/PI(s), and external scientific advisor will have one vote each and the NIH will have one vote through the participation of the Project Scientist(s). The frequency of meetings will be determined by the Project Scientist who will be responsible for scheduling the time and place and for preparing concise proceedings or minutes which will be delivered to the Steering Committee members within 30 days after the meeting. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

The BICCN Steering Committee will:

• Discuss progress in meeting the research community's need for cell census datasets.
• Facilitate the development of uniform procedures and policies, for example for data standards, quality measures and assessment, nomenclature and annotation conventions for data depositions, and so forth.
• Awardee members of the Steering Group will be required to accept and implement the common guidelines and procedures approved by the Steering Group.
• Coordinate and improve cell census data production, for example by reporting progress, disseminating best practices and collectively evaluating new procedures, resources, and technologies.
• Establish subcommittees as needed to address particular issues. Subcommittees will include representatives from the BICCN, the NIH BRAIN Project Team, and possibly other experts. Subcommittees may be formed to: 1) develop and implement data production and analysis standards including spatial and semantic standards for integrating heterogeneous data sets and information; 2) address data submission, management, and analysis issues; 3) develop quality standards and methods for quality control and assurance; and 4) develop common reagents and informatics tools. In these cases, common policies, uniform practices (as needed), and data exchange will be critical to the success of the effort and will enable harmonization and eliminate duplication/overlap.

External Scientific Panel (ESP):

The ESP will provide recommendations to the NIH BRAIN Project Team and BICCN about the progress and scientific direction of all components of the program. The ESP will be composed of four to six senior scientists who represent broad research community and have relevant expertise, although the membership may be enlarged permanently or on an ad hoc basis as needed. The ESP will meet at least twice a year; some meetings may be conducted by telephone conference. At least once a year, there will be a joint meeting with the Steering Committee for the members of both ESP and Steering Committees to interact directly. Twice a year the ESP will make recommendations regarding progress of the BICCN and present advice to the NIH BRAIN Project Team about changes, if any, that may be necessary in the BICCN program.

Dispute Resolution:

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

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

The effectiveness of data and resource sharing will be evaluated as part of the administrative review of the annual non-competing Grant Progress Report.

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.

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
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Contact Center Telephone: 800-518-4726
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GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
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Telephone: 301-945-7573

Yong Yao, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-6102
Email: [email protected]

David Armstrong
National Institute of Mental Health (NIMH)
Telephone: 301-443-3534
Email: [email protected]

Tamara Kees
National Institute of Mental Health (NIMH)
Telephone: 301-443-8811
Email: [email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.