Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

This Funding Opportunity Announcement (FOA) is developed as a Common Fund initiative (http://commonfund.nih.gov/) through the Office of Strategic Coordination, Division of Program Coordination, Planning, and Strategic Initiatives, Office of the NIH Director (http://dpcpsi.nih.gov/osc/). This FOA will be administered by the National Institute of Mental Health (NIMH) on behalf of the NIH.

Funding Opportunity Title

Studies to evaluate cellular heterogeneity using transcriptional profiling of single cells (U01)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

New

Related Notices

None

Funding Opportunity Announcement (FOA) Number

RFA-RM-11-013

Companion FOA

RFA-RM-11-014 (R21); RFA-RM-11-015 (R01)

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.310

FOA Purpose

The purpose of this funding opportunity is to support projects to examine the transcriptional signatures of individual human cells in order to measure and analyze cellular heterogeneity and to define specific cell types and/or cell “states” in a given population.  In addition, projects supported through this FOA must devise and test methods to detect, analyze, and interpret “noise”, which may be technical or biological in origin.  These studies will identify methods to minimize artifactual noise while simultaneously exploring the biological significance of heterogeneity among single cells.

Key Dates
Posted Date

November 23, 2011

Open Date (Earliest Submission Date)

December 23, 2011

Letter of Intent Due Date

December 23, 2011

Application Due Date(s)

January 23, 2012, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

March 2012

Advisory Council Review

August 2012

Earliest Start Date(s)

September 2012

Expiration Date

January 24, 2012

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (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.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

The purpose of this funding opportunity is to support projects to examine the transcriptional signatures of individual human cells in order to measure and analyze cellular heterogeneity and to define specific cell types and/or cell “states” in a given population.  In addition, projects supported through this FOA must devise and test methods to detect, analyze, and interpret “noise”, which may be technical or biological in origin.  These studies will identify methods to minimize artifactual noise while simultaneously exploring the biological significance of heterogeneity among single cells.

Background

This initiative is part of the Single Cell Analysis Program (SCAP) and is funded through the NIH Common Fund (See http://nihroadmap.nih.gov/), which supports cross-cutting programs that are expected to have exceptionally high impact. Common Fund initiatives address key roadblocks in biomedical research that impede basic scientific discovery and its translation into improved human health. In addition, these programs capitalize on emerging opportunities to catalyze progress across multiple biomedical fields.

Single cell analysis has recently emerged as an important field of research because technologies have improved in sensitivity and throughput sufficiently to begin measuring and understanding heterogeneity in complex biological systems and correlating it with changes in biological function and disease processes. By profiling individual cells it is possible to resolve rare cells, transient cell states, and the influence of organization and environment on such cells and states, which cannot be described by ensemble measurements. The long-term goal of the SCAP is to accelerate this move towards personalizing health to the cellular level by understanding the link between cell heterogeneity, tissue function and emergence of disease through the discovery, development and translation of innovative approaches which will dramatically change the way cells are characterized.

The SCAP will focus on supporting work which will systematically measure, analyze and model cell-to-cell variation, and identify crucial differences and rare biological states, which may have important functional consequences. To robustly and systematically describe cell level heterogeneity, projects are expected to take a multiplexed approach with minimal perturbation, which can be applied reproducibly to any complex tissue. Technologies and methods must also be capable of capturing spatiotemporal information to understand the organization, evolution and response of cell states as part of a functional population. In addition, the SCAP emphasizes the application of these technologies to in situ populations of cells from multicellular organisms to link cell state measurements with complex, functional tissues which can inform our understanding of disease processes.

The SCAP has been designed as a five-year program with several components: (1) the collection, analysis and sharing of comprehensive expression datasets to understand the role of heterogeneity in tissues and systemically and identify critical parameters and states; (2)  the discovery of new, innovative tools for spatiotemporal imaging, manipulation, analysis and modeling of a biologically relevant population of cells with minimal perturbation; (3) milestone-driven validation and translation of technologies for characterizing single cells in situ meeting the needs of end-users; and (4) development and coordination of a multidisciplinary research community through workshops and other collective endeavors. Further details can be found on the Program’s website (http://commonfund.nih.gov/singlecell/).

Research Objectives:

This Funding Opportunity Announcement (FOA) issued by the National Institutes of Health, solicits applications for projects to examine the transcriptional signatures of individual human cells in order to assess the degree of cellular heterogeneity within a population, including heterogeneity among ostensibly similar cells, and to define specific cell types and/or cell states in the population. These projects are exploratory in that they will help develop the paradigm for the comparative analysis of heterogeneity at the single cell level, which can then be applied at much more comprehensive levels across cell types in the human body.  The RNA signature is a feature of the cell’s functional state and can be regarded as a measure of the biological identity of a particular cell or class of cells.  Feasibility for this effort is assumed based on current unbiased, state-of-the-art approaches, most of which involve RNA amplification steps followed by sequencing.  While the transcriptome is only one aspect of a cell’s biological potential, it is clear that the technology to evaluate transcriptional states is currently the most advanced among molecular endpoints when considering the requirement for single cell resolution.  A comprehensive evaluation of the transcriptome would include all classes of transcribed RNA including non-coding species; however, it is recognized that there are may be issues with regard to detection and quantification for rare and/or short transcripts.  Further, this FOA presents a potential opportunity to identify core subsets of transcripts that define a particular cell type or cell state. The concepts and challenges around cell variability will be important for other types of analyses as additional single cell methods are developed in the future (for genomics, proteomics, epigenomics etc).  Each application submitted in response to this FOA must: 1) propose to define and classify cell types and/or cell states using transcriptomic profiles of individual cells from human tissue samples, 2) propose approaches to detect and evaluate biological and technical “noise”, and 3) develop and validate analytical tools to examine and manage transcriptome datasets to assess heterogeneity among individual cells in a population, taking into consideration the dynamic nature of gene expression.

An important research objective is to understand commonalities and differences in the function of cellular heterogeneity across cell and tissue types. Thus, a set of projects will be supported that focus on an appropriate selection of cell/tissue types and that coordinate research priorities, methodologies, data sharing, and analysis to uncover insights that would not be apparent from isolated efforts. The awards will be cooperative agreements to facilitate this coordination. Once funded, the PD(s)/PI(s) and the Steering Group will develop and formalize the coordination plan.

Specific Areas of Research Interest

Applications should propose to evaluate the RNA signatures in single human cells using state-of-the-art approaches (such as RNAseq or similar method) in order to assess heterogeneity within a population of cells. While approaches such as RNAseq are feasible in single cells, a number of obstacles and unknowns exist such as reliable methods for harvesting isolated cells from human tissue, RNA detection resolution, amplification bias etc; investigators are expected to define and explore ways to overcome technical and analytical hurdles. Applicants should propose to analyze multiple cell types harvested from complex (or intact) human tissue specimens or other preparations that preserve the three-dimensional architecture of the tissue.  Applicants are expected to propose cell and tissue types to be analyzed. In addition, there are many challenges in data analysis at the single cell level including separating cell types; accounting for inherent dynamism of the cellular, such as occurs in the cell cycle; and assessing the reproducibility of single cell measurements. The application should describe plans for data analysis that address these challenges.

Applicants may propose to develop advancements in technology as part of the application. Examples may include improved detection of rare RNA species or detection of rare cell types/cell states in a population. Additionally, computational advances such as defining the minimal transcriptional signature that defines a cell type or cell state would be appropriate.

While the focus of this initial effort should be the evaluation of healthy cells/tissues, investigators may propose to examine disease states as a component of the project.

As this is a Common Fund activity, cells from any human tissue or organ system may be examined. Tissue may be derived from post-mortem samples, surgical specimens, biopsied material etc.; processing steps must ensure that the RNA will be of sufficiently high quality to analyze appropriately. The use of human cell lines or cultured cells will be considered unresponsive except in rare cases where it may be deemed appropriate (e.g stem cell studies in support of studies evaluating intact tissue or the use of blood samples).

Scientific Knowledge to be Achieved:

Projects supported through this FOA will help explore ways to understand cellular heterogeneity using single cell transcriptomics and provide novel analytical tools to detect and assess biological and technical noise.  The overall goal is to have novel and reproducible ways to classify human cell types and cell states in order to better understand complex tissue functioning and to facilitate the detection of rare cells and/or functional cell states.

Applicants are strongly encouraged to consult the appropriate program official, listed in Section VII, to discuss the alignment of their proposed work with the Single Cell Analysis Program goals. A Technical Assistance phone conference will be held for potential applicants on December 7, 2011 from 11:30-12:30 EST. NIH staff will be available to answer questions related to this FOA.  Please contact Andrea Beckel-Mitchener (amitchen@mail.nih.gov) for information on how to access to this conference.  For applicants not able to join the live teleconference, the information will be made available in transcript form through the Common Fund Single Cell Program website (http://commonfund.nih.gov/singlecell/) within a few days following the call.

Section II. Award Information
Funding Instrument

Cooperative Agreement

Application Types Allowed

New
The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The NIH Common Fund intends to fund an estimate of 2-4 awards, corresponding to a total of $4,000,000 for fiscal year 2012 contingent upon sufficient number of meritorious applications and availability of funds.

Award Budget

Application budgets are not limited, but need to reflect actual needs of the proposed project.

Award Project Period

The maximum period is 5 years.

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.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

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.

Required Registrations

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

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 PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.

PD(s)/PI(s) should dedicate a minimum of 2.4 calendar months to this project.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

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

Letter of Intent

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:

The letter of intent should be sent to:

Andrea Beckel-Mitchener 
National Institute of Mental Health
Neuroscience Center/Room 7187/MSC 9641
6001 Executive Boulevard
Bethesda, MD 20892-9641
[Rockville, MD 20852 (courier mail only)]
Telephone: 301-443-5288
Email: amitchen@mail.nih.gov

Required and Optional Components

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

Page Limitations

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

PHS 398 Research Plan Component

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

An application is expected to be put forward by scientific collaborators focused on research projects that will accomplish the goals of this initiative.  It is expected that the participating groups will include outstanding scientists and support staff with relevant scientific expertise and access to suitable facilities.  It is anticipated that three main research project components will need to be addressed adequately in each application (generation of single cell transcriptome datasets to evaluate heterogeneity among ostensibly similar cells, investigation of technical and biological noise, development and use of  analytical tools that can be used to evaluate the data).  In the applicable sections, the applicant should adequately address any technology development/improvement as well as the sharing plan.  Ultimately, the NIH Common Fund will support a collaborative effort (see definition below) to generate and validate single cell transcriptome datasets, so it is conceivable that partial funding of applications may result if it is determined that this could significantly strengthen the overall effort.

1. SPECIFIC INSTRUCTIONS FOR PREPARING THE Application

The objectives of the applications submitted should be relevant to and compatible with the goals specified in this FOA.  Applicants should describe their plans to accommodate the stated requirements and criteria with specific information that the reviewers will find to be helpful in assessing applications.  The following guidance summarizes the form and format that the applicant must use to provide that information.  If there is additional information not addressed in this guidance that the applicant wishes to present, s/he is encouraged to provide it in a concise form within the stated page limits, in addition to the information requested here.

Applications should conform with current guidelines taking care to address important elements related to Significance, Approach, Innovation, and Investigator involvement and Environment.   In addition, applicants for awards under this FOA in the appropriate section should:

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 modifications:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. An important and core goal of the SCAP-T program is to produce a community resource which substantially advances research in single cell analysis by providing new standards and tools. Detailed plans on how data will be made broadly available should be included as a portion of the plans for Data Analysis.

Plan for Sharing Research Data, Experimental Protocols, and Software:

The NIH is committed to the principle of rapid data, experimental protocol, model, and software release to the scientific community.  SCAP awardees are expected to release to the research community raw data, experimental protocols, models, and software in a timely fashion through an informatics platform and other standard mechanisms, consistent with the goals of this program.  The development of policies, methods, and standards for such sharing are critically important for SCAP.  The NIH expects that the SCAP awardees will develop such policies, methods, and standards in concert with the NIH and the SCAP Steering Group and Project Team.  These policies, methods, and standards will remain consistent with NIH-wide policies on data and resource sharing.

In their grant applications, all applicants should provide specific plans for data, experimental protocol, model sharing if applicable, and software release, consistent with achieving the goals of this program. Key Elements that should be considered when developing such data sharing plan are detailed at: http://grants.nih.gov/grants/sharing_key_elements_data_sharing_plan.pdf.

The reasonableness of the applicant’s data and model sharing and software release plans will be assessed by the reviewers, but will not be factored in to the overall score.

After completion of the initial review, NIH SCAP Working Group will be responsible for any additional administrative review of the data and model sharing and software release plans.  The adequacy of these plans will be considered by program staff of the funding organization when making recommendations about funding applications.  The accepted data, and model sharing and software release plans will become a condition of the award of the cooperative agreement.  The applicant’s progress in implementing the data and model sharing and software release plan will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

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 software dissemination 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.

The NIH expects that raw data will be submitted at least every six months to long-term publicly accessible archives such as GEO or dbGaP as appropriate. Some data sets generated as a result of this research may become a part of an individual patient’s medical record.  However, sequence and phenotype data resulting from this research may have value beyond that intended by the submitting investigators.  Therefore, submission of data sets to the database of Genotype and Phenotype (dbGaP) is encouraged, but required prior to publication; datasets are expected to be released at the time of publication, within the rules and regulations of the controlling IRB and local jurisdiction and with informed consent to permit broad data release via an NIH database.  Applications to this FOA are expecteded to include a discussion of whether or not release to dbGaP will be authorized in the informed consent for the study.  Any restrictions on data use (such as limitations to a specific disease or condition) should be described if applicable. Although this information must be included in the application, the plans for data sharing will not be a scored review criterion.

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,

Foreign Institutions

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

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via 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.

Applicants are responsible for viewing their application 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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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.   

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide.  Paper applications will not be accepted.

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD(s)/PI(s) 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 Central Contractor Registration (CCR). 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.  Following review, Program staff will consider the proposed tissue types and will make funding recommendations, in part, to promote portfolio balance ensuring that a diverse representation of tissues will be analyzed. The NIH is looking to fund complementary projects examining multiple cell types/states across the funded groups.

Applications Involving the NIH Intramural Research Program

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 PD(s)/PI(s) 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.  

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115,:

Section V. Application Review Information

1. Criteria

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.

Overall Impact

Reviewers will provide an overall impact/priority 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).

Scored Review Criteria

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? Are the proposed tissue and cell types important?   

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(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Do the proposed methodological improvements advance current practices in cell acquisition, throughput, assay sensitivity, and/or analytical tools? 

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 clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? Are the proposed approaches state-of-the art?  Are the plans to harvest cells and acquire RNA from intact human tissue adequate in terms of representing the predicted heterogeneity within the selected tissue, the number of cells to be analyzed, and the predicted quality of the tissue and RNA? Are the specific approaches to detect and evaluate "noise" adequate? Will the evaluation of "noise" be informative and useful? Is the plan to share materials and cross-validate results with other funded investigators adequate?

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?  Is the proposed plan to collaborate with other funded groups adequate?

Additional Review Criteria

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/priority 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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

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

Additional Review Considerations

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/priority score.   

Applications from Foreign Organizations

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

Select Agent Research

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

Resource Sharing Plans

The reasonableness of the applicant’s data and resource sharing and software release plans will be assessed by the reviewers.

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.

2. Review and Selection Process

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


As part of the scientific peer review, all applications:

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:

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD(s)/PI(s) 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.

Section VI. Award Administration Information

1. Award Notices

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

2. Administrative and National Policy Requirements

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 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 responsibility for:

 A PD(s) or PI(s) is a senior scientist with proven independent research capabilities who serves as director of one of the scientific research projects or project components for the group and is responsible for the scientific conduct of that program. Foreign scientists and NIH intramural scientists may be a PD(s) or PI(s). The PD(s)/PI(s) will have the primary authority and responsibility for defining the details for the production effort within the guidelines of the approved cooperative agreement and for performing the scientific activities.  The PD(s)/PI(s) will assume responsibility and accountability to the applicant organization and to the NIH for performance and proper conduct of all supported research in accordance with the Terms and Conditions of Award. The PD(s)/PI(s) will agree to accept close coordination, cooperation, and participation of NIH staff and external advisors in those aspects of scientific and technical management of the project as described under "NIH Responsibilities."

The PD(s)/PI(s) of project will:

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

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

PROJECT SCIENTIST(S). During performance of the award, two scientists from the extramural program staff representing the NIH Common Fund will serve as the SCAP-T Project Scientist(s), with substantial involvement above and beyond the normal program stewardship role of a Program Official, as described below.

The Primary Project Scientist interacts scientifically with the PD(s)/PI(s) of the cooperative agreement and other named key personnel and, using recommendations from the SCAP Working Group, facilitates the role of the NIH Common Fund as a partner in the research.    A second NIH scientist will be appointed as an Alternate Project Scientist who can attend meetings when the Primary Project Scientist is unavailable to ensure adequate NIH representation.  The Project Scientist(s) will be appointed after award in consultation with the SCAP Working Group (a group composed of extramural Program staff representing participating NIH Institutes and Centers and will have one vote on the Steering Group even when more than one Project Scientist (Primary and Alternate) is designated and present.

It is anticipated that decisions in all activities of the SCAP-T will be reached by consensus of the Steering Group and that NIH staff (through the participation of the NIH SCAP Working Group and the appointed Project Scientist(s) will be given the opportunity to offer input to this process.  The Project Scientist interacts scientifically with the group and may provide appropriate assistance, including assisting in research planning, recommending tissue/cell types within the scope of the SCAP-T objectives and research activities, presenting experimental findings to the group from published sources or from relevant contract projects, participating in the design of experiments agreed to by the group, participating in the analysis of results, and advising in management and technical performance and helping to ensure that duplication is avoided. The Project Scientist(s) will be a voting member(s) of the Steering Group, and offering a single vote. The NIH Program Official may attend Steering Group meetings as a non-voting participant. In all cases, the role of NIH will be to assist and facilitate and not to direct activities.

The Project Scientist(s) will:

An NIH SCAP WORKING GROUP, whose primary role is to ensure that the single cell transcriptome datasets generated represent the diverse interests of the Common Fund and NIH Institutes and Centers, will advise on tissue/cell types/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 SCAP Working Group will be composed of Program Officials and other relevant extramural staff from NIH Institutes and Centers and the Project Scientist(s).  The appointed Project Scientist(s) will communicate their opinions and recommendations to the Steering Group.

NIH intramural scientists involved in the SCAP-T will have the same rights and responsibilities as the comparable extramural scientists involved in the SCAP-T. 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).  for application that include NIH intramural components, the intramural resource level will be included in the total cost of the overall application.  The involvement of Intramural scientists needs to be consistent with NIH Policy.  http://sourcebook.od.nih.gov/ethic-conduct/ethical-conduct-toc.htm

Additionally, an NIH Program Official will be responsible for the normal scientific and programmatic stewardship and guidance for the overall project within the NIMH and will ensure that the generation of single cell transcriptome datasets are relevant to the diverse research community served by the Common Fund and NIH Institutes and Centers.  The Program Official will be responsible for ensuring that the milestones are achieved and goals are being met.  In addition, the NIH Program Official is responsible for monitoring and implementing the Data Sharing Plan (http://grants.nih.gov/grants/policy/data_sharing/index.htm).  The NIH Program Official may attend Steering Group meetings as a non-voting participant. The NIH Program Official will be named in the award notice.

Additionally, an NIH Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

Single Cell Analysis Program-Transcriptome (SCAP-T) Steering Group. A governing Steering Group, composed of the PD(s)/PI(s), Project Scientist(s) and external scientific advisors (experts to be named after award) will be established to help monitor progress, encourage improvements, and coordinate the development of the single cell transcriptome datasets through the SCAP-T. The SCAP-T Steering Group members will meet periodically to plan and design activities, review and discuss progress, and establish priorities and policies. A chair will be designated from the external scientific advisors 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, not fewer than one per year, will be determined by the Project Scientist who will be responsible for scheduling the time and place and for preparing concise proceedings or minutes (two or three pages) which will be delivered to the Steering Group members within 30 days of the meeting. 

The SCAP-T Steering Group will:

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 Group 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.

3. Reporting

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

Section VII. Agency Contacts

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

Application Submission Contacts

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Scientific/Research Contact(s)

Andrea C. Beckel-Mitchener Ph.D.
Division of Neuroscience and Basic Behavioral Science
Molecular, Cellular, and Genomic Neuroscience Research Branch
National Institute of Mental Health
Neuroscience Center/Room 7187/MSC 9641
6001 Executive Boulevard
Bethesda, MD 20892-9641
[Rockville, MD 20852 (courier mail)]
Phone:  301-443-5288
Email: amitchen@mail.nih.gov

Peer Review Contact(s)

David Balasundaram, Ph.D.
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 5136, MSC 7840
Bethesda, MD 20892-7840
Telephone: (301) 435-1022
Fax: (301) 480-1988
Email: balasundaramd@csr.nih.gov.

Financial/Grants Management Contact(s)

Victoria Carper
National Institute of Mental Health (NIMH)
Telephone: 301-443-3858
Email: carpervictoria@mail.nih.gov

Section VIII. Other Information

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.

Authority and Regulations

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.


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