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

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

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

Purpose

The NIH Blueprint for Neuroscience Research is a framework to enhance cooperative activities among NIH Institutes, Centers, and Offices that jointly support neuroscience-related research, with the aim of accelerating discoveries and reducing the burden of nervous system disorders. This Funding Opportunity Announcement (FOA) seeks to develop new technologies and create validated protocols for the isolation and characterization of extracellular vesicles (EVs) of Central Nervous System (CNS) origin. The primary goal for this initiative is to develop methods and novel approaches for the improved cell-type specific isolation of CNS specific EVs from various human biosamples. The secondary goal is the development of technologies for the characterization of the composition of CNS specific EVs, including the full range of EV cargo molecules such as RNA, proteins, lipids, and metabolites. Successful CNS-EV isolation and characterization has translational potential for use in the prognosis, diagnosis, and intervention in CNS disorders in a clinical setting.

Background

EVs encompass a diverse array of cell-derived, nano-scale (100-1000 nm), membrane bound vesicles that are present ubiquitously in many biological fluids, including blood, saliva, urine, semen, breast milk, cerebral spinal fluid, amniotic fluid, ascites, and pleural effusions. Although they were previously considered to be merely a cellular waste release mechanism, there is now evidence that EVs are important mediators of extracellular signaling. Through their capacity to transfer proteins, lipids, and nucleic acids, EVs can influence the physiological and pathological functions of recipient cells. In particular, their ability to transfer RNA represents a new paradigm of intercellular signaling.

In vitro and in situ studies have demonstrated that EVs are produced by all major CNS cell types and appear to play a role in normal physiological functions (e.g., neuromodulation, synaptic plasticity, neuron-glia-interaction, neuroprotection, and neuroregeneration), as well as in pathological processes. In neurodegenerative disorders and brain cancer, EVs have been demonstrated to directly influence the disease state by spreading misfolded or cancer proteins to healthy cells. The role of EVs in other mental health disorders has been gaining prominence.

CNS-EVs are known to cross the blood-brain barrier and can be found in peripheral circulation and other easily accessible biofluids (e.g. saliva and urine). CNS-EVs in such biofluids present an opportunity to access information about the health and function of the brain in living individuals in a non-invasive manner. The key barrier to utilizing peripherally accessible CNS-EVs is the limited availability of technologies and protocols that allow for specific detection, isolation, and characterization of CNS-EVs by cellular origin from appropriate biosamples. For example, the current methods used for isolating CNS-EVs rely on relatively non-specific enrichment strategies for EVs of neuronal origin, such as immunoabsorption (i.e., L1CAM antibody), and characterization of EV-derived cargos is highly diverse and lacks standardized experimental and analytical approaches. It is therefore necessary to enhance current strategies and develop new methodologies to specifically identify the EVs derived from different CNS cell types in plasma, saliva, and other biofluids. Development of reliable technologies and reproducible methods would potentially lead to new strategies in prognosis, diagnosis, and intervention in CNS disorders.

Program Scope:

The primary goal of this initiative is to significantly advance the current technologies, develop novel techniques and approaches, and standardize protocols to reliably and specifically isolate EVs of CNS origin from human biofluids, identify the cell type from which they were derived, and characterize their composition. Improved sensitivity and quantitative methods are essential to characterize cargo contents present in the EVs of interest for use as markers. Markers should inform the extent of co-isolation of EVs of different CNS cellular origins (e.g., different glial and neuronal cell types) and be comparable to those described for EVs derived from other tissue sources (e.g., those listed in databases, such as EVpedia and Vesiclepedia). Contaminant-free EV separation is an important technical concern (e.g., removal of free RNA, apoptotic bodies, non-vesicular contaminants, etc.). It will also be important to identify the best combinations of technologies and biofluid sources (e.g., blood, saliva, urine, semen, breast milk, cerebral spinal fluid, amniotic fluid, ascites, and pleural effusions) to maximize the yields of biologically meaningful CNS-derived vesicles from different cell types.

Program Objectives

Using the R21/R33 phased research award mechanism, we seek the development (R21) and validation (R33) of innovative technologies and approaches for enrichment, isolation, and characterization of EVs derived from different CNS cell types from human biofluids. The methodologies or tools developed should significantly advance the current state of the art. This should include reducing cost, increasing specificity, increasing throughput, and/or enhancing the depth of characterization of CNS-derived EV populations.

Strategies to accomplish this goal include, but are not limited to:

• Development of high-throughput isolation, specific detection, and quantification approaches and technologies.
• Development of novel or improved methods for enrichment and/or purification of CNS-EVs.
• Identification of specific markers to distinguish different CNS-EVS based on the cell type from which they were derived in clinical biofluids, such as serum and plasma. For example, all CNS-EVs may contain common and unique surface or cargo markers where relative proportions of different elements, such as RNAs or proteins, may vary in EVs derived from different cell types.
• Development of protocols optimized for CNS-EV isolation from different biosample sources (plasma or other body fluid).
• Development of methods, techniques, and/or in silico approaches to characterize the composition of CNS-EVs. These techniques may include deep characterization of EV cargo, such as RNA, protein, lipid, and/or metabolites.
• These approaches to CNS-EV characterization and cargo analyses may extend to the study of CNS disorders.

This FOA uses the R21/R33 with two phases, both of which are required for a complete application:

• The R21 phase is for milestone-driven, exploratory/feasibility studies that will support the initial development of technologies and generation of pilot data as proof-of-concept testing of new technologies, protocols, or techniques. Whereas,
• The R33 will support validation of technologies and methods that are developed in the R21 including, but not limited to: 1) iterative improvement and refinement of technologies for sensitivity and scalability, 2) establishment of reproducibility and detection limits of the methods and technologies for different biofluids, 3) confirmation of cell of origin for CNS-EVs.

Both phases should focus on peripheral human biofluids, although it is expected that the feasibility (R21) and/or validation (R33) phases may necessitate the use of cell lines, organoids, or animal models. Applications are strongly encouraged to leverage existing biosamples wherever possible (e.g., BioSEND and NIMH Repository and Genomics Resource).

It is expected that some of the R21 awardees will not proceed to the R33 phase. Program staff will conduct an administrative review of grants nearing completion of the R21 phase for readiness to transition to the R33 phase. Transition from the R21 to the R33 phase is contingent upon program priorities, the availability of funds, and the successful completion of proposed milestones. Milestones are quantifiable goals for measuring success that can be used for go/no-go decision making, and should have timelines and quantitative criteria associated with them, such as sensitivity, throughput or cost savings (e.g., 50% faster) to demonstrate that the technological development represents a major leap beyond the current state of the art, resulting in new never before possible capabilities or order of magnitude enhancements. The clarity and completeness of the R21/R33 application regarding specific goals and feasibility milestones in each phase is critical.

Applicants should pay close attention to the application instructions and review criteria for special requirements concerning the approach, project innovation, and the inclusion of quantitative milestones.

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 from this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

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

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

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

Applicant Organizations

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The letter of intent should be sent to:

Email:nimhpeerreview@mail.nih.gov

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.

Facilities and Resources:

Applications must describe the facilities and resources available. Applicants should provide evidence for the availability of needed resources and especially focus on the unique resources at their institution and any sub-contracts which lend themselves to the completion of the project.

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

Provide evidence that the applicants have the capability to conduct the research by documenting the training and experience of the investigator(s) and/or the conduct of related studies.

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: Include headers titled "R21 Phase Specific Aims" and "R33 Phase Specific Aims". Clearly state the Specific Aims for each phase, indicating under which phase each aim belongs. The R21 phase could include descriptive, novel and untested approaches.

Research Strategy: All applications should include the following:

Applicants should submit a Research Strategy attachment organized into two phases, beginning with discussion of the R21 phase followed by discussion of the R33 phase in one application. In this attachment, applicants should include a final section describing the milestones, timeline, and the R21/R33 transition point. It is not necessary to repeat information or details that are described in the R21 section in the R33 section.

Innovation: Include headers titled "R21 Phase Innovation" and "R33 Phase Innovation", and address the Innovation for the R21 and R33 phases in the appropriate sub-section.

• R21 Phase Innovation
• Specifically define the current state of technology as a benchmark against which their proposed technology will be measured.
• Describe how the project addresses improvements to current isolation methods and techniques for isolating high-purity populations of CNS-EVs and their cargo molecules.
• Project should describe the detection, isolation, and/or characterization of CNS-EVs with cell-type of origin specificity
• Describe how and to what extent the resulting tools, protocols, and technologies:
• Enable studies that were previously impossible or
• Result in a significant improvement and high-impact advances that represent a significant technological or methodological leap as compared to the current state of the art in terms of reducing cost, increasing specificity, decreasing sample size, increasing throughput, and enhancing the depth of characterization.
• Provide evidence to demonstrate that the approaches proposed are significantly more innovative than would normally be expected
• R33 Phase Innovation
• Address how this phase will build upon the results of the R21 phase to achieve further innovation

Approach: Include headers titled "R21 Phase Approach" and "R33 Phase Approach", and address the Approach for the R21 and R33 phases in the appropriate sub-section.

• R21 Phase Approach
• Describe what population of EVs (based on size and origin) will be purified and why. Include justification of the diversity of this choice. Include justification of the choice of biofluid (i.e., plasma, CSF, etc). Describe any plans to leverage existing human biosamples for this purpose.
• Provide an appropriate theoretical justification and a sound hypothesis for the proposed approach. Since exploratory applications are expected to be descriptive and hypothesis-generating in nature, pilot data that provide support for the proposed hypotheses and aims (i.e., Proof of Concept) are not required. If no pilot data is provided, the theoretical justification should be sufficient to engender confidence that the initial R21 project is well thought out and feasible.
• Describe plans for proof-of-concept testing of the new technology, protocol, or technique on human derived bio-samples.
• R33 Phase Approach
• Describe the validation process to determine that the protocol or technology has been properly developed, optimized, and standardized for its intended purpose. Assay validation should be clearly outlined to cover critical topics, including, but not limited to: i) definition of the intended purpose(s), ii) optimization (including iterative improvement), iii) standardization, iv) reproducibility/repeatability, v) sensitivity, vi) specificity, vii) thresholds (cut-offs), viii) scalability, and ix) confirmation of identification of the specific CNS cell-type from which the EVs were derived.

Milestones and Timeline: The Research Strategy should include a distinct final section, entitled Milestones and Timeline , that briefly proposes indicators of progress at critical junctures.

Describe a clearly delineated timeline with milestones for each phase of the project, as well as for the transition from the R21 to the R33 Phase. These milestones will be evaluated as part of the scientific and technical merit of the R21/R33 application and will be considered in programmatic review for transition from R21/R33 phase.

Propose milestones tailored to the unique scope of the project that are well-described, quantifiable, scientifically justified, and written concretely enough to evaluate what will have been achieved to allow program staff to assess progress.

• R21 Milestones and Timeline

Given that projects are likely to be early stage and high-risk in nature, include specific proof-of-concept test(s) that will indicate whether/how a proposed technology or method actually works , along with alternative strategies should the proposed effort fail to perform as expected. Tests should include a comparison against existing benchmark technologies; if the protocol is truly first-in-class, comparisons may be done against the nearest neighbor technology.

• R21/33 Transition Milestones and Timeline

Include at least three well-described, measurable scientific or technical final milestones for the R21 phase which demonstrate the feasibility for the R33 phase.

Include a discussion of the milestones relative to the progress of the R21 phase and the implications of successful completion of the milestones for the R33 phase.

• R33 Milestones and Timeline

Address the timeline and milestones for the validation process described in the approach section and indicate when it is anticipated that essential components of the project will be completed.

Include alternative strategies based on possible outcomes of R21/R33 transition milestones.

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

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Data generated through this initiative are expected to be shared with public EV databases (e.g, exocarta, exRNA, and dbGaP), consistent with achieving the goals of the program.
• Resources used and created through this initiative should be made available through the Neuroscience Information Framework (NIF; http://www.neuinfo.org/).

Appendix:

Only limited Appendix materials are allowed. 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.

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.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the 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.

The R21/R33 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. An R21/R33 grant application need not have preliminary data, extensive background material or preliminary information; however, they may be included if available. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data.  Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding.  Reviewers will assign a single impact score for the entire application, which includes both the R21 and R33 phases.

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

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

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

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?

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 focus on high-impact advances that represent a significant technological or methodological leap as compared to the current state of the art? Does the technology or protocol described enable studies that were previously impossible or result in a significant improvement to the current state of the art in terms of reducing cost, increasing specificity, decreasing sample size, increasing throughput, etc.? What is the evidence to demonstrate that the approaches proposed are significantly more innovative than would normally be expected? How will innovation be continued in the R33 phase (i.e. further refinement and improvements)?

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?

Is the choice of EV population and biofluid appropriate and well justified? Are an appropriate theoretical justification and a sound hypothesis provided for the R21 phase approach? Are adequate plans described for proof-of-concept testing in the R21 phase? How will the proposed validation phase lead to a properly developed, optimized and standardized technology or protocol? Are adequate and appropriate milestones and timelines provided for each phase of the project, including at least three for the transition point? Are the milestones sufficiently quantitative to provide go/no go assessments during each phase and at the transition? Are appropriate alternative strategies provided should a milestone not be reached? How well does the application address the detection, isolation, and/or characterization of CNS-EVs with cell-type of origin specificity?

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

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

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

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

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

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

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following 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.

Not Applicable

Not Applicable

Not Applicable

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

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

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

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

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 Center for Scientific Review, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate National Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. 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.

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.

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.

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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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

A final RPPR, 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)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Geetha Senthil, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-402-0754 
Email: senthilgs@mail.nih.gov

Douglas Meinecke, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-6767
Email: dmeineck@mail.nih.gov

Carole Jelsema, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-435-1248
Email: jelsemac@csr.nih.gov

Terri Jarosik
National Institute of Mental Health
Telephone: 301-443-3858
Email: tjarosik@mail.nih.gov

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

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