Research Grants for Ocular Surface Innervation, Sensation, Pain Circuits and Tearing Reflexes (RFA-EY-21-004)

Research Grants for Ocular Surface Innervation, Sensation, Pain Circuits and Tearing Reflexes (RFA-EY-21-004) is sponsored by National Eye Institute (NEI) of the National Institutes of Health (NIH). This Funding Opportunity Announcement (FOA) aims to identify and support collaborative projects that will comprehensively delineate ocular surface innervation from corneal sensation to pain circuits and tearing reflexes.

Expired RFA-EY-21-004: Ocular Surface Innervation from Cell Types to Circuit Functions (U01 Clinical Trial Not Allowed) This notice has expired. Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Eye Institute ( NEI ) Funding Opportunity Title Ocular Surface Innervation from Cell Types to Circuit Functions (U01 Clinical Trial Not Allowed) U01 Research Project – Cooperative Agreements Funding Opportunity Announcement (FOA) Number Companion Funding Opportunity See Section III. 3.

Additional Information on Eligibility . Assistance Listing Number(s) Funding Opportunity Purpose This Funding Opportunity Announcement (FOA) aims to identify and support collaborative projects that will comprehensively delineate ocular surface innervation – from corneal sensation to pain circuits and tearing reflexes.

The Request for Applications (RFA) aims to explore this system at three levels of analysis: morphologic, molecular, and functional. Successful projects will incorporate and integrate at least two of these levels of analysis, and ideally all three. Collaborative multi-disciplinary teams are expected with investigators having complementary areas of expertise.

The premise of this FOA is that such basic biology will facilitate a deeper understanding of related pathobiology including neuropathic ocular pain and dry eye disease that will lay a foundation for future translational and clinical research on the anterior segment of the eye.

Open Date (Earliest Submission Date) Letter of Intent Due Date(s) Renewal / Resubmission / Revision (as allowed) All applications are due by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Required Application Instructions It is critical that applicants follow the instructions in 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 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 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 Introduction and Background: The NEI has launched the Anterior Segment Initiative (ASI) in order to capitalize on research opportunities at the front of the eye. The anterior segment includes the cornea, iris, ciliary body, and ocular lens. Disruptions in the health of the anterior segment manifest in a variety of ways including dry eye disease, ocular pain, Sjogren’s syndrome, migraine, and uveitis.

The NEI has supported both basic and clinical research in these areas and significant progress has been made. Scientific advances in areas such as ocular imaging present exciting research opportunities.

There are significant knowledge gaps in understanding the role the nervous system in maintaining the health of the anterior segment and how disruption of normal nervous system functioning contributes to disorders and disease such as ocular surface pain, itch, inflammation, dry eye and other neurological symptoms such as migraine and photophobia.

Unpleasant ocular sensations substantially decrease a patient’s quality of life by interfering with activities of daily living. Options for effective treatment and long-term relief of these conditions are currently limited. Dissecting ocular sensation and tearing circuits is integral to understanding the processes that contribute to and result from certain types of disease, infection, and trauma.

These processes may be at the level of the peripheral nervous system (PNS) or the central nervous system (CNS). PNS sensitization and plasticity may involve the corneal afferent nerve terminals and surrounding tissues. CNS sensitization that leads to chronic conditions may involve the trigeminal nuclei and thalamus and/or higher brain centers.

In addition to the ascending pathways, descending pathways are also important to anterior segment homeostasis and disease mechanisms. The purpose of this FOA is to gain a comprehensive understanding of the neuronal cell types, cell-to-cell interactions and peripheral and central neural circuitry involved with normal anterior segment homeostasis as well as the changes in these pathways that contribute to disease and abnormal sensations.

The objective of this RFA is to develop a comprehensive understanding of the afferent and efferent neuronal pathways in the anterior segment of the eye that subserve ocular pain and tearing at the anatomical, cellular and functional levels.

This research will also provide a foundation for understanding the role of ocular surface sensation in the development of other disorders such as itch, migraine and photophobia, with the long-term goal of advancing translational and clinical research on the anterior segment of the eye to improve ocular health.

It is expected that applicants will assemble multidisciplinary Research Teams to address important questions related to anterior segment innervation. Research Teams funded under this initiative are expected join in a consortium to share ideas, technology, and data at the earliest stages of their individual projects. Each Research Team is expected to meaningfully address at least two of the following levels of research and analysis: 1.

Anatomy/morphology - the research objectives may include but are not limited to: Anatomical characterization including cell spatial location and morphology (e.g., cell size, shape, dendritic arborization) Mapping long- and short-distance neuronal connectivity Identifying input and output neurons and their projections (e.g., using retrograde and anterograde viral tracings), as well as the local circuit neurons and their connections Determining the location and prevalence of non-neuronal cell types Examining innervation patterns in normal corneas versus acute and chronic pain and/or dry eye disease 2.

Cellular/molecular properties - the research objectives may include but are not limited to: Characterizing cell classes and types based on single-cell transcriptome signatures Identifying cell types using immunohistochemistry and immunocytochemistry approaches Using single cell epigenome approaches (e.g., chromatin accessibility, DNA methylation) to define cell types Molecular characterization of primary afferents including mechanoreceptors, chemoreceptors, thermoreceptors and nociceptors Identifying neurotransmitters at synaptic junctions Discovering the molecular composition of non-neuronal cell types 3.

Functional properties - the research objectives may include but are not limited to: Determining the polymodal stimulus/response properties of identified neurons Identifying patterns of activity and interactions across functionally connected neurons Characterizing functional connectivity motifs across local circuits and long ranging networks Identifying factors that regulate and/or disrupt normal circuit activity Examining the functional impact of perturbing normal circuit activity Characterizing the bidirectional communication between sensory afferents and non-neuronal cells and tissues Building upon and incorporating previously established knowledge and atlases are highly desirable.

Artificial Intelligence/ Machine Learning/ Deep Learning approaches for informatics, data mining, and integrating knowledge (established and newly acquired) across the three levels of analysis are encouraged.

Activities not responsive to this FOA:&#1#160; The following application types will be considered nonresponsive to this FOA and will not be reviewed: Applications that do not address at least two research levels of analysis: anatomical, molecular, and functional Applications that do not include multidisciplinary research teams and approaches Applications narrowly focused on a single disease condition that are not aimed at a comprehensive understanding of the related circuitry Applications attempting to recreate, rather than leverage, existing database/atlas resources Studies of only cultured cells Applications that do not include milestones and objective measures of their attainment Applicants are strongly encouraged to consult the Scientific/Research Contact listed below to discuss the alignment of their proposed work with the FOA goals.

This FOA is dependent on the establishment of Research Teams that are multidisciplinary with the complementary expertise required for anatomical, molecular and functional analysis. Applicants are strongly encouraged to reach out to experts outside the vision research community, where appropriate, to bring in relevant state-of-the-art approaches established outside the eye.

Investigative teams are allowed but not required to have a demonstrated working relationship. Collaborative Activities: Research Teams are required to participate in a consortium composed of the projects funded under this FOA. Requirements include regular meetings, the sharing of data, resources, technology, new tools, and model systems.

Investigators funded through this FOA are expected to participate in an annual investigators' meeting intended to facilitate collaboration across the Research Teams and promote data sharing and coordination. The budget should include travel expenses for PI/PDs to attend these annual meetings. Virtual meetings to assess progress and assist with problem solving will be held 2-3 times each year as is appropriate.

External Scientific Oversight Committee: An External Scientific Oversight Committee (ESOC) will be assembled by NEI staff in order to provide recommendations about the progress and scientific direction of all components of this Consortium. The ESOC will be composed of senior scientists who represent the broad research community and have relevant expertise.

ESOC membership may be adjusted as warranted by scientific developments and program needs. The ESOC is expected to meet twice a year either in-person or by teleconference. Applications to this FOA should not include suggestions for ESOC members.

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

Award Information Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.

2 for additional information about the substantial involvement for this FOA. Application Types Allowed The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

Not Allowed: Only accepting applications that do not propose clinical trials. Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards NEI intends to commit up to $5 million in FY2022 to fund up to 5 awards.

Application budgets are not limited but need to reflect the actual needs of the proposed project. The maximum project period is 5 years NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA. Section III.

Eligibility Information 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 (Other than Small Businesses) 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 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 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 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.

System for Award Management (SAM) – 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. Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM. gov registration process.

SAM registrations prior to fall 2021 were updated to include a UEI. For applications due on or after January 25, 2022, the UEI must be provided on the application forms (e.g., FORMS-G); the same UEI must be used for all registrations, as well as on the grant application. Dun and Bradstreet Universal Numbering System (DUNS) – Organization registrations prior to April 2022 require applicants to obtain a DUNS prior to registering in SAM.

By April 2022, the federal government will stop using the DUNS number as an entity identifier and will transition to the Unique Entity Identifier (UEI) issued by SAM. Prior to April 2022, 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.

eRA Commons - Once the unique organization identifier (DUNS prior to April 2022; UEI after April 2022) is established, organizations can register with eRA Commons in tandem with completing their full SAM and Grants. gov registrations; all registrations must be in place by time of submission.

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 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.

Eligible Individuals (Program Director/Principal Investigator) 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. 3. Additional Information on Eligibility 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, per 2. 3. 7.

4 Submission of Resubmission Application . 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 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). Section IV. Application and Submission Information 1.

Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.

gov Workspace 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. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) 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. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. By the date listed in Part 1.

Overview Information , prospective applicants are asked to submit a letter of intent that includes the following information: Descriptive title of proposed activity Name(s), address(es), and telephone number(s) of the PD(s)/PI(s) Names of other key personnel Participating institution(s) Number and title of this funding opportunity The letter of intent should be sent to: Email: [email protected] All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

For this specific FOA, the Research Strategy section is limited to 30 pages. Instructions for Application Submission 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.

SF424(R&R) Project/Performance Site Locations All instructions in the SF424 (R&R) Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the SF424 (R&R) Application Guide must be followed. SF424(R&R) Senior/Key Person Profile 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. PHS 398 Cover Page Supplement 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: Describe overall research aims and strategy of the multidisciplinary research project.

The aims of the proposed project must explicitly state which levels of analysis (anatomical, cellular/molecular, and/or functional measures) will be addressed and indicate how the project will contribute to the overarching goal of a comprehensive understanding of the ocular sensation/pain and/or tearing circuits. The application must include studies that integrate at least two levels of analysis.

A comprehensive understanding of anterior segment circuitry may include the following elements: 1) a cell census that characterizes anatomical and/or molecular signatures of cell types and neurotransmitter systems that compose the afferent, efferent and central processing circuitry, 2) connectomics that fully describe the connection among neurons and non-neuronal cell types that comprise anterior segment circuits, and 3) functional properties including neural and synaptic activity and how they are modified in disease states.

The following points should be addressed in the research strategy section: Motivation for studies in terms of prior research findings, needs, gaps, and opportunities Approaches to enhance scientific rigor and reproducibility Animal models and portions of circuitry to be analyzed Detailed methodology including experimental designs, data to be collected and statistics Preliminary data to support feasibility Innovative aspects of the methodology and/or scientific approach Identification of potential pitfalls and alternative strategies Database infrastructure including management and standards for complex multimodality data Timelines and milestones with specific criteria for judging their achievement The organizational structure of the Research Team including leadership, oversight, individual responsibilities, and dispute resolution Procedures to ensure efficient cooperation, communication and coordination among the members of Research Team 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.

The following modifications also apply: The following modifications also apply: All applications, regardless of the amount of direct costs requested for any one year, must address a Data and Resource Sharing Plan. Further instructions on exactly how to write this https://grants. nih.

gov/grants/guide/notice-files/NOT-OD-21-014.

html Data Sharing: Applications must include a detailed plan for sharing data and include the following key elements: A description of specific data to be generated and shared (e.g., single cell transcriptome data, immunohistochemistry data, cell morphology data, neuronal connectivity data, electrophysiological data, functional connectivity data), Project management of data sharing Schedule/timeline for availability of data to members of the consortium and the general public A plan to address issues related to the public release of data and data analyses (see the rationale for FAIR (Findability, Accessibility, Interoperability, and Reusability) Data Principles.

Access and timelinesfor sharing withmembers of the consortium and the broader community NEI staff will be responsible for review of the plan for sharing data and may negotiate modifications of the data sharing plan with the prospective awardee prior to award. The final negotiated version of the data sharing plan will become a term and condition of the award of the cooperative agreement.

After all the awards have been made, a final, common data release plan as appropriate for the consortium will be developed. Resource Sharing: Resources generated by the projects funded under this FOA are expected to be made rapidly available to the research community in order to accelerate scientific exploration and avoid duplicative resource development effort.

The applicant should provide specific plans for resource sharing and distribution in the application. These resources include but are not limited to software, model organisms, reagents, devices, tools, etc. Resource sharing plans will be reviewed and negotiated by NEI staff and will become a term and condition of the award of the cooperative agreement. Only limited Appendix materials are allowed.

Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions: If you answered “Yes” to the question “Are Human Subjects Involved?

” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record. Study Record: PHS Human Subjects and Clinical Trials Information All instructions in the SF424 (R&R) Application Guide must be followed.

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed. PHS Assignment Request Form All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement , and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide. 3. Unique Entity Identifier and System for Award Management (SAM) 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 4.

Submission Dates and Times 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.

5. Intergovernmental Review (E. O.

12372) 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 .

7. Other Submission Requirements and Information 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 How to Apply – Application Guide . If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII .

All PD(s)/PI(s) must include their eRA Commons ID in the Credential fieldof the Senior/Key Person Profile form . 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 unique entity identifier (DUNS number or UEI as required) provided on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide. See more tips for avoiding common errors.

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

In order to expedite review, applicants are requested to notify the NEI Program Officer by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application. Post Submission Materials 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. Section V. Application Review Information Only the review criteria described below will be considered in the review process.

Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

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

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

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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? Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed 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? 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)