This Notice of Funding Opportunity (NOFO) is for support of National Centers for Cryoelectron Tomography (CryoET) to provide nationwide access to advanced cryoET instrumentation and technical support, and to assist investigators in acquiring the skills needed to perform cryoET studies.

PAR-26-138: National Centers for Cryo-electron Tomography (cryoET) (R24 -Clinical Trial Not Allowed)

Part 1. Overview Information

Participating Organization(s) National Institutes of Health (NIH)

Components of Participating Organizations National Institute of General Medical Sciences (NIGMS)

Funding Opportunity Title National Centers for Cryo-electron Tomography (cryoET) (R24 -Clinical Trial Not Allowed)

Activity Code R24 Resource-Related Research Projects

Announcement Type New

Related Notices Check for any recent Notices of NIH Policy Changes that may impact application requirements.

Funding Opportunity Number (FON) PAR-26-138

Companion Funding Opportunity None

Number of Applications See Part 2, Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s) 93.859

Funding Opportunity Purpose This Notice of Funding Opportunity (NOFO) is for support of National Centers for Cryoelectron Tomography (CryoET) to provide nationwide access to advanced cryoET instrumentation and technical support, and to assist investigators in acquiring the skills needed to perform cryoET studies.

Funding Opportunity Goal(s) The National Institute of General Medical Sciences (NIGMS) supports basic research that increases our understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment, and prevention. NIGMS also supports research in specific clinical areas that affect multiple organ systems: anesthesiology and peri-operative pain; clinical pharmacology common to multiple drugs and treatments; and injury, critical illness, sepsis, and wound healing. NIGMS-funded scientists investigate how living systems work at a range of levels—from molecules and cells to tissues and organs—in research organisms, humans, and populations. Additionally, to ensure the vitality and continued productivity of the research enterprise, NIGMS provides leadership in supporting the training of future scientists and developing research capacity throughout the country.

Key Dates

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.

Expiration Date January 27, 2027

Due Dates for E.O. 12372 Not Applicable

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

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

• Use the NIH ASSIST system to prepare, submit and track your application online.
• Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
• Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.

Table of Contents

• Part 1. Overview Information
  • Key Dates
• Part 2. Full Text of Announcement
  • Section I. Notice of 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. Notice of Funding Opportunity Description

Background Technical advances in single particle cryoelectron microscopy (cryoEM) have enabled generation of reliable atomic models of complete and fully functional macromolecular complexes. NIGMS currently supports three National Centers that provide technical training in and access to instrumentation for single particle cryoEM analysis of purified samples. In cryoET, a related method, recent advances in sample preparation, electron optics, detectors, and image processing enable determination of macromolecular complex structures in unstained frozen cells. However, the high cost of microscopes and supporting instrumentation for specimen preparation present barriers to the broad utilization of cryoET. This program will support centers to provide access to instruments for sample preparation and cryoET data collection. Additionally, because the workflows for specimen preparation are complex and technically challenging, the cryoET centers will provide training in sample preparation and collecting tomographic data.

Program Objectives This program will support service centers for nationwide access to state-of-the-art cryoET technology, expertise, and training. A goal of this program is to increase national expertise in cryoET; service centers will therefore prioritize training users to work independently rather than focusing on only providing user service.

The primary objectives of the centers are to provide:

• Access to state-of-the-art facilities for cryoET
• User training in the theory and practice of cryoET
• Assistance in sample preparation and tomographic data collection

Facility Requirements Each center must have:

• At least one cryogenic focused ion beam-scanning electron microscope (cryo-FIB-SEM) reserved for the sole use of the center
• At least one state-of-the-art 300keV cryoEM microscope equipped with a direct electron detector reserved for the sole use of the center
• Equipment for correlative light and electron microscopy (CLEM) reserved for the sole use of the center
• Bench space and equipment for specimen preparation, including for biochemistry, handling of cells and tissues, and plunge and high-pressure freezing
• Computational resources for standard initial processing and correction of raw image data, for standard calculation of tomographic density maps, and for short-term image storage
• A web-based resource to facilitate remote user access to instruments and data

Both the cryo-FIB-SEM and a 300keV microscope must be at one site. Centers proposing to incorporate more than one cryo-FIB-SEM or one 300keV electron microscope must justify the need for multiple instruments within the goals of the center. Microscopes that are currently part of a federally-funded resource or center must remain assigned to the relevant active award.

Service Requirements The scope of this initiative is limited to analysis of native, frozen-hydrated biological specimens using 3-D (tomographic) transmission electron microscopy. Other emerging technologies, for example those using embedded specimens and/or scanning electron microscopy, while important, are outside the scope of the initiative and should not be offered.

Specimen Preparation. The center’s technical staff will work with user laboratories to prepare specimens for cryoET using standard or user-provided protocols. Methods may include plunge freezing, high-pressure freezing, CLEM, or cryo-FIB-SEM milling. Center staff will supervise and assist on-site users and may work with these users to customize preparation methods for particular specimens, as required. Provision must be made for users to participate remotely to supervise and direct workflow as needed.

Tomographic Data Collection. Center staff will collect cryoET data on samples prepared at the center or elsewhere.

Data Processing. The center will provide standard initial processing and correction of raw image data and standard calculation of tomographic density maps if requested by users but will not perform project-specific analyses. The center will provide short-term storage and efficient transfer of users' cryoET data, with users responsible for their own long-term data storage.

Training. The center will offer training to user laboratories in the general theory and practice of cryoET methods. Users may be trained to operate equipment on their own, on site, or remotely. Such training should cover the basic skills laboratories need to undertake their own independent cryoET specimen preparation.

Center Research. The center may engage in research that directly advances its service objectives. Centers are expected to keep pace with advances in practice by implementing new protocols into their workflows. The center will adapt outside developers' protocols into robust and reproducible workflows and implement them as standard services. Centers may develop technology to improve their data collection capabilities during the approved project period. No more than 10% of center effort may be invested in integrating new technology. Technology development that does not directly advance the center's service objectives is beyond the scope of this NOFO and may be supported through other sources of funding such as the NIGMS Technology Development Programs R21 (PAR-25-202) and R01 (PAR-25-203).

Administrative Requirements

User Application and Review Process. Applications for center access should be prioritized through a formal scientific review process by a User Review Committee as well as programmatic and administrative review by center staff. The review process for instrument usage and training should be consistent with the objectives of equal opportunity and nationwide access to state-of-the-art cryoET equipment, technical support, and training. There should be a single, public application track for all users, including local and institutional users. Except for the center's own internal development, quality control, maintenance, and evaluation projects, other institutional or local use must be reviewed and prioritized through the same public channels as all other users.

User Charges. There will be no facility charges for users from non-profit institutions.

User Accommodation. Information should be provided to users about local lodging, meals, and transportation available at reasonable cost.

Staffing. Since professional effort on center appointments will be mainly service-related activities, centers are encouraged to develop strategies for the recruitment and development of highly qualified staff. Center personnel with part-time appointments may participate in research outside of the center, provided their effort on this research is supported by other funding sources. Center staff must apply as users through the center's public application process for use of center facilities for their outside research.

Website and Information Sharing Activities. The center is expected to inform the scientific community of their capabilities and services, promote broader application of cryoET, and actively recruit users. The center must have a website that provides up-to-date and complete information about facilities and services, policies, and the application process. The center must also engage in active outreach.

Partnerships. The center may form partnerships that advance its mission. Examples include, but are not limited to, partnerships with instrumentation manufacturers/vendors and collaboration with academic technology developers.

Center-to-Center Coordination. Centers funded through this NOFO are encouraged to coordinate on:

• Providing backup for service interruptions
• User application reviews
• Sharing websites, best practices and newly developed technologies
• Developing and cross-honoring training certifications in standard practices

Data and Data Sharing. Center users, not the center itself, are responsible for long-term storage of any data generated from user samples. As a condition of center services, users must agree to follow all applicable NIH policies for the sharing of their data and research resources, as appropriate.

Advisory Committee. The use of an Advisory Committee for the center is optional and may not involve NIH personnel.

Record Keeping and Progress Reviews. Centers should keep records to track activities, applications, users, specimens, microscope usage, outcomes, and user feedback. They should be kept current and accessible for review by the PD(s)/PI(s) and summarized in the annual progress reports. A records system should be used to track progress for the following items:

• Applications and Review: Types and numbers of applications received, review evaluations, and outcomes.
• User Base: Users served (persons visiting, institutional affiliation, career level, instrument time allocation). Type of project (sample preparation, data collection, training). Breakout of visits (in person, remote, mail-in). Geographic distribution.
• Service summaries: Types of services provided. Sample preparation (FIB-Milling, CLEM). Data collection (number of projects, number/size of data sets) and outcomes (quantity/resolution, usability, status). Training (number of projects, visit type, topics covered, certifications received).
• Microscope use: Log of hours for each microscope (electron microscopes, cryo-FIB-SEM, cryo-light microscope) for: Center usage, Idle time, Time unavailable (repair/downtime, holidays, etc.).
• Workshop training: Dates, location, and topics of workshops. Number of attendees, in-person, virtual, hands-on access. Evaluation outcomes.

Non-Responsiveness Criteria The following types of applications are non-responsive to this NOFO and will be withdrawn without review:

• Applications from institutions with insufficient instrumentation for the proposed center according to specifications listed under Facility Requirements.
• Applications from institutions where the cryo-FIB-SEM and the 300keV cryoEM microscope are located at different sites.

Due to the NOFO’s restricted scope, special application instructions, and additional review criteria, potential applicants are strongly advised to discuss their plans with the Scientific/Research contact listed in Section VII prior to submitting an application.

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

Section II. Award Information

Funding Instrument Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed

• New
• Revision

The OER Glossary and the How to Apply - Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial? 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 The number of awards is contingent upon NIH appropriations and the number of meritorious applications.

Award Budget Application budgets are not limited but must reflect the actual needs of the proposed project.

Award Project Period 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 NOFO.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

• Higher Education Institutions - Includes all types
  • Public/State Controlled Institutions of Higher Education
  • Private Institutions of Higher Education
• 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)
• Local 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)
• Federal Governments
  • 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 Organizations) are not eligible to apply. Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply. Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Required Registrations

Applicant Organizations Applicant organizations must complete and maintain the following registrations as described in the How to Apply - 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• 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. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their 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 their organization to develop an application for 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 How to Apply - Application Guide.

• At least one PD/PI should be an expert in cryoET and at least one PD/PI should have experience managing a scientific resource. These roles can be filled by the same person.

2. Cost Sharing This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications 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 NIH Grants Policy Statement Section 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 NIH Grants Policy Statement 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 NOFO. 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 How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise (in this NOFO, in a policy notice, or other notice from NIH Guide for Grants and Contracts). Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Page Limitations All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

Instructions for Application Submission The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

• SF424(R&R) Cover All instructions in the How to Apply - Application Guide must be followed.
• SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply - Application Guide must be followed.
• SF424(R&R) Other Project Information All instructions in the How to Apply - Application Guide must be followed.
• Facilities & Other Resources:
  • Describe the microscope infrastructure to be provided for both tomographic data collection and sample preparation.
  • Explicitly indicate how the proposed physical location of the center satisfies the vendors' environmental specifications for microscopes, other instrumentation, and computers. These include, but are not limited to, temperature, humidity, electric and magnetic fields, vibration, and electrical power.
  • Describe the microscope facilities that will be available, both for in-person and remote access.
  • Describe the laboratory facilities that will be available to users for sample preparation and biochemistry, cryoET sample grid preparation, and computation. Indicate the distances between the facilities comprising the center.
  • Provide a general description of local accommodation options for out-of-town users.
• SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply - Application Guide must be followed.
• R&R Budget All instructions in the How to Apply - Application Guide must be followed.
  • Funding may be requested for the supported activities described in Section I or other well-justified activities.
  • Inflationary escalation should not be included in any cost categories. Any add-on costs in a budget year must be well justified.
  • Equipment requests are limited to the -01 year and must be well justified and of immediate need. The budget justification section may include, but is not limited to, comparison with other commercially available instruments of similar function. Price quotes should be included for equipment costing more than $25,000. Service contracts and extended warranties may be included as part of the equipment requests.
  • Service contracts for existing equipment are allowed. Any service contract costs for existing equipment should be totaled and included as a line item under Section F. Other Direct Costs. The Budget Justification should also provide additional detail as to the terms of service contract as well as clearly identify the equipment item to which it applies.
  • Travel and other costs for center personnel and consultants (including User Review and Advisory Committee members) are permitted. These may include travel to committee meetings, scientific meetings, and for information-sharing activities. Where feasible, NIGMS encourages the use of virtual meetings to reduce unnecessary travel time and costs.
  • Funds for support of a common website or other Center-to-Center activities to share information are allowed.
  • In the Budget Justification, for each staff position, describe the technical responsibilities. At least one PD/PI, preferably a PD/PI who is an expert in cryoET, must devote a minimum of three person-months effort to the center. Provide detailed information about support received or anticipated from other funding entities. This could include additional funding from other government agencies or institutional support. Department of Energy Laboratory Directed Research and Development (LDRD) costs are not allowed.
• R&R Subaward Budget All instructions in the How to Apply - Application Guide must be followed.
• PHS 398 Cover Page Supplement All instructions in the How to Apply - Application Guide must be followed.
• PHS 398 Research Plan All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:
  • Research Strategy:
    • Infrastructure and Technical Operations:
      • Describe the equipment that will be available at the center. Justify the inclusion of more than one 300keV cryoelectron microscope or cryo-FIB-SEM, if applicable. Describe how the instruments will be maintained and operated to achieve state-of-the-art performance.
    • Sample Preparation Services:
      • Describe the sample preparation protocols that will be offered as standard services during the project period. Explain how prepared samples will be evaluated. Estimate the capacity of the center in terms of annual throughput for sample preparation. Assess the technical challenges and estimate the staff effort and resources needed to deliver the different services. Include timelines for implementing services. If applicable, describe coordination with other sites on the shipping or transportation of data collection-ready samples and, in cases where these samples cannot be shipped, on the completion of sample preparation at the data collection site.
    • Data Collection, Processing, and Computational Services:
      • Describe the center’s services for data collection, image correction, and computation of tomograms. Estimate the center’s capacity in terms of annual throughput for data collection. Justify the adequacy of computational resources for the expected production and volume of raw data. Describe the categories and extent of computational support for users. Discuss the handling (volume, storage, security, disposal schedules) of raw high-throughput data. Describe the protocols for transfer of data to users.
    • Workflow:
      • Describe the deployment of staff and instruments in multiple simultaneous workflows. Indicate how workflows will be adjusted in response to demand. Explain how effort will be coordinated to maximize efficiency, including communication with users and scheduling.
    • Training:
      • Describe the principles, strategies, and management of user training. Provide estimates of the training capacity in terms of annual throughput. Outline the management of space, facilities, and assistance for visitors. Explain the scheduling strategy and the balance between sample and data services and training.
    • Training Certification:
      • Describe methods, strategies and services that may be offered to standardize training in common practices in sample preparation, microscope operations, and data management and processing.
    • Staffing:
      • Together, the Biosketch(es), Budget Justification, and Research Strategy should provide the qualifications and roles for each staff position. Describe how well-qualified staff will be recruited, trained, and retained. To sustain efficient management of the resource, include a contingency plan in the event the PD(s)/PI(s) can no longer fulfill the obligation due to health, retirement, or other unforeseeable circumstances.
    • Record Keeping and Progress Reviews:
      • Describe how information regarding center operations and the delivery of services will be recorded and made accessible for review by the PD(s)/PI(s). Describe how follow-up information about outcomes will be obtained and made accessible. Describe how user feedback will be obtained and utilized to improve center performance.
    • User Application and Review Process:
      • Describe the principles and strategies for ensuring open and fair access for applicants by the User Review Committee. Briefly describe qualifications for User Review Committee members. Names of potential members of this committee (and any other committees) should not be included in the application, nor should they be contacted prior to the completion of the review process.
    • Website and Information Sharing:
      • Describe the plans for informing the scientific community about center capabilities and services, promoting the wider application of cryoET, and recruiting users. Describe the website; do not include URLs (e.g., if there exists a currently operating center).
    • Backup Plans:
      • Describe plans for contingencies in which the center is unable to perform its functions for an extended period (months or longer). The plan should include provisions for support (for example, alternative employment) of center personnel if they are unable to perform their resource functions for an extended period.
    • Advisory Committee:
      • If an Advisory Committee is proposed, describe the committee's role and how the members would be chosen. If an advisory committee already exists, list the current members and briefly describe their qualifications. If a new advisory committee is proposed, the names of potential members of this committee (and any other committees) should not be included in the application, nor should they be contacted prior to the completion of the review process.
    • Multiple PD/PI Leadership Plan (if applicable):
      • The sharing of management responsibilities by a team of PDs/PIs, rather than a single PD/PI, may pose challenges for direction and management. It is important to devise a robust and workable management scheme and describe it clearly and completely. Useful guidance for management of projects by multiple investigators is posted on the NIH Multiple PD/PI webpage.
    • Letters of Support:
      • Letters of support should come only from individuals who are named in the application and have a role in the project that is described in the application, for example, expert consultants. Statements of commitment from institutional officials also must be provided and should describe the extent of availability of facilities and services (percent time and effort) committed to the project.
    • Resource Sharing Plan:
      • Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide.
      • Describe the major categories of resources likely to be produced and the plans for sharing them, as appropriate. Where applicable, the plan should specifically address computer algorithms and software (including source code).
    • Other Plan(s):
      • All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:
        • A Data Management and Sharing Plan is not applicable for this NOFO.
    • Appendix:
      • Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - 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 How to Apply - 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 How to Apply - Application Guide must be followed.
  • Delayed Onset Study 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 How to Apply - Application Guide must be followed.
• PHS Assignment Request Form All instructions in the How to Apply - Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM) See Part 2. 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. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372) This initiative is not subject to intergovernmental review.

6. 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 Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information

• Applications must be submitted electronically following the instructions described in the How to Apply - 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.

Important reminders:

• All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of 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 NOFO for information on registration requirements.
• The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - 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.

Mandatory Disclosure Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35. Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov.

Post Submission Materials Applicants are required to follow the instructions for post-submission materials, as described in the policy.

Section V. Application Review Information

1. Criteria 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.

For this particular NOFO, note the following: The intent of this NOFO is to support cryoET service centers that deliver nationwide access to state-of-the-art cryoET equipment, technical support, and training. Applications should have at least one PD/PI with expertise in cryoET structure determination and solving technical problems in cryoET, and at least one PD/PI with experience in solving the types and range of technical and managerial challenges expected to arise during center operations. The equipment and infrastructure available must include at least one cryo-FIB-SEM, one 300keV cryoEM microscope, and equipment for CLEM. Applications should also propose plans for recruiting, training, and retaining experienced center staff for the effective delivery of technical support, user training, and equipment maintenance and operation.

Overall Impact 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).

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 proposed center address the needs of the research community that it will serve? Is the scope of activities proposed for the center appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the center? Specific to this NOFO: How effective will the center be in assisting new users to develop cryoET skills and transition to independent cryoET research?

• Investigator(s) Are the PD(s)/PI(s) and other personnel well suited to their roles in the center? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing CryoET research? Do the investigators demonstrate significant experience with managing research resources? If the center is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their leadership approach, governance, plans for conflict resolution, and organizational structure appropriate for the center? Does the applicant have experience overseeing selection and management of subawards, if needed? Specific to this NOFO:

  • Describe the suitability of the PD(s)/PI(s) for running a service facility whose scope is limited to sample preparation, data collection, training, and guidance of outside users.
  • What is the likelihood of success of the plans to recruit and retain well-trained and experienced staff? How adequate are the roles and qualifications of the center staff?
  • How suitable are backup plans for the PD(s)/PI(s) and staff in the event the facility is unable to perform its functions for an extended period? Evaluate the contingency plan in the event the PD(s)/PI(s) can no longer fulfill their obligations.

• Innovation Does the application propose novel organizational concepts, management strategies, or instrumentation in coordinating the research the center will serve? Specific to this NOFO:

  • How inventive are strategies for recruiting and assisting new users in the development of cryoET skills?
  • To what extent does the application include novel insights and approaches for recruiting and retaining qualified staff, and achieving and maintaining state-of-the-art capabilities and service?

• Approach Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the center? Will the investigators promote strategies to ensure a robust and unbiased scientific approach across the center, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the center is in the early stages of operation, does the proposed strategy adequately establish feasibility and manage the risks associated with the activities of the center? Are an appropriate plan for work-flow and a well-established timeline proposed? Specific to this NOFO:

  • How well does the research strategy address issues and challenges, both administrative, such as gathering feedback and maintaining performance records, and technical, such as instrument breakdowns? How flexible and adaptable is the approach to changing circumstances, technological change, community needs, or user feedback?
  • To what extent will the center be a leader in expanding the number of researchers with cryoET expertise?
  • Describe the suitability of the transparent, open access application process, whether already in place or planned.
  • If proposed, evaluate the role of the advisory committee and the plans for its formation.

• Environment Will the institutional environment in which the center will operate contribute to the probability of success in facilitating the research it serves? Are the institutional support, equipment and other physical resources available to the investigators adequate for the center proposed? Will the center benefit from unique features of the institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling? Specific to this NOFO:

  • How adequate are environmental controls for the performance and maintenance of the microscopes?
  • How adequate are the wet labs and sample preparation facilities for users who must prepare their samples at the center?
  • How appropriate are plans for remote access?

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 score, but will not give separate scores for these items.

• Study Timeline Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate? Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

• Protections for Human Subjects For research that involves human subjects but does not involve one of the 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 categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

• Inclusion of Human Subjects Policies When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for inclusion. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

• Vertebrate Animals The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the American Veterinary Medical Association (AVMA) Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals 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 For Resubmissions (as applicable), the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

• Renewals For Renewals (as applicable), the committee will consider the progress made in the last funding period.

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

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 score.

• Applications from Foreign Organizations Not Applicable.
• Select Agent Research Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
• Resource Sharing Plans Reviewers will comment on whether the Resource Sharing Plan(s) (e.g., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.
• Authentication of Key Biological and/or Chemical Resources For resources involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
• 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, in accordance with NIH peer review policies and practices, 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 will receive a written critique. 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. Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the National Advisory General Medical Sciences Council. 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.
• Geographic distribution.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding. Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates 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 Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official. In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions. Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk. For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process. Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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, Recipients, and Activities.
• All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.
• By applying for or accepting federal funds from HHS, recipients certify compliance with all federal antidiscrimination laws and these requirements and that complying with those laws is a material condition of receiving federal funding streams. Recipients are responsible for ensuring subrecipients, contractors, and partners also comply.
• Applicants and recipients are strongly encouraged to refer to the NIH Director’s Statement of Priorities, entitled “Advancing NIH’s Mission Through a Unified Strategy.”
• Recipients are responsible for ensuring that their activities comply with all applicable federal regulations. Pursuant to 2 CFR 200.340, by accepting an NIH award, the recipient agrees that continued funding for the award is contingent upon the availability of appropriated funds, recipient satisfactory performance, compliance with the Terms and Conditions of the award, and may also otherwise be terminated, to the extent authorized by law, if the agency determines that the award no longer effectuates the program goals or agency priorities, in line with 2 CFR 200.340(a)(4).
• Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that: When recipients, subrecipients, or third-party entities have:

• ongoing and consistent access to HHS owned or operated information or operational technology systems; and
• receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award. Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information.

Cooperative Agreement Terms and Conditions of Award Not Applicable

3. Data Management and Sharing Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

Tracking the demand for and utilization of the resource is important for ongoing improvements in the short-term and for gauging the impact of usage on science in the long-term. A reporting plan tailored to the resource to best evaluate the productivity, availability, efficiency, and impact of the resource is required. Report data on an annual basis to track the demand for and utilization of the resource, as outlined in the Record Keeping section of the Research Strategy. Sample data should include the following:

• Applications and Review: Types and numbers of applications received, review evaluations, and outcomes.
• Outreach: Research community outreach and engagement (website, webinars, conferences).
• User Base: Users served (number of persons, institutional affiliation, career level, instrument time allocation). Type of project (sample preparation, data collection, training). Breakout of visits (in person, remote, mail-in). Geographic distribution.
• Service Summaries: Types of services provided such as cryo-FIB-SEM, CLEM, and data collection (number of projects), as well as training (number of projects, visit type, topics covered, certifications received).
• Microscope Use: Log of hours for each microscope (electron microscopes, cryo-FIB-SEM, cryo-light microscope) for: center usage hours, idle hours, time unavailable for cause (repair/downtime, holidays, etc.).
• Workshop Training: Dates, locations, and topics of workshops. Number of attendees, training type (in-person, virtual, hands-on access). Evaluation outcomes (post-training satisfaction surveys, trainee feedback).
• Impact on User Research: Publications list. Electron Microscopy Data Bank (EMDB) and Protein Data Bank (PDB) deposition numbers for all publications supported. Funding sources and grant numbers for all center-supported projects.

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 Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

5. Evaluation In carrying out stewardship of grant programs, NIGMS will periodically evaluate the National CryoET Centers program, employing the measures identified below. In assessing the effectiveness of the program in serving the needs of the research community and in expanding the user base, NIGMS may use information from progress reports and public databases, the PD(s)/PI(s), and from participants themselves. Where necessary, the PD(s)/PI(s) and participants may be contacted after the completion of the grant period for updates on participants' subsequent outcomes.

In evaluating the National CryoET Centers program, NIGMS expects to use the following measures: Measures of resource utilization across the program, such as:

• Information about the size and characteristics of the userbase.
• Instrument time requested and fulfilled.
• Hours used for high-resolution cryoET data collection.
• Projects prepared using cryo-FIB-SEM and/or CLEM
• Publications, and PDB, and EMDB depositions citing use of the resource.
• Availability of workshops, seminars or other means of training.
• Indicators of research community outreach and engagement.

Section VII. Agency Contacts

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

Application Submission Contacts

• eRA Service Desk - Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues.
• Grants.gov Support Center - Questions regarding Grants.gov registration and services (e.g., Workspace, subscriptions).

Scientific/Research Contact(s) Email: NIGMSCryoET@mail.nih.gov

Peer Review Contact(s) Center for Scientific Review (CSR) Email: NOFOReviewContact@csr.nih.gov

Financial/Grants Management Contact(s) Email: BBCBGABNOFO@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 2 CFR Part 200.