Part I Overview Information


Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH) (http://www.nih.gov/)

Components of Participating Organizations
National Institute of General Medical Sciences (NIGMS) (http://www.nigms.nih.gov/)

Title:  Molecular Probes for Microscopy of Cells (R01)

Announcement Type
This is a reissue of PAR-06-288, which was previously released March 26, 2006

NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).

A registration process is necessary before submission and applicants are highly encouraged to start the process at least four weeks prior to the grant submission date. See Section IV.

Program Announcement (PA) Number: PAR-07-234

Catalog of Federal Domestic Assistance Number(s)
93.859

Key Dates
Release/Posted Date: February 23, 2007
Opening Date: April 25,2007 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): April 25, 2007, July 29, 2007, April 25, 2008 and July 29, 2008
NOTE: On time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization). 
Application Submission/Receipt Date(s): May 25, 2007, August 29, 2007, May 27, 2008 and August 29, 2008
Peer Review Date)s): September/October and February/March
Council Review Date(s): January 2008, May 2008, January 2009 and May 2009
Earliest Anticipated Start Date(s):  April 1, 2008, July 1, 2008, April 1, 2009 and May 1, 2009
Additional Information To Be Available Date (Activation Date): Not Applicable
Expiration Date: August 30, 2008

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

Table of Contents


Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives


Section II. Award Information

1. Mechanism of Support

2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants

    A. Eligible Institutions
    B. Eligible Individuals
2. Cost Sharing or Matching
3. Other-Special Eligibility Criteria

Section IV. Application and Submission Information
1. Request Application Information

2. Content and Form of Application Submission
3. Submission Dates and Times
    A. Submission, Review, and Anticipated Start Dates
          1. Letter of Intent
    B. Submitting an Application Electronically to the NIH
    C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Sharing Research Data
    D. Sharing Research Resources
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices

2. Administrative and National Policy Requirements
3. Reporting

Section VII. Agency Contacts
1. Scientific/Research Contact(s)

2. Peer Review Contact(s)
3. Financial/Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement


Section I. Funding Opportunity Description


1. Research Objectives

The purpose of this initiative is to evaluate promising but unproven general purpose enabling technologies for the routine detection by microscopy of single molecules and single molecular events inside cells.  Applications are invited for (1) feasibility studies for new classes of high-signal output molecular imaging probes; (2) evaluation of general purpose methods for the quantitative delivery and specific targeting of externally administered imaging probes without disturbing cellular physiology; and (3) basic research on underlying fundamental photophysical phenomena relevant to improving the spectral properties of fluorescent probes.

This initiative is intended only for the evaluation of possible new enabling technologies of high potential impact but unproven feasibility.  Responding projects are not required to deliver a working technology in a single project period, but should address clearly defined questions about the capabilities and feasibility of the possible new technology.  Applicants are invited to initiate work on unexplored, poorly understood topics but should set well-defined goals.  Review of applications will focus on significance, innovation, rationale, strategy, and the qualifications of the investigators. 

Individuals and interdisciplinary teams are invited to apply.  Since a key goal is to bring fresh perspectives and ideas to bear on imaging technology, investigators who are established in other research fields are especially encouraged to apply.  Applicants need not have preliminary results or an active program in imaging technology, but should have a track record of innovation.

For the development of technologies for which proof of principle has already been achieved and/or extensive preliminary data are already available, or for the refinement of established technologies, investigators should seek other means of support, for example, a Bioengineering Research Grant (BRG) (PA-06-419) or Partnership (BRP) (PAR-06-459).  For exploratory studies on topics outside the objectives of this FOA, investigators should consider the Exploratory/Developmental BRG (EBRG) [R21] (PA-06-418).

Background

The long term goal of this announcement is to develop new general purpose technologies for the routine detection by microscopy of single molecules and single molecule events inside cells with minimal disturbance of normal cellular physiology.  This goal requires both molecular probes with high signal output and the supporting technologies for their specific targeting and non-disruptive delivery.

Over the last decade, use of green fluorescent protein (GFP) fusion proteins to observe protein dynamics in living cells by fluorescence microscopy has made a vast range of biological processes amenable to investigation.  More recently, sensors based on fluorescent resonance energy transfer (FRET) have extended the capabilities of light microscopy to report on molecular transitions and interactions in living cells.

The genetic encoding of fluorescence offers many advantages for specific targeting and delivery.  GFP labeling often does not interfere with normal cellular physiology.  However, the spectral properties of GFP are inadequate for routine single molecule imaging.   Routine single-molecule reporting of all classes of molecular events in living cells will require fluorescent probes capable of producing 20-1000 times more signal (number of photons emitted before bleaching) than GFP.

Externally administered probes based on organic and inorganic compounds and materials (dyes and nanoparticles like quantum dots) offer advantages for diagnostic and high-throughput research applications.  Nanoparticles can deliver outstanding spectral performance (high signal over lifetime and multichannel capability), but to realize their potential as practical tools, they must be supported by better packaging, delivery, and targeting technologies.

The ideal molecular probe technology would offer absolute specificity (like genetically-encoded GFP tags), high signal output and narrow bandwidth (like nanoparticles), advantageous photophysical properties (e.g., no bleaching or blinking), modularity (interchangeable contrast and targeting moieties), minimal size, deliverability (access to all cell types and compartments, comparable to that achievable with GFP), and physiological neutrality (non-cytotoxic, biochemically inert).  Although it may not be practical to realize all these characteristics in a single probe technology at this time, it should be possible to achieve major improvements over existing probe classes in one or several of these performance categories.

Objectives

This initiative addresses  technological barriers to imaging the locations, states, interactions, reactions, and proximities of single macromolecules in cells: (1) achieving probe signal output sufficient for single molecule sensitivity;  (2) designing probes whose size and surface properties do not interfere with normal cellular physiology or with targeting;  (3) specific targeting of molecular probes to subcellular targets and (4) non-disruptive delivery of probes into the cytoplasm of living cells.   The goal is to develop high-output probes and general purpose targeting and delivery strategies that interfere minimally with normal cellular functions and can be adapted to a wide range of  intracellular targets. 

 The objectives of this initiative are:

o  New fluorescent probes for light microscopy offering signal output sufficient for routine real time detection of single molecule events in living cells.  A research strategy that has the potential to achieve a minimum 20-fold improvement over existing fluorophores should be proposed and justified. 

o  Basic research in relevant areas of physics, chemistry, biochemistry, and protein engineering on the mechanisms of photobleaching, blinking, quenching, and other photophysical phenomena influencing fluorophore behavior.  Research should aim to develop the knowledge needed to design new classes of greatly improved fluorescent probes that achieve a minimum 20-fold improvement over existing fluorophores.

o New classes of genetically encodable probes for light microscopy.  Possibilities include probes based on nucleic acids, or natural or engineered  apoproteins that bind optically active prosthetic groups or externally administered dyes.  Protein engineering approaches to the design of artificial fluorophores with enhanced spectral properties are invited.

o  Genetically-encoded probes for electron and X-ray microscopy.  The revolutionary impact of genetically-encoded fluorescence for detection and event reporting in light microscopy suggests that important advances would result if genetically-encodable contrast labels were available for other kinds of microscopy.  Possibilities include natural or engineered proteins that bind large numbers of heavy metal atoms.

o  Methods for packaging externally administered probes (e.g., dyes and nanoparticles), delivering them into the cytoplasm of living cells, and directing them to their subcellular destinations and molecular targets without disrupting cellular physiology and with low or zero background of untargeted probe. 

o  Strategies for genetically-encoded intracellular targeting of externally administered probes.

This Funding Opportunity Announcement has special application instructions and restrictions, altered review emphasis, and special award criteria.  Their purpose is to level the playing field for applications that pursue new directions and high-risk goals.  The Research Plan is limited to 10  pages.  The purpose of this page restriction is to focus the attention of applicants and reviewers on the significance of the questions being asked, rationale and general research strategy, and the qualifications of the investigators.  The page limits are sufficient only to explicitly define objectives and outline a well-founded and -designed general research strategy.  By design, the page limits are insufficient for a complete predefined research agenda that anticipates all contingencies that may arise in the course of a project.  Unpublished preliminary data shall not be included in the application.  The purpose of this restriction is to make it possible for applicants to initiate new lines of research without a large prior investment of funds and effort.  The objective of this funding opportunity to broaden the scope of imaging research and to recruit skilled investigators from other areas into the field, not to increase funding for research that is already underway.  Responsiveness to the goals of the initiative will be an award criterion.

Potential applicants are strongly encouraged to discuss their ideas with the Institute Scientific/Research contacts listed in Section VII to see if they fit within the goals of this initiative, and to send a letter of intent prior to submission.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information


1. Mechanism of Support

This Funding Opportunity Announcement (FOA) will use the NIH Research Project Grant (R01) award mechanism.   

The applicant will be solely responsible for planning, directing, and executing the proposed project.  

This FOA uses “Just-in-Time” information concepts. It also uses the modular as well as the non-modular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are a U.S. organization and are submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs), use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide (see specifically Section 5.4, “Modular Budget Component,” of the Application Guide). 

U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component found in the application package for this FOA. See NOT-OD-06-096, August 23, 2006.      

Competing renewal (formerly “competing continuation”) applications will be accepted as normal unsolicited R01s, or in response to the FOA, if it is reissued.

2. Funds Available

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the Institutes and Centers (ICs) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

F&A costs requested by consortium participants are not included in the direct cost limitation. See NOT-OD-05-004, November 2, 2004.  

Section III. Eligibility Information


1. Eligible Applicants

1.A. Eligible Institutions
You may submit an application(s) if your institution/organization has any of the following characteristics:

1.B. Eligible Individuals

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI 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.

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a “team science” approach that clearly does not fit the single-PD/PI model. Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a single PD/PI or multiple PD/PI grant is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for multiple PD/PI grants will require additional information, as outlined in the instructions below. The NIH review criteria for approach, investigators, and environment have been modified to accommodate applications involving either a single PD/PI or multiple PDs/PIs. When considering multiple PDs/PIs, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PD/PIs will be factored into the assessment of the overall scientific merit of the application.  Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria
 
Competing renewal (formerly “competing continuation”) applications will be accepted as normal unsolicited R01s, or in response to the FOA, if it is reissued.   

Applicants may submit more than one application, provided each application is scientifically distinct.    

Section IV. Application and Submission Information


To download a SF424 (R&R) Application Package and SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for this FOA, link to http://www.grants.gov/applicants/apply_for_grants.jsp and follow the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

PDs/PIs should work with their institutions/organizations to make sure they are registered in the eRA Commons.

Several additional separate actions are required before an applicant institution/organization can submit an electronic application, as follows:

1) Organizational/Institutional Registration in Grants.gov/Get Registered

2) Organizational/Institutional Registration in the eRA Commons

3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.

Both the PD/PI(s) and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the application image.

Note that if a PD/PI is also an NIH peer-reviewer with an Individual DUNS and CCR registration, that particular DUNS number and CCR registration are for the individual reviewer only. These are different than any DUNS number and CCR registration used by an applicant organization. Individual DUNS and CCR registration should be used only for the purposes of personal reimbursement and should not be used on any grant applications submitted to the Federal Government.

Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the "Attachment" files may be useable for more than one FOA.

For further assistance, contact GrantsInfo: Telephone 301-435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

All SF424 (R&R) requirements (see below) should be followed, with the exception of items affected by the following instructions.

o Unpublished experimental results may not be included or cited anywhere in the application. 

o INTRODUCTION (required for a revised application) is limited to one (1) page.  This section may only be included in a revised application.  It does not count against the 10 page limit for the Research Plan.

o RESEARCH PLAN.  Do not exceed 10 pages.  Do not include Item c, the PRELIMINARY STUDIES/PROGRESS REPORT section.  The page limits and content restrictions must be followed for all application types: new, revised, and competing continuation.  To ensure that the rationale and strategy are both adequately described, it is recommended that items b and d be of comparable length.

o Item a, SPECIFIC AIMS  The Specific Aims should address clearly defined questions about the potential and feasibility of unproven new enabling technologies as specified in the Research Objectives of this FOA.  The Aims may be intermediate steps to a longer-term goal, but they should be well-defined and achievable in the project period.  Where feasibility is uncertain, the Specific Aims should address only proof of principle, and downstream development activities contingent upon this proof should not be proposed.

o Item b, BACKGROUND AND SIGNIFICANCE  (a)  Describe the new technology, its projected capabilities, and how it relates to the Research Objectives of this announcement.  (b)  Review the state of the art and explain how the new technology would be a substantial advance beyond it.  Cite alternative (existing and prospective) technologies that might offer comparable capabilities, comparing and contrasting their strengths and weaknesses.  Identify and critically evaluate all unresolved feasibility issues and critical technical bottlenecks.  (c)  Describe the theoretical and conceptual underpinnings of the proposed approach.  The strategy should be justified by reference to published research, which may (but need not) be from the applicant's own laboratory.  Unpublished experimental results may not be included or cited anywhere in the application. 

o Item c, PRELIMINARY STUDIES/PROGRESS REPORT  This item should not be included.

o Item d, RESEARCH DESIGN AND METHODS  This item should explain the concepts and rationale of the research strategy and specify and justify priorities.  Feasibility issues, bottlenecks, and alternative research strategies should be addressed.  When the timeline to a working technology extends beyond the project period, this section should address the larger strategy of which the Specific Aims are part.  Specify the criteria by which proof of principle will be assessed.  Strategies should be robust enough to justify the full requested period of support.  For example, the later stages of the project should not depend on make-or-break approaches that may fail feasibility tests early in the project period, leaving no viable alternative plan for the remaining period of support.  In view of the long-term nature and anticipated difficulty of the goals, significant risks are expected and acceptable.  Nevertheless, potential difficulties and feasibility issues must be identified and addressed in the research plan.  Where specific solutions to them cannot yet be identified (as will often be the case), more general strategies may be proposed.  Applicants should describe their expertise and technical qualifications to undertake the work.  It is not necessary that the investigators demonstrate prior hands-on experience with every technique and experiment, but the research team should document relevant experience and adequate expertise.  The research plan should describe any collaborative arrangements needed to bridge gaps in expertise.

Prepare all applications using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. There are fields within the SF424 (R&R) application components that, although not marked as mandatory, are required by NIH (e.g., the “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component must contain the PD/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see “Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.”

The SF424 (R&R) application has several components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY includes all applicable components, required and optional. A completed application in response to this FOA includes the data in the following components:

Required Components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
PHS398 Modular Budget or Research & Related Budget, as appropriate (See Section IV.6., “Special Instructions,” regarding appropriate required budget component.)  
Research & Related Budget (required for foreign applications)

Optional Components:
PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form

Foreign Organizations (Non-domestic (non-U.S.) Entity)

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

Applications from foreign organizations must:

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

SPECIAL INSTRUCTIONS  

Applications with Multiple PDs/PIs

When multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the "Contact” PI, who will be responsible for all communication between the PDs/PIs and the NIH, for assembling the application materials outlined below, and for coordinating progress reports for the project. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PDs/PIs, but has no other special roles or responsibilities within the project team beyond those mentioned above.

Information for the Contact PD/PI should be entered in item 15 of the SF424 (R&R) Cover component. All other PDs/PIs should be listed in the Research & Related Senior/Key Person component and assigned the project role of “PD/PI.” Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission. The Commons ID of each PD/PI must be included in the “Credential” field of the Research & Related Senior/Key Person component. Failure to include this data field will cause the application to be rejected.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership of the project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled “Multiple PD/PI Leadership Plan” (Section 14 of the Research Plan Component in the SF424 (R&R)), must be included. A rationale for choosing a multiple PD/PI approach should be described.  The governance and organizational structure of the leadership team and the research project should be described, including communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators. 

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan.  In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award.

Applications Involving a Single Institution

When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.

Applications Involving Multiple Institutions 

When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a subcontract to be administered by the prime institution. When submitting a detailed budget, the prime institution should submit its budget using the Research & Related Budget component. All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form. 

When submitting a modular budget, the prime institution completes the PHS398 Modular Budget component only. Information concerning the consortium/subcontract budget is provided in the budget justification. Separate budgets for each consortium/subcontract grantee are not required when using the Modular budget format. See Section 5.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.

3. Submission Dates and Times

See Section IV.3.A. for details.

3.A. Submission, Review, and Anticipated Start Dates

Opening Date: April 25, 2007 (Earliest date an application may be submitted to Grants.gov)

Letters of Intent Receipt Date(s): April 25, 2007, July 29, 2007, April 25, 2008 and July 29, 2008

Application Submission/Receipt Date(s): May 25, 2007, August 29, 2007, May 27, 2008 and August 29, 2008
Peer Review Date(s): September/October and February/March
Council Review Date(s): January 2008, May 2008, January 2009 and May 2009
Earliest Anticipated Start Date(s):  April 1, 2008, July 1, 2008, April 1, 2009, and May 1 2009

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

James F. Deatherage, Ph.D.
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
Building 45, Room 2AS.13J, MSC6200
Bethesda MD 20892-6200
Telephone: (301) 594-0828
Email: deatherj@nigms.nih.gov

3.B. Submitting an Application Electronically to the NIH

To submit an application in response to this FOA, applicants should access this FOA via http://www.grants.gov/applicants/apply_for_grants.jsp  and follow steps 1-4. Note:  Applications must only be submitted electronically.  PAPER APPLICATIONS WILL NOT BE ACCEPTED. 

3.C. Application Processing

Applications may be submitted on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization) on the application submission/receipt date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the receipt date(s) and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two business days to view the application image.

Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the (Add IC Here). Incomplete and non-responsive applications will not be reviewed.  If the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle.

There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. The submitting AOR receives the Grants.gov acknowledgments. The AOR and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific Review Group is also in the Commons. 

Note: Since email can be unreliable, it is the responsibility of the applicant to check periodically on their application status in the Commons.

The NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of an application already reviewed with substantial changes, but such application must include an “Introduction” addressing the previous critique. Note such an application is considered a "resubmission" for the SF424 (R&R).

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing renewal (formerly “competing continuation”) award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing renewal award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See the
NIH Grants Policy Statement.

6. Other Submission Requirements

PD/PI Credential (e.g., Agency Login)

The NIH requires the PD/PI(s) to fill in his/her Commons User ID in the “PROFILE – Project Director/Principal Investigator” section, “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component.

Organizational DUNS

The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see “Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.”

PHS398 Research Plan Component Sections

Items 2-5 of the PHS398 Research Plan component are limited to 25 pages. While each section of the Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.   

All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating "Just-in-Time" information concepts, and with the following additional requirements:

Special Instructions for Modular Grant applications

R01 applications from U.S. institutions/organizations requesting up to $250,000 per year in direct costs (excluding consortium F&A costs) must be submitted in a modular budget format. Additional information on modular budgets is available at http://grants.nih.gov/grants/funding/modular/modular.htm. When submitting a modular budget, the applicant organization will include only the PHS398 Modular Budget component. See Section 5.4 of the SF424 (R&R) Application Guide for further instructions regarding the use of the PHS398 Modular Budget component.

Foreign organizations may not submit modular budgets. See NOT-OD-06-096

Special Instructions for Applications Requesting $500,000 (direct costs) or More Per Year

Applicants requesting $500,000 or more in direct costs for any year (excluding consortium F&A costs) must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study;

2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and,

3) Include the PHS398 Cover Letter component with the application to identify the staff member and IC who agreed to accept assignment of the application.

This policy applies to all new applications, competing renewal (formerly “competing continuation”) applications, resubmission (formerly “revised/amended”) applications, and revision (formerly “competing supplemental”) applications. See NOT-OD-02-004, October 16, 2001. 

Appendix Materials

IMPORTANT NOTE: NIH has published new limitations on grant application appendix materials to encourage applications to be as concise as possible while containing the information needed for expert scientific review. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-018.html

Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See http://grants.nih.gov/grants/funding/424/index.htm).

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not observe the required page limitations may be delayed in the review process.

Note: While each section of the PHS398 Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to monitor better formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.

Foreign Applications (Non-domestic (non-U.S.) Entity)

Plan for Sharing Research Data

Applicants should indicate how the findings of the research will be communicated (for example, both positive and negative outcomes of proof-of-principle studies, or the outcomes of screens which do not turn up positives).

Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a plan for sharing research data in their application. The funding organization will be responsible for monitoring the data sharing policy (http://grants.nih.gov/grants/policy/data_sharing).

The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement  http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590). See Section VI.3., “Reporting.”

Section V. Application Review Information


1. Criteria 

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications submitted for this funding opportunity will be assigned to the ICs on the basis of established PHS referral guidelines.

Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit.

As part of the initial merit review, all applications will:

Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application.

Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

If successful, would this proposed research make an important advance towards achieving single molecule imaging under physiological conditions inside cells?  For fluorescent probes, does the research strategy have the potential to achieve at least 20-fold improvement over existing methods, such as those using GFP? 

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? For applications designating multiple PDs/PIs, is the leadership approach, including the designated roles and responsibilities, governance, and organizational structure, consistent with and justified by the aims of the project and the expertise of each of the PDs/PIs?

Most applications that are responsive to the goals of this funding opportunity will be of unproven feasibility and high risk.  In this context, reviewers will be asked to evaluate:  Is the rationale for exploring this area sound?  Are the objectives clearly defined?  Is the strategy promising?  Do the potential benefits justify the risks?  Since exploratory work is invited, and page limits are too short for experimental details, in most cases it will not be practical for applicants to set out a predefined research sequence that anticipates every contingency that might arise in the course of the research. Nevertheless, are the major classes of difficulties addressed?

Innovation:  Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?  

The Innovation criterion is critical for this funding opportunity, which is specifically intended only for the exploration and invention of unproven new enabling technologies, and not for the refinement of existing technology.  Reviewers will be asked to identify what the project offers beyond the steady improvement and extension of established technologies currently underway in the applicants' or others' laboratories.  Reviewers will also be asked to assess innovation in the composition of the project team.  Do the investigators bring new perspectives and skills to the field?

Investigators: Are the PD/PI(s) and other key personnel appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the PD/PI(s) and investigative team bring complementary and integrated expertise to the project (if applicable)?

Since investigators new to the field have been encouraged to apply for this funding opportunity, applicants need not have an active research program on the problem.  Reviewers will be asked to evaluate:  Can the investigator(s) be relied upon to design well-founded research approaches and execute them effectively?  Do they have a record of innovation and achievement on difficult problems in related areas?  Does their history suggest that they will be resourceful enough to solve the kinds of problems expected to arise in the course of the research?   Will they be able to master the techniques that will be needed?

Environment:  Do(es) the scientific environment(s) in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

2.A. Additional Review Criteria

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Resubmission Applications (formerly “revised/amended” applications): Are the responses to comments from the previous scientific review group adequate? Are the improvements in the resubmission application appropriate?

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the adequacy of the plans for their care and use will be assessed. See the “Other Research Plan Sections” of the PHS398 Research Plan component of the SF424 (R&R). 

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget and Period of Support: The reasonableness of the proposed budget and the appropriateness of the requested period of support in relation to the proposed research may be assessed by the reviewers. The priority score should not be affected by the evaluation of the budget.

Applications from Foreign Organizations: Whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources will be assessed. 

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The funding organization will be responsible for monitoring the data sharing policy. http://grants.nih.gov/grants/policy/data_sharing.

2.D. Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement  http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590), See Section VI.3., “Reporting.”  

Model Organism Sharing Plan: Reviewers are asked to assess the sharing plan in an administrative note. The sharing plan itself should be discussed after the application is scored. Whether a sharing plan is reasonable can be determined by the reviewers on a case-by-case basis, taking into consideration the organism, the timeline, the applicant's decision to distribute the resource or deposit it in a repository, and other relevant considerations.

3. Anticipated Announcement and Award Dates

For applications received in May and August and reviewed at the January and May Councils, the earliest start dates are April 1 and July 1.

Section VI. Award Administration Information


1. Award Notices

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 NIH eRA Commons

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Section IV.5., “Funding Restrictions.”       

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts


We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contact(s):

o Direct general questions, and questions about targeting and delivery and probes for electron and X-ray microscopy to:

James F. Deatherage, Ph.D.
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
Building 45, Room 2AS.13J, MSC6200
Bethesda MD 20892-6200
Telephone: (301) 594-0828
Email: deatherj@nigms.nih.gov

o Direct questions about photophysical studies and fluorescent probe development to:

Catherine Lewis, Ph.D.
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
Building 45, Room 2AS-13C, MSC6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0828
Email: lewisc@nigms.nih.gov

2. Peer Review Contact(s):

Ross D. Shonat, Ph.D.
Scientific Review Administrator (SRA)
Microscopic Imaging (MI) Study Section
Bioengineering Sciences and Technologies (BST) IRG
Center for Scientific Review
6701 Rockledge Drive, Room 4190, MSC 7849
Bethesda, Maryland, 20892
Telephone:  (301) 435-2786
Email:  shonatr@mail.nih.gov

3. Financial/Grants Management Contact(s):

Grace Olascoaga
Grants Management
National Institute of General Medical Sciences
Building 45, Room 2AN.32E, MSC6200
Bethesda, MD  20892-6200
Telephone:  (301)594-5520
Email: olascoag@nigms.nih.gov

Section VIII. Other Information


Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov/) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process, please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov// and view the Policy or other Resources and Tools, including the Authors' Manual.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (HHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the HHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, Internet addresses (URLs) or PubMed Central (PMC) submission identification numbers must be used for publicly accessible on-line journal articles. Publicly accessible on-line journal articles or PMC articles/manuscripts accepted for publication that are directly relevant to the project may be included only as URLs or PMC submission identification numbers accompanying the full reference in either the Bibliography & References Cited section, the Progress Report Publication List section, or the Biographical Sketch section of the NIH grant application. A URL or PMC submission identification number citation may be repeated in each of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov/.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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