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
This announcement is developed as an NIH Roadmap Initiative (http://nihroadmap.nih.gov). All NIH Institutes and Centers participate in Roadmap initiatives. The announcement will be administered by the National Institute of Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA) on behalf of the NIH.

Title: Solicitation of Assays for High Throughput Screening (HTS) in the Molecular Libraries Probe Production Centers Network (MLPCN) (R03)

Announcement Type
This is a reissue of PAR-08-035.

Update: The following updates relating to this announcement have been issued:

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 (4) weeks prior to the grant submission date. See Section IV.

Program Announcement (PA) Number: PAR-09-129

Catalog of Federal Domestic Assistance Number(s)
93.310

Key Dates
Release/Posted Date: March 12, 2009
Opening Date: April 13, 2009(Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): Apr. 13, 2009; Aug. 4, 2009; Dec. 4. 2009; Apr. 4, 2010; Aug. 3, 2010; Dec. 4, 2010; Apr. 4, 2011; Aug. 2, 2011; and Dec. 4, 2011.
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 13, 2009; Sept. 4, 2009; Jan. 4. 2010; May 4, 2010; Sept. 3, 2010; Jan. 4, 2011; May 4, 2011; Sept. 2, 2011; and Jan. 4, 2012.
Peer Review Date(s): July 2009; November 2009; March 2010; July, 2010;November 2010; March 2011; July 2011;November 2011; and March 2012.
Council Review Date(s): October 2009; January 2010; May 2010; October 2010; January 2011; May 2011; October 2011; January 2012; and May 2012.
Earliest Anticipated Start Date: December 1, 2009
Additional Information To Be Available Date (Activation Date): Not Applicable
Expiration Date: January 5, 2012

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 and Information


Section V. Application Review Information
1. Criteria
2. Review and Selection Process

A. Additional Review Criteria
B. Additional Review Considerations
C. Resource Sharing Plan(s)
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 Contact(s)
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

Introduction

The NIH Molecular Libraries and Imaging Roadmap Initiative (MLI) offers public sector biomedical researchers access to the large-scale screening capacity necessary to identify small molecules that can be optimized as chemical probes to study the functions of genes, cells, and biochemical pathways. This will lead to new ways to explore the functions of genes and signaling pathways in health and disease.

The MLPCN (https://mli.nih.gov/mli/mlpcn/mlpcn/) is a collaborative research network that is composed of different types of centers in order to provide improved handling of assays and enhanced chemistry support for the large number of active compounds identified by the screening centers. Three types of centers have been identified to meet these challenges. 1). Comprehensive Centers with the capability to screen 300-500,000 compounds per assay and provide structure-activity relationship (SAR) analysis and support chemistry to identify potent and selective chemical probes; 2). Specialized Screening Centers with the capability to provide expertise and experience in specific technologies needed to successfully implement complex and technically difficult assays (e.g., ion channel screening, BSL3 containment screening, and flow cytometry screening); and 3). Specialized Chemistry Centers with outstanding capabilities in medicinal and synthetic chemistry to advance early hits to chemical probe status. As an integral part of the network, the Specialized Chemistry Centers will actively interact with both types of screening centers to generate probes.

HTS assays will be selected for implementation in the MLPCN from those submitted by the research community in response to this FOA. Each screening center will implement innovative HTS approaches to identify compounds that are active in target-based and phenotypic assays using 96-well, 384-well or 1536-well plate formats, as appropriate to the specific assay and screening platform. Early stage HTS assay developments are supported by the Assay Development for High Throughput Molecular Screening (R21), PAR-08-024 (http://grants.nih.gov/grants/guide/pa-files/PAR-08-024.html).

As a national research resource, the MLPCN interfaces with other components of the Molecular Libraries Roadmap initiative, including the Molecular Libraries Small Molecule Repository (MLSMR at http://mlsmr.glpg.com/MLSMR_HomePage/), PubChem (http://pubchem.ncbi.nlm.nih.gov/), and ongoing initiatives for technology development in the areas of assay development. The Small Molecule Repository will acquire and maintain a collection of up to 500,000 compounds, from compound providers representing both commercial and academic sources, with well-known or unknown biological activities and diverse chemical structures. The repository will provide compounds to the screening centers for HTS within the MLPCN. HTS hits, the active compounds identified through initial screening, will be optimized through chemistry and further assays into useful bioactive probes that can be used by the scientific community to study molecular targets, cellular pathways, and potentially as starting points for drug development that will occur outside the MLPCN. The chemical structures of the compounds in the Small Molecule Repository, along with the related screening data, and assay protocols generated by the MLPCN will be deposited into a public database, PubChem. PubChem will support investigators with information for obtaining active compounds for their use in further research by identifying a source for purchase or synthesis of particular compounds. Information about the bioactive compounds will be made available to all researchers, who will be free to adapt them in biological and biomedical research studies. Any users of the data deposited into PubChem will be required to acknowledge the source of the data.

It is anticipated that the NIH Molecular Libraries and Imaging Roadmap Initiative (MLI) effort will catalyze scientific breakthroughs that will contribute to the identification of molecular entities or molecular classes that may accelerate the development of therapeutics by the private sector. Through this approach, NIH wishes to stimulate research in the following areas: 1) discovery of novel biological targets that can inform studies of cell function and disease mechanisms; 2) development, validation, and application of screening assays and disease models to evaluate the activity of novel small molecules; and 3) use of chemical genomic approaches to characterize the biology of genes of interest, cellular processes, and proteins associated with disease processes relevant to the missions of the Institutes of the NIH (http://www.nih.gov/). The MLPCN, along with PubChem and the MLSMR, offers a new dimension in research opportunities for pharmacologists, chemists and biologists in the academic and non-profit sector. The sharing of small molecules, biological assays, and screening data with the larger scientific community represents a new public sector paradigm that promises to facilitate the understanding of basic biological mechanisms and shorten the timeline for drug development, with resulting benefits to public health, especially for rare and neglected disorders.

Objective

The purpose of this FOA is to promote and support discovery and development of new chemical probes as research tools for use by the research community to advance the understanding of biological functions and disease mechanisms. The MLPCN offers biomedical researchers access to large-scale automated screening centers, diverse compound libraries, medicinal chemistry resource, and information on biological activities of small molecules. The goal of the MLPCN is to implement a variety of innovative biochemical and cell-based assays for phenotypes or biological targets for which there are limited selective and potent small molecule modulators available to the public. Applications are invited from investigators who have developed assays for novel targets and targets in need of new probes for use both in basic research and in therapeutics development programs, and who are interested in having them used within the MLPCN to screen the NIH Small Molecule Repository Library and to develop a novel chemical probe.

Resources provided by the MLPCN

The MLPCN is established as a collaborative research network of Comprehensive Screening Centers, Specialized Screening and Chemistry Centers with complementary abilities that will enable screening of diverse types of assays and generation of chemical probes to address a wide range of biological opportunities (http://mli.nih.gov/mli/mlpcn/mlpcn-probe-production-centers/). Each center brings to the network a specific set of expertise and skills in the main functions/cores appropriate to the type of center (i.e., assay development, assay adaptation, HTS, cheminformatics, and chemistry).

1. Technical assistance: For applicants who need expert advice on their assays, the MLPCN centers will provide consultation via telephone, email, or lab visit arrangement to assist in HTS assay design, development, and optimization. The applicants may submit an online Technical Assistance Request Form at https://mli.nih.gov/mli/mlpcn/access-to-technical-assistance-of-mlpcn/tech-assistance-request-form/.

Centers can provide advice such as identification and selection of commercial HTS assay reagents, and suitable assay format and readout. In addition, the centers may be able to provide assistance in adapting assays to microplate format and in performing a pilot screen of a small library of compounds (e.g. the Library of Pharmacologically Active Compounds, LOPAC collection) to generate sufficient preliminary assay data to support a R03 grant application submission by the assay provider. Further, the potential assay providers might seek advice from the MLPCN centers about orthogonal assays to validate the hits, and advice on chemistry for improvement of the initial hits via structure-activity relationship (SAR) and other medicinal chemistry approaches. Overall, the MLPCN centers will provide needed assistance to assay submitters who are committed to preparing an adequate screening plan and grant application for the identification of small molecule probes.

Other technical resources about HTS assay development include the online comprehensive guidebook Assay Guidance Manual (http://www.ncgc.nih.gov/guidance/manual_toc.html), HTS assay protocols deposited on PubChem BioAssay data base (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pcassay), ASSAY and Drug Development Technologies, a peer-reviewed bimonthly journal, and the Journal of Biomolecular Screening, the official Journal of the Society for Biomolecular Screening.The MLPCN provides the following resources for the assays selected for implementation in this program.

2. Assay Implementation and Probe Development: The MLPCN centers will be responsible for importing, adapting and optimizing specific assays selected for implementation within the MLPCN. The first step is the creation of a Compound Probe Development Plan (CPDP, https://mli.nih.gov/mli/mlpcn/documents-definitions/) by a project team composed of the center staff, the assay submitter and an NIH Science Officer assigned to the assay project. The CPDP outlines the projected probe development path for the specific assay. The plan assigns tasks to each member of the project team and predicts appropriate benchmarks and timelines. Importantly, the CPDP defines the specific criteria that a compound must meet to be considered a probe for the project. MLPCN chemists will participate in the CPDP discussion on topics including state-of-the-art of chemical probes, probe definition, and structure-activity relationships of bioactive compounds.

In this collaborative effort, the center will be responsible for the following three operational stages:

A. Hit identification: The MLPCN Comprehensive Centers and Specialized Screening Centers will adapt, optimize and automate biochemical and cell-based assays obtained from the scientific community. It is expected that HTS assays submitted via this Solicitation Announcement will have been configured and characterized in 96-well plate format as a minimal standard, and can be rapidly adaptable to 384-well, 1536-well plate format as appropriate to the specific assay, screening approach, and level of throughput anticipated. The MLPCN will be capable of implementing assays using a variety of detection readouts such as fluorescence, luminescence, absorbance, fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), biophysical readouts, and imaging based screens. Certain types of assays requiring specialized instrumentation and facilities (e.g., multiplexed flow cytometry, ion channel assays, and biocontainment assays) may not fit well in the comprehensive center format due to their special requirements. These assays will be run by the Specialized Screening Centers.

It is anticipated that some re-configuration of primary assays used in HTS may need to be performed with the aim of optimizing parameters such as reagent preparation and consumption, choice of optimal assay readout, and automation in parallel or multiplex screening format. Such adaptation work will be accomplished through joint efforts between the submitting investigator and the MLPCN screening center that is selected to implement the assay.

B. Hit validation and prioritization: Fresh compound samples of initial hits will be selected (cherry-picked) by the MLSMR and sent to the centers for further characterization. Working with the assay provider, hits should be characterized in a hit validation assay orthogonal to that used in the primary screen. This provides additional verification that the hits are acting on the target of interest. Depending on the assay and target, the assay development/implementation and HTS cores may choose to develop counter-screens to validate the hits for the target. Hits validation screens (concentrationdependent and orthogonal screens) are the responsibility of the screening center. In addition, the MLPCN will provide cheminformatics expertise to analyze the data for correlations between compound structure and the observed biological activity (SAR analysis) and hit prioritization.

C. Hit to probe optimization: To optimize initial hits, the center staff of chemistry, assay development/ implementation, HTS, and informatics will work together with the assay provider through successive rounds of synthesis and testing of new compounds to improve the potency and selectivity of the original hits. New compounds for testing in this phase often begin with the purchase of analogs structurally related to the hit, if they are available. In many instances, a compound may not be found by purchase that meets the probe criteria defined in the CPDP. In those instances, the center will need to provide sufficient synthetic chemistry to generate a library of structurally related analogs to identify compounds of improved affinity, specificity, solubility, and cell membrane penetration. The center will perform chemical optimization until a compound is identified with the appropriate properties of a probe or determine by analysis that the structure series under investigation will be unproductive. This may involve testing anywhere from <20 to a few hundred analogs. If active compounds were provided by non-commercial sources in the scientific community, the compound provider will be invited to join the collaboration in the development of a probe.

To increase the chance for successful development of a chemical probe, the applicants may be required to perform some low- throughput secondary and tertiary screens that require special expertise of the applicants.

3. Compound Library: The Small Molecule Repository (http://mlsmr.glpg.com/MLSMR_HomePage/), has acquired a collection of 300,000 compounds in 2008 and will continue to expand up to 500,000 compounds through careful selection of both commercial and donated natural product and synthetic compounds to provide a library of diverse chemical structures of high purity (all with >90% purity, rule of 5, solubility >20ug/ml, and most importantly, QCed) that meet preset restrictions on solubility, number of reactive groups and compound size. The repository has unique compounds based on known biological targets, active ingredients of FDA approved drugs, clinical candidates, chemically diverse compounds with SAR clusters of 3-5, and natural product scaffolds. These compounds are maintained under strict storage conditions and periodically distributed to the MLPCN screening centers. The chemical structures of the compounds in the repository can be accessed at PubChem Substance at http://www.ncbi.nlm.nih.gov/sites/entrez?db=pcsubstance under MLSMR.

Material and Data Sharing

Submitting investigators will be required to provide necessary and sufficient reagents such as purified protein, cells expressing recombinant enzymes/proteins, primary and secondary antibodies, tagged peptide substrates, and available positive controls (e.g., a known inhibitor of the target).

Investigators are required to adopt uniform policies for data sharing and procedures recommended by the MLPCN committee. All data generated by the MLPCN will be deposited into PubChem upon data verification. For purposes of this policy, the term data will include, but will not be limited to, assay descriptions, protocols and/or links to published assays implemented in the MLPCN; performance data for assays and compounds; primary data from HTS and data generated in the secondary screen (e.g., EC50s, IC50s, AC50s, counter screens) chemical structures, synthesis protocols, and/or links to published synthesis protocols for chemical analogs of hits, for probes, and the biological activity of analogues and chemical probes. PubChem is a public database through which the MLPCN data will be available to all researchers, in both the public and private sectors, for further use in studying biology and disease.

Project Oversight

As part of the larger Molecular Libraries Roadmap initiative, projects that are awarded under this FOA are subject to oversight and evaluation by each of the following entities. Selection plan for assays to be implemented by the MLPCN will be developed and approved by the following committees based on scientific merit, NIH program priority and feasibility for HTS.

NIH PROJECT TEAM. The NIH Project Team will serve as the governing body that coordinates and oversees the interaction of NIH with the centers and the MLPCN Steering Committee.

MLPCN STEERING COMMITTEE. The steering committee for the overall MLPCN consists of the Director (PI) of each of the screening centers and the Small Molecule Repository, as well as NIH Program Managers and Science Officers, and will be the primary operational governing board of the MLPCN. The functions of this group include: 1) recommending the assignment and scheduling of assays and tasks, 2) developing guidelines to standardize the validation of screening data in different types of assays across centers; and 3) developing uniform procedures and policies for assay validation, data quality measures, assessment procedures, and annotation conventions for data depositions in PubChem.

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

Section II. Award Information


1. Mechanism(s) of Support

This Funding Opportunity Announcement (FOA) will use the NIH Small Research Grant (R03) award mechanism for biomedical researchers to obtain access to the MLPCN HTS and chemical optimization resources. Investigators are expected to provide required reagents that are not commercially available, travel to the screening centers and support development of chemical probes with secondary and counter-screening assays. Through its funding of the MLPCN, NIH will support the costs of assay automation, screening and optimization chemistry.

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

For specific information about the R03 programs, see: http://grants.nih.gov/grants/funding/r03.htm.

All foreign applicants must complete and submit budget requests using the Research & Related Budget component.

2. Funds Available

The total project period for this R03 application may not exceed two years. Budget for direct costs is limited to $50,000 for each award, with no more than $25,000 in direct costs in any single year. The first year budget can be applied to defray costs including reagents supply, implementation of secondary assays to remove false positives and validate biological relevance of the screening hits. The second year budget may be applied to defray costs of tertiary assays that will be used for the purpose of hit-to-probe development and probe characterizations (e.g. selectivity, specificity, cell and tissue penetration, and mechanisms of action).

The total number of R03s awarded will depend on the number of applications received and their relative scientific merit. The NIH Roadmap intends to commit approximately 4 M dollars every year from FY 2009-2012 to fund 60-100 applications annually. All awards are subject to the availability of NIH Roadmap funds.

NIH grants policies as described in the 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. 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

Number of Applications. Applicants may submit more than one application, provided each application is scientifically distinct. One application can contain parallel screens for multiple related molecular targets or cellular systems within a screening plan. However, preliminary data should be included for each target. Similarly, an assay designed for identifying both inhibitors/activators and agonists/antagonists, should include preliminary data for both objectives.

Resubmissions. Applicants may submit a resubmission application. Such application must include a one-page Introduction addressing the previous peer review critique (Summary Statement). Beginning with applications intended for the January 25, 2009 official submission due date, all original new applications (i.e., never submitted) and competing renewal applications will be permitted only a single amendment (A1). See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-09-003.html and NOT-OD-09-016 Original new and competing renewal applications that were submitted prior to January 25, 2009 will be permitted two amendments (A1 and A2). For these grandfathered applications, NIH expects that any A2 will be submitted no later than January 7, 2011, and NIH will not accept A2 applications after that date.

Renewals. The R03 is not renewable.

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, use the Apply for Grant Electronically button in this FOA or link to http://www.grants.gov/Apply/ 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 NIH eRA Commons.

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

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

Grants.gov Customer Support
Contact Center Phone: 800-518-4726
Business Hours: M-F 7:00 a.m. - 9:00 p.m. Eastern Time
Email
support@grants.gov

2) Organizational/Institutional Registration in the eRA Commons

eRA Commons Help Desk
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Business hours M-F 7:00 a.m. 8:00 p.m. Eastern Time
Email
commons@od.nih.gov

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

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 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 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

Prepare all applications using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide.

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/PIs 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 is comprised of data arranged in separate components. Some components are required, others are optional. The forms package associated with this FOA inGrants.gov/APPLY will include all applicable components, required and optional. A completed application in response to this FOA will include 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

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

Foreign Organizations (Non-domestic [non-U.S.] Entities)

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.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 (U.S.) 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 13 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 plan approach for the proposed 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, 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, and should include 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 (NoA).

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 3.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.

Applications Involving Federal Agencies

The requests from federal agencies, including the NIH intramural program, will not include any salary and related fringe benefits for career, career conditional or other federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative costs).

In general, the budget requests will be limited to the incremental costs required for carrying out the proposed work. These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. While support for extramural collaborators may be requested in a separate grant application, funds can be requested for services by an external investigator or contractor as a subcontract/consortium including the applicable indirect (F&A costs) of the contractor/collaborating institution.

Justification must be provided for all requested support and for the Federal employees who will be committed to the project although no funds are requested in the application.

Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

3. Submission Dates and Times

3.A. Submission, Review and Anticipated Start Dates
Opening Date: April 13, 2009(Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): Apr.13, 2009; Aug. 4, 2009; Dec. 4. 2009; Apr. 4, 2010; Aug. 3, 2010; Dec. 4, 2010; Apr. 4, 2011; Aug. 2, 2011; and Dec. 4, 2011.
Application Due Date(s): May 13, 2009; Sept. 4, 2009; Jan. 4. 2010; May 4, 2010; Sept. 3, 2010; Jan. 4, 2011; May 4, 2011; Sept. 2, 2011; and Jan. 4, 2012.
Peer Review Date(s): July 2009; November 2009; March 2010; July, 2010;November 2010; March 2011; July 2011;November 2011; and March 2012.
Council Review Date(s): October 2009; January 2010; May 2010; October 2010; January 2011; May 2011; October 2011; January 2012; and May 2012.
Earliest Anticipated Start Date: Nov. 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:

Yong Yao, Ph.D.
NIH Roadmap Molecular Libraries and Imaging
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Blvd, Rm 7175, MSC 9641
Bethesda, MD 20892-9641
Phone: 301-443-6102
Email: yyao@mail.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/Apply 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 due date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the due 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 weekdays (Monday Friday, excluding Federal holidays) to view the application image to determine if any further action is necessary.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Incomplete applications will not be reviewed.

There will be an acknowledgement of receipt of applications from Grants.gov and the Commons https://commons.era.nih.gov/commons/. 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 that 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 award if such costs: 1) are necessary to conduct the project, and 2) 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 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 NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.

6. Other Submission Requirements and Information

SF424 Research & Related Other Project Information

9. Facilities & Other Resources. Describe only those resources that are directly applicable to the proposed work. Provide any information describing the Other Resources available to the project and the extent to which they would be available to the project. This information is used to assess the capability of the organizational resources available to perform secondary assays, low-throughput screening of chemical analogs of hits developed by the MLPCN center, or chemical optimization efforts after the high throughput screening at the MLPCN. If appropriate, indicate previous interactions with screening centers in the MLPCN.

10. Equipment. Not applicable. Do not include an attachment here.

11. Other Attachments. If required, biosafety information for the biological material should be attached separately in line 11.

PHS398 Research Plan

Proposals for funding under this R03 mechanism are expected to include primary HTS assay, secondary hit validation assays, tertiary assays, and a plan for using identified active compounds in a follow-up research program, although innovative proposals that are limited in scope will also be considered. One research plan can contain parallel or multiplex screens for multiple related molecular targets or cellular systems within a screening campaign. However, preliminary data should be included for each target. Similarly, an assay designed for identifying inhibitors and activators respectively, should include preliminary data for both objectives.

Research plan must include the following information:

Note: Item 3 attachments of the PHS398 Research Plan component may not exceed 6 pages, including tables, graphs, figures, diagrams, and charts. Item 1 "Introduction is required only for a resubmission application and limited to one page. Item 18 Appendix may include up to three publications, manuscripts (accepted for publication), abstracts, patents, or other printed materials directly relevant to the proposed project (See NOT-OD-06-053 and NOT-OD-07-018)

The specific instructions for completing Item 3 of the Research Plan Attachments are provided below.

Item 2. Specific Aims:

Applicants may provide specific aims of the project for the identification and characterization of chemical probe within a 2-year project period. Aims may specify:

1) Primary HTS assay to be implemented in the MLPCN centers, including information on

2) Secondary assays that are crucial for the validation of biological relevance of hits generated in the primary HTS assay;

3) Tertiary assays that are crucial for the development and characterization of chemical probe, including mechanisms of action, selectivity, specificity, and other assays that are complementary to primary and secondary assays.

Item 3. Significance:

Applicants may describe in Item 3 the biological and/or therapeutic significance of the target or phenotype and potential impact of biological data and small molecule probes derived from the assay on the scientific field of study. Describe the current status of chemical probes for the target or phenotype, i.e. if a chemical probe already exists for the target protein, or if the screening data exist in PubChem BioAssay (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pcassay) for this target, or if the NIH Molecular Libraries Program has accepted the same assay for screening previously (see Funded Research listed at MLI website https://mli.nih.gov/mli/funding-opportunities/funded-assay-projects/, then justify the need to screen for chemical probes with novel or improved pharmacological attributes. The information on current state-of-the-art of chemical probes may be found by searching journal and patent databases (e.g. PubMed, PubChem, SciFinder, etc.).

For phenotypic assays with a goal to identify molecular targets implicated in the phenotypic change, applicants may describe rationales that justify performing a chemical screen vs. siRNA screen or using other genetic approaches.

Item 4. Preliminary Studies:

Applicants may provide in the Approach preliminary data obtained from both HTS and hit validation assays to demonstrate HTS readiness:

1) A description of HTS assay, including reagents and readouts. HTS assay is an assay that is configured for the purpose of HTS, which should retain signal intensity and assay sensitivity when the assay is miniaturized to an automated HTS platform with an assay volume of a few to tens of microliters. Assays developed for HTS can be roughly characterized as target-based, or pathway and phenotypic assays. A target-based assay evaluates activities of a macromolecule or a set of macromolecules in a biological preparation. A pathway/phenotypic assay measures a signal which corresponds to a complex response such as cell survival, proliferation, localization of a protein, nuclear translocation etc. The molecular target is not assumed in a phenotypic assay. Below are some examples of HTS assays: a) target-based biochemical or cellular assays that measure activities of enzymes, receptor-ligand bindings, protein-protein interactions, ion channels, transporters, nuclear receptors, and new targets emerging from genetic and proteomic research in model systems and in human diseases; b) cell- or organism- based assays that detect phenotypic changes that involve unidentified molecular targets; c) non-traditional targets of interest such as nucleic acids, protein folding, polymorphic gene products, post-transcriptional editing or splicing of gene products, and protein or RNA stabilization; and d) profiling assays of compound liabilities in metabolism, bioavailability, toxicity, tissue permeability, and solubility.

The assay detection methods may include fluorescence, luminescence, absorbance, fluorescence resonance energy transfer (FRET), time-resolved fluorescence resonance energy transfer (TR-FRET), fluorescence polarization, flow cytometric measurements, fluorescence imaging, bioluminescence resonance energy transfer (BRET), AlphaScreen, biophysical readouts, and scintillation proximity assay (SPA)). For flow cytometric detection, multiple targets can be assayed in parallel in a single HTS campaign (i.e. multiplex screening). In general, the proposed HTS assay should adopt an adequate detection principle that results in low rates of false positives and false negatives.

Note: Assays that require only addition of reagents (i.e. mix and measure or homogeneous assays) and endpoint measurements are preferable. Assays that require long-time kinetic recordings, high content imaging, multiple washing and aspiration steps, whole organism preparations, reagents of exceedingly high cost, and radioactive materials may be re-configured using alternative assay technologies to simplify the process. In this regard, the applicants may seek technical assistance by the MLPCN center staff for assay design or re-configuration prior to preparing the grant application, at https://mli.nih.gov/mli/mlpcn/access-to-technical-assistance-of-mlpcn/tech-assistance-request-form/. The necessity of implementing a complex and high-cost assay in the MLPCN centers will be examined by the peer reviewers and determined by the NIH Project Team to meet the communitys need and improve cost-benefit performance. The MLPCN centers have capabilities in implementing high content imaging based and other complex assays if needed.

2) A description of HTS assay conditions under which the preliminary data were collected, including:

3) A description of HTS assay performance: signal dynamic range, sensitivity, robustness, and hit rate, including:

Note: Assistance to perform a pilot screen against a small collection of compounds may be requested by submitting an on-line form at https://mli.nih.gov/mli/mlpcn/access-to-technical-assistance-of-mlpcn/tech-assistance-request-form/

4) A description of hit validation assays. A hit validation assay is an assay independent from the HTS assay, which is employed for the purpose of validating biological relevance of hits generated in the HTS assay. The hit validation assay should have sufficient throughput to remove false positives that act on detection system or assay reagents rather than the assumed molecular targets, pathways, or phenotypes per se. Hit validation assays include but will be not limited to the following examples:

Note: Hit validation assays that can be run in multi-well plate format (e.g. 96-, 384-, and 1536-well plate) are preferable, or required if the hit rate of the HTS assay is expected to be high. Low throughput assays that require special expertise might need to be performed in applicants laboratory or other facilities outside the MLPCN centers.

Research Design & Methods:

Primary HTS assay and secondary hit validation assays: This section may provide:

1) A recapitulation of the HTS assay and hit validation assays in the form of a step-wise protocol including reagents and assay conditions, timings and sequences to facilitate the review of assays;

2) Commercial and laboratory sources of assay reagents such as purified or crude protein reagents, cells, and dyes. Describe readiness of assay reagents if they are not commercially available, i.e., whether sufficient assay reagents will be supplied to the centers for a screening of about 500,000 compounds;

3) An estimation of the costs for commercial assay reagents. These costs should be calculated for a single well of a 96-well plate assuming an assay volume of 100 ul.

Note: All primary HTS assay and secondary hit validation assays are in principle performed in the centers. The assay submitter is expected to provide non-commercially available reagents, such as protein reagents and stable cell lines. Costs associated with the adaptation and implementation of assays within the MLPCN centers are in principle absorbed by the centers through the NIH funding of MLPCN (http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-08-005.html), including commercial reagents, multi-well plates, and dispensing tips. The centers might need to re-configure the assays in some cases to reduce the costs.

Tertiary assays: Tertiary assays may include assays that are complementary in nature to the primary HTS assay and secondary hit validation assays for the refinement of Structure Activity Relationships (SAR) and determination of Mechanisms of Action (MoA) of chemical entities. They may include, but will not be limited to selectivity assays, specificity assays, mode of action assays, and target identification assays. (a) Selectivity assays are employed to distinguish biological activities of chemical entities towards a set of closely related homologous targets (e.g. muscarinic acetylcholine receptor subtypes M1, M2, M3, M4, and M5); (b) Specificity assays are performed to distinguish biological activities of chemical entities towards orthologous targets across organism species through kingdoms (e.g. yeast vs. mammalian cell targets, parasite vs. host targets); (c) Mode of action assays (e.g. allosteric vs. othosteric, competitive vs. non-competitive); and (d) Target identification assays are conducted to determine molecular targets involved in a signaling pathway or phenotype of cells and organisms (e.g. assays in cells and organisms with different genetic background). Other tertiary assays may also be conducted for the evaluation of effects of chemical probes on cellular and tissue models pertaining to physiology or pathophysiology.

This section may provide:

1) A description of tertiary assays that are crucial for the optimization of chemical probes;

2) Availability of the tertiary assays from the laboratory or commercial sources;

3) An estimate on throughput of the tertiary assays if the assays are not adaptable to the plate format;

4) A plan to work with chemists in the MLPCN or external institutions if the assays are expected to be performed in the applicants laboratory, to ensure rapid communication of the assay data during iteration cycles of chemical modifications.

Note: Tertiary assays that can be run in multi-well plate format (e.g. 96-, 384-, and 1536-well plate) are preferable. Low throughput assays that require special expertise might need to be performed in applicants laboratory or other facilities outside the MLPCN centers.

For assays to identify unknown molecular targets involved in a signaling pathway or phenotype, please provide additional approaches available (e.g. using small molecule chemical entities as a bait to extract macromolecule binding targets, etc.).

Future Plan: Describe concisely a plan for the use of small molecule probe in a follow-up research program, either biological research or therapeutics development (e.g. tests in animal models of disease for the research).

To conclude, applicants may provide a project overview by presenting a flow chart to show the screening process or critical path leading to the identification of chemical probes. The flow chart may include all assays in sequence or in parallel and benchmarks to reach. (a) For assays with a goal to generate chemical probes of a known molecular target, this flow chart may define hit cut-off and Go/No-go criteria in terms of potency, selectivity, and specificity. (b) For signaling pathway or phenotypic assays with a goal to identify molecular targets that are involved in the signaling and phenotypic modification, this flowchart may define endpoints towards the identification of molecular targets within the 2-year project period.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value and further the advancement of the research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in the Resource Sharing section of the application (see http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.)

Data Sharing Plan: Investigators are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact (see Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.)

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. See Section VI.3., Reporting.

Guidance for Community Resources. The following data and materials generated or developed through the MLI Roadmap initiative are expected to be community resources: (1) primary data from HTS and from secondary screens; (2) protocols for assays implemented in the MLPCN; (3) the chemical structures of compounds tested in the MLPCN; and (4) the optimization chemistry protocols for probe development conducted within the MLPCN centers. In keeping with this approach, NIH expects that (1) all assays and assay protocols submitted to the NIH under this FOA, and (2) biological screening data derived from implementing the assays in the MLPCN will be made readily available and accessible, consistent with other facets of the MLI Roadmap http://grants.nih.gov/grants/guide/notice-files/NOT-RM-04-014.html.

For the MLPCN Project Team Policy on Data Sharing and IP in the MLPCN Program, see details in NIH Molecular Libraries Program Data Sharing and Intellectual Property Policy (July 2008) document.

Submitting investigators will be required to provide necessary reagents such as cells expressing recombinant enzymes/proteins, primary and secondary antibodies, tagged peptide substrates, and available positive controls (e.g. a known inhibitor of the target).

Submitting investigators and MLPCN Centers will be expected to use an unmodified version of the Material Transfer Agreement (MTA) approved by the MLPCN Steering Committee for transfer of assays and materials to the individual MLPCN Centers.

Foreign Applications (Non-domestic [non-U.S.] Entities)

Indicate how the proposed project has specific relevance to the mission and objectives of the NIH/IC and has the potential for significantly advancing the health sciences in the United States

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

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

The NIH R03 small grant is a mechanism for supporting discrete, well-defined projects that realistically can be completed in two years and that require limited levels of funding.

Applications that are complete will be evaluated for scientific and technical merit by an appropriate scientific review group(s) in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/) using the review criteria stated below.

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

The following will be considered in making funding decisions:

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

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

Significance. Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Is this assay for a novel biological target or cellular process? Does the applicant address whether or not there are known small molecule modulators for this biological target available? Is there a need for better small molecule modulators against the target? Is this class of target extensively investigated? Are there important and well-defined goals for the use of chemical probes identified with the proposed assay, either as research tools or for therapeutics development?

Investigator(s). Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Are the investigators sufficiently knowledgeable about the screening target area of science to support the collaborative screening effort and capable of advancing active compounds identified by the MLPCN? Are the investigators reasonably knowledgeable and experienced about assay development and the process of screening compound libraries? Are the investigators reasonably knowledgeable and experienced to conduct follow-up studies and further probe optimization?

Innovation. Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach. Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Is the assay well established and ready for HTS? Is the assay well designed to minimize false positives and false negatives? Is there sufficient preliminary data for assay validation? Is there an assay performance parameter calculated, such as Z-factor? Is the assay readily adaptable to an HTS format that is primarily characterized by miniaturization and automation? Is the assay reproducible? Are non-commercial reagents required for this assay? If so, how are they characterized for purity and activity, and are they readily available from the applicant(s)? Is there an adequate plan for secondary and tertiary assays to evaluate active compounds identified in the primary assays and for the generation and characterization of chemical probe?

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

Additional Review Criteria: As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

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

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials.

Vertebrate Animals. The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia.

Resubmission Applications. When reviewing a Resubmission application (formerly called an amended application), 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.

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.

Additional Review Considerations

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

Budget and Period Support. Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Select Agents 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).

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

Resource Sharing Plans. Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan (http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

Assay Cost and Workload. Reviewers will assess cost effectiveness and workload of the proposed primary and secondary assays that will be performed in the MLPCN, including choice of commercial assay reagents, assay technologies and protocols.

3. Anticipated Announcement and Award Dates

Selection of assays for the MLPCN: The following is the anticipated process for assay selection following peer review:

Recommendations of the Peer Review Committee will be communicated to the NIH MLPCN Project Team and to the MLPCN Steering Committee.

NIH MLPCN Project Team: Summary statements will be assessed and prioritization of applications will be developed that is consistent with the review results and NIH-wide programmatic priorities. The list of recommended assay applications will be presented to the MLPCN Steering Committee for implementation. The recommendations of the MLPCN Steering Committee regarding the choice and distribution of assays to specific centers will be reviewed and final assignments of these assays to specific centers will be made. The Project Team gives final approval for assay assignments to individual centers.

Program staff will be responsible for the administrative review of the plan for sharing research resources. The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant.

Submitting investigators will be required to indicate whether or not they have Material Transfer Agreements or Sponsored Research Agreements in place to use patented technology or assay reagents proposed in this application for non-commercial, research purposes. Investigators will be asked to provide documentation prior to assay being selected for implementation within the MLPCN.

MLPCN Steering Committee: HTS assay applications are selected by NIH project team and a plan for distribution of assays to specific centers within the screening centers network are developed. The plan is based on the NIH Project Team's prioritization of assays that have fared well in peer review and are acceptable for implementation. Information is also considered regarding existing capacity and expertise of each center such as assay target, cost, workload, detection system, etc.

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 the 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 ofAward (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.

The following terms and conditions will be incorporated into the NoA and will be provided to the PD/PI and the appropriate institutional official at the time of award.

Investigators are expected to collaborate with the MLPCN center, compound providers, and NIH Science Officer in the development of chemical probes and to meet their commitments, to the best of their ability, as defined in the Chemical Probe Development Plan. The collaboration begins with joint design of the Chemical Probe Development Plan which includes but is not limited to, facilitating primary HTS, implementing secondary screens, and final characterization of the chemical probe. Investigators are also expected to further characterize the chemical probe with respect to its behavior in physiological processes, cellular phenomena, and disease mechanisms in the context of biological research or therapeutics development as detailed in this FOA.

3. Reporting

Awardees will be required to submit annual Non-competing Grant Progress Report through the electronic Streamlined Non-competing Award Process (eSNAP) at http://era.nih.gov/services_for_applicants/reports_and_closeout/esnap.cfm and financial statements as required in the NIH Grants Policy Statement. In addition, a final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Awardees are expected to work together with the MLPCN centers to ensure fidelity of the data reported in Primary Screening AID, Confirmatory AID, and Summary AID on PubChem BioAssay (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pcassay). As a large amount of work is conducted in the MLPCN, awardees may need to obtain scientific input from the Center staff for the annual Progress Report to summarize the project progress and data generated in primary HTS assays, secondary hit validation assays, and tertiary assays. The MLPCN program staff will review the success of the screening campaign based on the Progress Report and the PubChem data to determine feasibility of advancing or ending the project.

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 Contacts:

Yong Yao, Ph.D.
NIH Roadmap Molecular Libraries and Imaging
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Blvd, Rm 7175, MSC 9641
Bethesda, MD 20892-9641
Phone: 301-443-6102
Email: yyao@mail.nih.gov

Christine Colvis, Ph.D
NIH Roadmap Molecular Libraries and Imaging
National Institute on Drug Abuse
6001 Executive Blvd, Room 4282, MSC 9555
Bethesda, MD 20892-9555
Telephone: (301) 443-6480
Email: ccolvis@nida.nih.gov

2. Peer Review Contacts:

George Chacko, Ph.D.
Division of Molecular and Cellular Mechanisms
Center for Scientific Review /NIH
CSR, Room 5170
6701 Rockledge Dr.
Bethesda, MD 20892
Telephone: (301) 435-1245
Email: chackoge@csr.nih.gov.

3. Financial or Grants Management Contacts:

Victoria C. Carper, MPA
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6118, MSC 9608
Bethesda, MD 20892-9604
Tel: 301-443-3858
Email: carpervictoria@mail.nih.gov

Section VIII. Other Information


Required Federal Citations

Vertebrate Animals:
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.

Human Subjects Protection:
Federal regulations (45 CFR 46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

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 institutional review board (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 impact/priority score.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/

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.

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.

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for Federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-09-116.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov/). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy, investigators funded by the NIH must submit or have submitted for them to the National Library of Medicines PubMed Central (see http://www.pubmedcentral.nih.gov/), an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made publicly available no later than 12 months after the official date of publication. The NIH Public Access Policy is available at (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html). For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

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. 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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