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-06-545 which was previously released September 7, 2006.

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 weeks prior to the grant submission date.  See Section IV.

Program Announcement (PA) Number: PAR-08-035

Catalog of Federal Domestic Assistance Number(s)
93.310

Key Dates
Release/Posted Date: November 30, 2007
Opening Date:  December 30, 2007 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): Dec. 30, 2007; Apr. 23, 2008; Aug. 26, 2008; Dec. 23, 2008; Apr. 22, 2009; Aug. 24, 2009; Dec. 26, 2009; Apr. 26, 2010; and Aug. 24, 2010
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): Jan. 30, 2008; May 23, 2008; Sept. 26, 2008; Jan. 23, 2009; May 22, 2009; Sept. 24, 2009; Jan. 26, 2010; May 26, 2010; and Sept. 24, 2010.  
Review Date(s): March-April 2008; July-August 2008; November-December 2008; March-April 2009; July-August 2009; November-December 2009; March-April 2010; July-August, 2010;  and November-December 2010.
Council Review Date(s): May 2008; October 2008; January 2009; May 2009; October 2009; January 2010; May 2010; October 2010; and January 2011.  
Earliest Anticipated Start Date: July 1, 2008
Additional Information To Be Available Date (Activation Date): Not Applicable
Expiration Date: New Date March 14, 2009 (per issuance of PAR-09-129) Original Date: September 25, 2010

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
  A. Cooperative Agreement Terms and Conditions of Award
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), now administered by the NIH Office of Portfolio Analysis and Strategic Initiatives (OPASI), is committed to a major effort to broaden access to high-throughput screening (HTS) technologies, and the information produced by these approaches, for researchers in academia, government, and non-profit institutions.  The NIH Molecular Libraries and Imaging Roadmap initiative launched the Molecular Libraries Screening Centers Network (MLSCN) on June 15, 2005, which aims to enable the rapid transformation of new scientific knowledge into tangible benefits for public health.  During the pilot phase, the MLSCN has implemented a diverse array of HTS assays, developed the capacity to conduct nearly 150 assay campaigns per year against a library of 200,000 compounds, and generated over 10 million data points in PubChem.  The HTS screening data from the MLSCN assays, including functional and pharmacologic selectivity data, are deposited into an open access database, PubChem http://pubchem.ncbi.nlm.nih.gov/.  The assays screened to date span a variety of target classes (e.g. GPCRs, ion channels, transporters, enzymes, kinases, protein-protein interactions, cell phenotypes, and model organisms) in under-studied areas of disease. Chemical probes have been developed for a number of targets (http://mli.nih.gov/mlscn/screening-centers/).  Over time, the use of the shared library by the MLSCN should provide extensive biological annotation, generating a unique and rich dataset available in the public domain.  This MLSCN effort has been empowering multi-disciplinary academic teams to discover small molecule tools that can be used in basic biological and biomedical studies.  Descriptions of the ten network screening centers and their capabilities are available at http://mli.nih.gov/mlscn/

In the production phase, the Molecular Libraries Screening Centers Network (MLSCN) will become the Molecular Libraries Probe Production Centers Network (MLPCN) on July 1, 2008 with the emphasis on probe discovery and development.  The MLPCN will continue to offer the research community an opportunity to leverage biology and chemistry resources to identify small molecule probes for innovative or challenging targets with the potential for insight into biological pathways that impact public health. It is anticipated that the MLPCN will perform high-throughput screening (HTS) of > 100 biochemical or cell-based assays solicited from the scientific community against a high quality library of >300,000 compounds maintained in a shared repository (expanding up to 500,000 with 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; all with >90% purity, >10mg, ± rule of 5, solubility >20ug/ml, and most importantly, QCed).  The network provides synthetic chemistry to optimize "hits" identified in the initial screening to produce chemical probes that can be used for in vitro studies to interrogate the targets or phenotypes studied in the assays. 

The MLPCN will be 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 that may not be amenable to HTS (e.g., high content screening, phenotypic assays, ion channel screening, whole organism 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. The integration of the probe pipeline, center cores and the overlapping roles of the comprehensive and specialized screening centers can be seen under “Center Infrastructure” at http://mli.nih.gov/funding-2/.

HTS assays will be selected for implementation in the MLPCN from those submitted by the research community in response to this FOA or the FOA that solicits applications for the MLPCN under the X01 Resource Access mechanism.  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), RFA-RM-07-008.

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), PubChem, 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 to the extent resources allow, HTS hits, the active compounds identified through initial screening, will be developed through optimization chemistry and further screening 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.  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.

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

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 and information on biological activities of small molecules.  The goal of the MLPCN is to implement a variety of innovative biological, biophysical 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.

This FOA provides an opportunity to identify compounds that regulate proteins and pathways of interest to the research community.  Investigators interested in identifying active compounds in their biochemical and cellular assays and in developing chemical probes useful to the broader scientific community should submit a proposal for access to the screening, informatics and synthetic chemistry resources provided by the MLPCN.  The proposal must provide a description of a well-developed assay that can be automated for HTS and a systematic plan, including secondary and counter-screening assays, for evaluating active compounds identified in the primary HTS.  The proposal should also include a strategy for further testing, in collaboration with the MLPCN center and compound providers, to provide a final refinement in structure and function of the active compounds leading to the optimum chemical probe.

Capabilities of the MLPCN

The MLPCN will be 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.  It is envisioned that each center will bring 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/implementation, HTS, informatics, structure-activity relationships (SAR)/cheminformatics and chemistry).

The MLPCN will provide the following capabilities for those assays selected for implementation in this program.

1. Assay Implementation: The MLPCN Comprehensive Centers and Specialized Screening Centers will adapt, optimize and automate existing target-based and cell-based phenotypic 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 absorbance, fluorescence, luminescence, fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), biophysical readouts, and cell based imaging screens.  Certain types of assays requiring multiple steps or specialized instrumentation (e.g. phenotypic imaging assays, multiplexed flow cytometry, ion channel assays) may not fit well in the comprehensive center format due to their special requirements and slower screening rates.  These more difficult assays will be run by the Specialized Screening Centers, which will be smaller in scope, but similarly expected to apply novelty and innovation to specific types of assays or platforms.

Assays accepted by the MLPCN screening centers should be rapidly adaptable to HTS formats employed by the MLPCN with reasonable effort.  However, 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.  HTS assay projects include those directed towards novel proteins, cellular phenotypes, biological functions, and disease mechanisms solicited from the research community.  Descriptions of the funded assay projects are available at http://mli.nih.gov/funded-research/assay-solicitation/.

2. Compound Library: The Small Molecule Repository, with 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, is expected to have 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, QC’ed) that meet preset restrictions on solubility, number of reactive groups and compound size.  The repository will maintain these compounds under strict storage conditions and periodically distribute them to the MLPCN screening centers.  The chemical structures of the compounds in the repository can be accessed at PubChem Substance under MLSMR. 

3. HTS Screening: 1). To identify and confirm HTS hits, the MLPCN performs high-throughput screening (HTS) of biochemical or cell-based assays solicited from the scientific community against a high quality library of 300,000-500,000 compounds maintained in a shared repository.  The MLPCN is capable of  implementing cell-based, biochemical, protein-protein interactions, and some model organism assays using a diverse set of screening platform technologies (e.g. ultra HTS, cell based imaging, and flow cytometry) and detection systems (such as luminescence, fluorescence, FLIPR, FRET, SPA, absorbance, ELISA, microscopy-based imaging, and small molecule microarray); 2). To develop a probe, the MLPCN center will work closely with the assay provider to define secondary assays used to verify these hits and identify false-positives. Collaboration among the assay provider, MLPCN biologists, and chemists has been essential for development of a critical path work plan for progressing from assay to probe.  Screening data from both primary and secondary assays performed by the MLPCN will be deposited in PubChem BioAssay under the Depositor Category, “Molecular Libraries Probe Production Centers Network”.

4. Optimization Chemistry: Although the primary goal of the MLPCN is the identification and development of novel chemical probes, the MLPCN cannot guarantee that every assay will lead to discovery of a chemical probe.  Following hit verification, the assay provider, compound provider, MLPCN screening center and NIH Science Officer will work as a team to define the best course of action to optimize the initial hits.  The MLPCN will provide cheminformatics and optimization chemistry to produce analogues of initial hit compounds to identify a chemical probe demonstrating the best properties of potency, specificity and solubility.

5. HTS Informatics: The MLPCN will provide informatics support to track compounds, assays, and screening data.  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. Any users of the data deposited into PubChem will be required to acknowledge the source of the data.

Guidance for HTS Assay Application

HTS is rapid screening of a large number of compounds in a biological assay.  Through a combination of modern robotics, data processing and control software, liquid handling devices, and sensitive detectors, HTS allows a researcher to effectively conduct millions of biochemical, genetic or pharmacological tests in a short period of time.  Through this process one can rapidly identify active compounds which modulate a particular biomolecular pathway.  The results of these experiments provide starting points for understanding the interaction or role of a particular biochemical process in biology. Assay applications will be evaluated in terms of the following characteristics:

1. Readiness for or adaptability to HTS: HTS assays are primarily characterized by miniaturization and automation, and are usually conducted in microtiter plates, such as 96-well, 384-well or 1536-well plates. Assays submitted for HTS should be well established and characterized.  If achievable, assays should have simple procedures readily adaptable to automation. Steps such as centrifugation, filtration and extraction should be avoided.  Homogeneous, i.e. “mix and measure,” assays are preferable.  However, some assays requiring multiple steps or specialized instrumentation (e.g. phenotypic imaging assays, multiplexed flow cytometry, ion channel assays) may fit well with Specialized Screening Centers format due to their specialized instrumentations.

2. Assay performance and robustness: Performance characteristics of an assay should be suitable and reliable for automated HTS.  Assays should be robust, reproducible and meet minimum statistical thresholds for robotic screening.  Robustness is a measure of the capacity of the assay to remain unaffected by small changes in method parameters and provides an indication of its reliability during normal run conditions.  The Z’-factor, a calculated parameter, is commonly used to quantify assay performance, and it accounts for both the signal-to-background and the amount of variability in the assay.  Assays with Z’ parameters >0.5 are typically HTS compatible assays.  The coefficient of variation (CV) determined from the entire sample and control wells of the microtiter plate should not exceed 10%.  Reproducibility between plates and day-to-day experiments also provides useful information on how well the assay will perform.

3. Diversity of assay types: Assays developed for HTS can be roughly characterized as target-based or phenotypic assays.  A biological target is a macromolecule or a set of macromolecules in a biochemical pathway. Phenotypic assays measure 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.

The following are some examples of HTS assays: 1) target-based biochemical assays may include enzymatic assays (such as kinases, proteases and transferases), and receptor-ligand binding assays such as those for G-protein coupled receptors (GPCRs), orphan GPCRs, ion channels, transporters, nuclear receptors, and new targets emerging from genetic and proteomic research in model systems and in human diseases; 2) cell-based assays could include functional assays, reporter gene assays and phenotypic assays for cellular processes and pathway analysis (e.g., viability assays for proliferation or apoptosis); 3) non-traditional targets of interest include transcription factors, nucleic acids, multimeric proteins, membrane proteins, and polymorphic gene products; and subcellular processes such as molecular trafficking and translocation, post-transcriptional editing or splicing of gene products, and protein or RNA stabilization; and 4) other assays of interest include those for metabolism, bioavailability, cytotoxicity, tissue permeability and compound solubility.

To learn more about HTS assay development, please refer to the online comprehensive guidebook “Guidance for Assay Development and HTS”. Additional resources include: the “ASSAY and Drug Development Technologies”, a peer-reviewed bimonthly journal that publishes articles, papers, and editorial commentary that emphasize early-stage screening techniques including assay design, target development, high throughput technologies, and the Journal of Biomolecular Screening, the official Journal of the Society for Biomolecular Screening.

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.

For the MLPCN Project Team Policy on Data Sharing and IP in the MLPCN Program, see http://mli.nih.gov/wp-content/uploads/data-sharing-and-ip.pdf. See details of NIH data sharing guidance http://grants1.nih.gov/grants/guide/notice-files/NOT-RM-04-014.html

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 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. Competing renewal (formerly “competing continuation”) applications will not be accepted for the R03 grant mechanism. Small grant support may not be used for thesis or dissertation research. Up to two resubmissions (formerly “revisions/amendments") of a previously reviewed small grant application may be submitted. See NOT-OD-05-046, April 29, 2005. 

2. Funds Available

Budgets for total costs are limited to $25,000 for each award and the project period is limited to one year with one year no-cost extension. Total costs include direct and facilities and administrative (F&A) cost.

Up to 12 months no-cost extension may be requested by the applicants without additional funds to extend a grant's project period in order to complete probe development.

The total number of R03s awarded will depend on the number of applications received and their relative scientific merit.  The earliest possible start date for applications submitted in response to this FOA is July 1, 2008.

The NIH Roadmap intends to commit approximately 2.5 M dollars every year from FY 2008-2011 to fund 100 applications annually. All awards are subject to the availability of NIH Roadmap funds.

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.

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 with the skills, knowledge, and resources necessary to carry out the proposed research as the Project Director/Principal Investigator (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

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.

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/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 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 Started

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 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 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 is comprised of data arranged in separate components. Some components are required, others are optional. The forms package associated with this FOA in Grants.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
Research & Related Budget

PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist 

Optional Components:

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

Note: While both budget components are included in the SF424 (R&R) forms package, for this R03 use the detailed Research & Related Budget.

SPECIAL INSTRUCTIONS  

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 Cover Page Supplement

2. Human Subjects. Check “no” to both the Clinical Trial and Agency-Defined Phase III Clinical Trial questions.

4. Human Embryonic Stem Cells. Check “no”. (Check “yes” only when applicable).

PHS398 Research Plan

Screening projects proposed under this PAR should be aimed at the development of pharmacological tools to explore cellular and physiological function. Investigators are asked to state a question from their ongoing research that would be appropriately addressed through the use of a pharmacological probe.  Further, investigators are asked to identify the requisite attributes of this probe, and outline a screening plan of assays that would help them to find chemical small molecule structures possessing these attributes in a HTS of chemical small molecule libraries.   

Proposals for funding under this R03 mechanism are expected to include primary HTS assays, secondary 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 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 inhibitors/activators or agonists/antagonists, should include preliminary data for both objectives.

Research plan must include the following information:

Specifically, the MLPCN centers will be responsible for importing, adapting and optimizing specific assays selected for implementation within the MLPCN.  The first step in implementing an assay is the creation of a Compound Probe Development Plan (CPDP) by a project team composed of center staff, the assay provider and an NIH Network 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 milestones and timelines.  Importantly, the CPDP defines the specific criteria that a compound must meet to be considered a probe for the project. If the CPDP involves SAR around a chemotype/structural series contributed to the MLSMR by a non-commercial compound provider, the chemist(s) should be included in the CPDP hit optimization plan. 

In this collaborative effort, the center will need to provide sufficient synthetic chemistry to generate a library of structurally related analogs to identify compounds of improved affinity, specificity and solubility. The center should be expected to continue hit optimization until a compound is identified with the properties defined in the CPDP (~20-300 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.

The following section contains the specific instructions for completing the research plan for these R03 applications.  Page limitation for Research Plan: 10 pages single-spaced (excluding appendices). The PHS 398 Research Plan Component includes:            

A. Specific Aims: This section should contain the rationale for probe development for the biological target or phenotype of the HTS.  Aims should cover the collaboration with the MLPCN on implementing the primary assay, secondary assay, counter screen for selectivity if appropriate and collaboration with the MLPCN center for chemical probe optimization.  Describe a future plan for the use of the hits or small molecule probe in a follow-up research program, either biological research or therapeutics development.

B. Background and Significance: Describe the biological significance of the target or phenotype and potential impact of biological data and small molecule probes derived from the HTS 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 for this target, or if the NIH has accepted the same assay for screening previously, then justify the reason for development more chemical probes.  This information can be found by performing a text search in PubChem in the “PubChem Bioassay” database found in the dropdown menu at http://pubchem.ncbi.nlm.nih.gov/ and “Funded Research” listed at MLI website http://mli.nih.gov/funded-research/assay-solicitation/.

C. Preliminary Studies: Provide data and information on assay performance, quality controls, responses to pharmacological standards or other control conditions, feasibility for miniaturization and automation for HTS, tolerance to the effect of DMSO, reagent availability, reagent stability, etc.

D. Research Design & Methods:

Primary assay: Provide a detailed assay procedure for the primary assay, i.e. assay performed in a testing scheme to identify biologically active chemical entities in a screening mode. Include sources of specific materials such as purified or crude biochemical reagents or cells and the microtiter plate well density (e.g., 96-, 384- or 1536-well) and plate composition (e.g., clear bottom black or clear bottom polystyrene, etc.).  Specify reagents, software, and instrumentation used to measure response or output. (e.g. fluorescence polarization or radiometric counting).  The proposed assay should demonstrate highly robust and reproducible behavior in a 96-well or higher density format (e.g., 384- or 1536-well plates). Generally, the assay protocol should demonstrate: 1) a signal of sufficient intensity that it can be easily measured from a microtitre plate in low volume, 2) a signal-to-background ratio of at least 5 and a coefficient of variation (CV) below 10% determined from measurements across the entire plate (these factors are typically expressed as the statistical parameter, Z', which has an acceptable lower limit of 0.5), 3) reproducible, dose-dependent responses to pharmacological standards or other control conditions, 4) tolerance to the effect of DMSO at 0.1-1%. Between-plate and day-to-day variations also provide useful information on how well the assay will perform, as will the determination of reagent stability to storage and assay conditions.  The assay plan should include demonstration of selectivity and reproducibility of response to a small but diverse collection of at least several hundred compounds, such as a collection of FDA approved drugs or other bioactive molecules.

Cost estimation: Estimate the costs of reagents that are commercially available. These costs should be calculated for a single well of a 96-well plate assuming an assay volume of 200 ul.

Secondary assays: Provide an available confirmatory assay that should use a different readout than the primary assay to confirm hits and eliminate false positives.  Provide a systematic process or a typical screening cascade to be used for evaluating the significance of active compounds identified in primary HTS, including descriptions of the secondary and counter-screening assays to assess selectivity or specificity.  Selectivity assays are employed to elucidate the specificity of biologically active chemical entities towards a set of closely related targets.  Counter-screening is to eliminate those active compounds that may also possess undesirable properties.

A plan to collaborate with the MLPCN center:  To increase the chance for successful development of a chemical probe, a collaboration should be formed between the assay provider, MLPCN screening center, compound providers and NIH Science Officers.  Describe an optimization plan that can benefit from the resources provided by the collaborators to advance hits to a chemical probe.  The submitting investigators may be required to perform the following activities, including, but not limited to, facilitating the primary HTS, implementing secondary screens, and characterizing the final chemical probe(s).

Future Plans:  Describe a plan for further chemical development if a probe is identified or developed within the MLPCN.  Describe the intended use of the probe.  Applications proposing a phenotypic assay should describe the approach to be used to identify the target of the probe.

17. Resource Sharing plan (s): Describe material(s) to be provided to the screening center. Submitting investigators will be required to prepare and 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).  Indicate if any reagents are proprietary and if so, if there are Material Transfer Agreements in place to use the proprietary reagents within the MLPCN if the assay is selected for implementation.

18. Appendix: The 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).

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.

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.

Preliminary data, particularly for primary assays, are required for R03 applications in response to this FOA:

This NIH R03 small grant is to support discrete, well-defined assay projects that realistically can be screened by the MLPCN centers and that require limited levels of funding.   Because the Research Plan component is restricted to 10 pages, the PI/PDs should put emphasis on methodological details and certain indicators used in evaluating the performance of the assays including supportive preliminary data. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or from investigator-generated data. 

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

See Section IV.3.A for details.

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

Opening Date:  December 30, 2007 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): Dec. 30, 2007; Apr. 23, 2008; Aug. 26, 2008; Dec. 23, 2008; Apr. 22, 2009; Aug. 24, 2009; Dec. 26. 2009; Apr. 26, 2010; and Aug. 24, 2010
Application Submission/Receipt Date(s): Jan. 30, 2008; May 23, 2008; Sept. 26, 2008; Jan. 23, 2009; May 22, 2009; Sept. 24, 2009; Jan. 26. 2010; May 26, 2010; and Sept. 24, 2010.  
Peer Review Date(s): March-April 2008; July-August 2008; November-December 2008; March-April 2009; July-August 2009; November-December 2009; March-April 2010; July-August, 2010;  and November-December 2010.
Council Review Date(s): May 2008; October 2008; January 2009; May 2009; October 2009; January 2010; May 2010; October 2010; and January 2011.  
Earliest Anticipated Start Date: July 1, 2008

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:

Ingrid Li, Ph.D.
NIH Molecular Libraries & Imaging Roadmap.
National Institute of Mental Health/NIH/DHHS
Street Address
6001 Executive Boulevard, Room 7192, MSC 9641
Bethesda, MD 20892-9641
Telephone: (301) 443-7099
FAX: (301) 402-4740
Email: ili1@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 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 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. 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.

Allowable Costs: Investigators are expected to provide required reagents, travel to the screening centers and support development of chemical probes with secondary and counter-screening assays.  Budgeting travel for a brief visit to the collaborating center is recommended for setting up the primary and the secondary assays. 

Equipment purchase is not an allowable cost.  Through its funding of the MLPCN (RFA-RM-08-005), NIH will support the costs of assay automation, screening and optimization chemistry.  A related Program Announcement is available to support early stage HTS assay development through the Molecular Libraries Roadmap.  For more information on the assay development opportunities, contact the “Scientific/Research Contacts” listed in section VII.1 of this announcement.

6. Other Submission Requirements

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

The NIH requires the PD/PI 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. 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 “Registration FAQs – Important Tips -- Electronic Submission of Grant Applications.”

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.”

Warning: Please be sure that you observe the direct cost, project period, and page number limitations specified above for this FOA.  Application processing may be delayed or the application may be rejected if it does not comply with these requirements.

PHS398 Research Plan Component Sections

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 requirements for R03 applications:

All application instructions outlined in the SF424 (R&R) Application Guide (MS Word or PDF) are to be followed, with the following requirements for R03 applications:

Appendix Materials

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 these limitations may be delayed in the review process.

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

Plan for Sharing Research Data

All applicants must include a plan for sharing research data in their application. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will 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.

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.”

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

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization and by NIH Project Team staff when making recommendations about selecting assays for implementation within the MLPCN.

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.

Section V. Application Review Information


1. Criteria (Update: Enhanced review criteria have been issued for the evaluation of research applications received for potential FY2010 funding and thereafter - see NOT-OD-09-025).  

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

2. Review and Selection Process

Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened by an appropriate review group convened by Center for Scientific Review (CSR) in accordance with the review criteria stated below.

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

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.  For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

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?  Is this assay for a novel biological target or cellular process? Is there no known small molecule modulator for this biological target available? Is there a need for better small molecule modulators against the target? Is this class of target extensively investigated? Is there an adequate plan for evaluating the activities of the compounds identified in a high throughput screen, e.g., in secondary screens and functional assays? Are there important and well-defined goals for the use of small molecule compounds identified with the proposed assay, either as research tools or for therapeutics development?

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? Is the assay well established and ready for HTS? Is the assay pharmacologically validated? Is there sufficient preliminary data for assay validation? Is there an assay performance parameter calculated, such as Z-factor? Is the assay readily adaptable by screening centers to an HTS format that is primarily characterized by miniaturization and automation? Is the assay feasible and reproducible, and does it and meet minimum statistical thresholds for robotic screening? Are non-commercial reagents needed for this assay?  If so, how are they characterized for purity, activity, etc?  Is there an adequate plan for providing non-commercial assay reagents? Are the assay reagents readily available from the applicant(s) if reagents cannot be commercially supplied? What is the cost per well for commercially available reagents? Is there an adequate plan for secondary assays to evaluate active compounds identified in the primary assays? For applications designating multiple PDs/PIs, does the Leadership Plan ensure that there will be sufficient coordination and communication among the PDs/PIs?  Are the administrative plans for the management of the research project appropriate, including plans for resolving conflicts? 

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?   

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)? Are the investigators sufficiently knowledgeable about the target and 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?

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. The presence of a data sharing plan will be part of the terms and conditions of the award. Program staff of the funding organization and NIH Project Team staff 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 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.

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.

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 his/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.

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

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 Contacts:

Ingrid Li, Ph.D
NIH Molecular Libraries & Imaging Roadmap.
National Institute of Mental Health/NIH/DHHS
6001 Executive Blvd, Room 7192, MSC 9641
Bethesda, MD 20892-9641
Telephone: (301) 443-7099
Email: ili1@mail.nih.gov

Christine Colvis, Ph.D
NIH Molecular Libraries & Imaging Roadmap.
National Institute on Drug Abuse
6001 Executive Blvd, Room 4282, MSC 9555
Bethesda, MD 20892-9555
Telephone: (301) 435-1323
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

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.

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-02-005.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. Applications that do not provide this information will be returned without review.

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.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.



Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.