and Human Services (HHS)
EXPIRED
Participating Organization(s) |
National Institutes of Health (NIH) |
This Funding Opportunity Announcement (FOA) is developed as a Common Fund initiative (http://commonfund.nih.gov/) through the NIH Office of the NIH Director, Office of Strategic Coordination (http://dpcpsi.nih.gov/osc/). The FOA will be administered by the National Institute of Mental Health (NIMH) (http://www.nimh.nih.gov/index.shtml) and the National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov/) on behalf of the NIH. |
|
Funding Opportunity Title |
Assays for High Throughput Screening (HTS) to Discover Chemical Probes in the Molecular Libraries Probe Production Centers Network (MLPCN) (X01) |
Activity Code |
X01 Resource Access Award |
Announcement Type |
Reissue of PAR-08-034 |
Related Notices |
None |
Funding Opportunity Announcement (FOA) Number |
PAR-12-108 |
Companion Funding Opportunity |
NoneNNone |
Catalog of Federal Domestic Assistance (CFDA) Number(s) |
93.310 |
Funding Opportunity Purpose |
The purpose is to encourage the investigators to form collaborations with the Molecular Libraries Probe Production Centers Network (MLPCN) to implement HTS-ready assays for the discovery and development of small molecule chemical probes. Through this program, NIH wishes to stimulate research in 1) discovery and development of novel, small molecules for their potential use in studying disease treatment, and 2) discovery and/or validation of novel, biological targets that will inform studies of disease mechanisms. Emphasis will be placed on assays that provide new insight into important disease targets and processes. |
Posted Date |
February 16, 2012 |
Open Date (Earliest Submission Date) |
March 16, 2012 |
Letter of Intent Due Date |
March 16, 2012; July 16, 2012 |
Application Due Date(s) |
April 16, 2012; August 15, 2012, by 5:00 PM local time of applicant organization. |
AIDS Application Due Date(s) |
Not Applicable |
Scientific Merit Review |
June-July 2012; October-November, 2012 |
Advisory Council Review |
October 2012; January 2013 |
Earliest Start Date(s) |
December 1, 2012 |
Expiration Date |
August 16, 2012 |
Due Dates for E.O. 12372 |
Not Applicable |
Required Application Instructions
It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.
Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission
Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information
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. Through this program, NIH wishes to stimulate research in 1) discovery and development of novel, small molecules for their potential use in studying disease treatment relevant to the missions of the participating NIH Institutes, and 2) discovery and/or validation of novel, biological targets that will inform studies of disease mechanisms. Emphasis will be placed on assays that provide new insight into important disease targets and processes. For example, applications may involve emerging therapeutic targets and mechanisms for the discovery of chemical probes that may lead to further development of therapeutics or provide insight into the biology of relevant diseases.
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.
Technical Prerequisites
1. Primary HTS assay. Assays developed for HTS may be target-, pathway-, and phenotype-based assays. Some examples include: a) target-based biochemical or cellular assays that measure activities of enzymes, receptor-ligand bindings, protein-protein interactions, ion channels, transporters, nuclear receptors and other transcription factors, and other 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 may involve unidentified molecular targets; and 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. 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, scintillation proximity assay (SPA), electrophysiological assay, biophysical assay, etc. In general, the proposed HTS assay should adopt an adequate detection principle that results in a sensitive detection of even weak binders with expected low rates of false positives and false negatives. 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.
The application is expected to include preliminary data on the primary assay performance most often in microtiter plate format (96-, 384- and 1536-well plates). A scatter plot obtained from a pilot screen of a small collection of structurally diverse small molecules (e.g., NIH Clinical Collection at http://www.nihclinicalcollection.com/, LOPAC1280 at http://www.sigmaaldrich.com/chemistry/drug-discovery/validation-libraries.html, etc.) may provide an overview of the assay performance. An acceptable lower limit of Z factor is 0.5 that corresponds to a combination of Signal-to-Basal Ratio (S/B) of 4 with a Coefficient of Variation (CV) of 10%.
2. Follow-up assays. A cascade of follow-up assays need to be in place for validation of screening hits, study of Structure Activity Relationships (SAR), and determination of Mechanisms of Action (MoA) of chemical probes. The post-HTS follow-up assays include: a) an assay that is essentially an HTS assay with orthogonal detection scheme (e.g., switching light detection mode or wavelength to avoid intrinsic compound interference); b) a target-minus assay (e.g., coupling enzymes in the absence of the assay target enzyme, parental cell line without the assay target protein, etc.); c) an assay that is different in biological context and process (e.g., protein functional assay vs. protein binding assay, RT-PCR and Western assay vs. reporter gene assay, cell-based assay vs. biochemical assay, etc.); d) cytotoxicity assay; (e) target selectivity assays; (f) specificity assays to distinguish biological activities of chemical entities among orthologous targets across organism species through kingdoms (e.g., yeast vs. mammalian cell targets, parasite vs. host targets); (g) mode of action assays (e.g., allosteric vs. orthosteric, competitive vs. noncompetitive or uncompetitive); and (h) target identification assays. The assays farther downstream may also include cellular and tissue models pertaining to the relevant physiology or pathophysiology.
Resources provided by the MLPCN
The MLPCN is established as a collaborative research network 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 import, adapt and optimize specific assays selected based on the peer review for implementation within the MLPCN. The first implementation 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 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 (concentration dependent 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).
A goal of the program is to further research advancements across the scientific community as rapidly as possible. This will require synergies that can be achieved through broad sharing of research efforts in a collaborative and cooperative research environment. It will take the combined resources of researchers in the public and private sectors many years to use small molecule probes to characterize the biology of genes and proteins of interest, cellular processes, and disease processes, and then to use that information to develop products and other approaches that will improve public health. The open sharing of data, research tools, and resources will not only encourage scientific rigor in probe discovery process, but also lead more rapidly to the identification and validation of novel targets for drug discovery, and will facilitate more rapid development of therapeutics by both the private and public sectors, with resulting benefits to public health, especially for rare and neglected disorders. In order to reap the maximum benefit from this program, 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 achieving the goals of this program and 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.
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.
Funding Instrument |
Resource Access Award |
Application Types Allowed |
New The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types. |
Funds Available and Anticipated Number of Awards |
Through its funding of the MLPCN, NIH will support the costs of assay automation, screening and optimization chemistry. Investigators do not need to request funds or personnel to utilize the Resources. Applications received in response to this FOA will not receive any additional funds. Investigators are expected to provide required reagents, travel to the screening centers, and support development of chemical probes with secondary and tertiary assays. The total number of X01s awarded will depend on the number of applications received, their relative scientific merit and the existing capacity and expertise of the MLPCN. |
Award Budget |
The total project period for an application submitted in response to this program announcement may not exceed 1 year. |
Award Project Period |
1 year |
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.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
For-Profit Organizations
Governments
Other
Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.
Applicant organizations must complete the following registrations
as described in the SF 424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
registrations.
All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.
All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least 4-6 weeks prior to the application due date.
Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.
For institutions/organizations proposing multiple PD(s)/PI(s), visit the Multiple
Program Director(s)/Principal Investigator(s) Policy and submission details in
the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R)
Application Guide.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed. Resubmission applications may be submitted, according to the NIH Policy on Resubmission Applications from the SF 424 (R&R) Application Guide.
Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.
It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
Yong Yao, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7175, MSC 9641
Bethesda, MD 20892-9641
Telephone: 301-443-6102
Email: [email protected]
The forms package associated with this FOA includes all applicable components, mandatory and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed,
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Resource Sharing Plan
Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies(GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modifications:
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 achieving the goals of this program and 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.
Appendix
Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
Foreign (non-US) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.
Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.
Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.
Applicants are responsible for viewing their application in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.
Important
reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the
Credential field of the Senior/Key Person Profile Component of the SF
424(R&R) Application Package. Failure to register in the Commons and
to include a valid PD/PI Commons ID in the credential field will prevent the
successful submission of an electronic application to NIH.
The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the Central Contractor Registration (CCR). Additional
information may be found in the SF424 (R&R) Application Guide.
See more
tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115,
Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.
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 review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
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? Are there important and well-defined goals for the use of chemical probes identified with the proposed assays, either as research tools or for therapeutics development?
Investigator(s)
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Are the investigators reasonably knowledgeable and experienced about the biological target area of science? Are the investigators reasonably knowledgeable and experienced about assay implementation and the process of screening compound libraries? Are the investigators reasonably knowledgeable and experienced to conduct follow-up assays to validate screening hits? Are the investigators reasonably knowledgeable to examine non-specific chemical reactivity and interference of compounds?
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? Is this assay project for a novel biological target or cellular process? Does the application address whether or not known small molecule modulators are available for this biological target? Is there a need for better small molecule modulators against the target or cellular process? Will the innovation in assay design and compound assembly lead to better success likelihood of the screening?
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?
If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?
Is the HTS assay well designed to minimize false positives and false negatives? Is the preliminary data sufficient to support assay readiness for HTS? Is an assay performance parameter calculated, such as Z'-factor? 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? Are there adequate data and plan for secondary and tertiary follow-up assays to evaluate active compounds identified in the primary assays?
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?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, 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. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.
Inclusion of Women, Minorities, and Children
When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.
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. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Biohazards
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
Resubmissions
Not Applicable
Renewals
Not Applicable
Revisions
Not Applicable
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.
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.
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS). An accepted 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 data sharing plans.
Budget and Period of Support
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review (CSR), in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.
As part of the scientific peer review, all applications:
Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate National Advisory Council or Board. The following will be considered in making funding decisions:
After the peer review of the application is completed, the PD(s)/PI(s) will be able to access his or her Summary Statement (written critique) via the eRA Commons.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. 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.
Any application awarded in response to this FOA will be subject to the DUNS,
CCR Registration, and Transparency Act requirements as noted on the Award
Conditions and Information for NIH Grants website.
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. More information is provided at Award Conditions and Information for NIH Grants.
Cooperative Agreement Terms and Conditions of Award
Not Applicable.
When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.
A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.
Grants.gov
Customer Support (Questions regarding Grants.gov registration and
submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: [email protected]
GrantsInfo (Questions regarding application instructions and
process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]
eRA Commons Help Desk (Questions regarding eRA Commons
registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: [email protected]
Yong Yao, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: (301) 443-6102
Email: [email protected]
J. Thomas Peterson, Ph.D.
Center for Scientific Review (CSR)
Telephone: (301) 408-9694
Email: [email protected]
Not Applicable
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
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.
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NIH Funding Opportunities and Notices
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