Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Mental Health (NIMH) National Institute on Alcohol Abuse and Alcoholism (NIAAA) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) National Institute on Drug Abuse (NIDA) National Center for Advancing Translational Sciences (NCATS)
Funding Opportunity Title	High Throughput Screening (HTS) to Discover Chemical Probes (X01)
Activity Code	X01 Resource Access Award
Announcement Type	New
Related Notices	June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same. August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications. May 30, 2013 (NOT-OD-13-074) - NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013.
Funding Opportunity Announcement (FOA) Number	PAR-13-134
Companion Funding Opportunity	PAR-14-283, R21 Exploratory/Developmental Research Grant PAR-14-284, R01 Research Project Grant PAR-13-135, R03 Small Grant Program PAR-12-058, R01 Research Project Grant PAR-12-059, R21 Exploratory/Developmental Research Grant
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.242, 93.273, 93.865, 93.279, 93.350
Funding Opportunity Purpose	This Resource Access Opportunity 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 announcement encourages partnership between assay submitters and a funded High Throughput Screening (HTS)/chemical probe discovery facility to conduct the joint research. Through this announcement, 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 Centers, 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	March 6, 2013
Open Date (Earliest Submission Date)	March 4, 2013
Letter of Intent Due Date(s)	30 days before the application due date
Application Due Date(s)	August 6, 2013; December 4, 2013 April 4, 2014; August 6, 2014; December 4, 2014 April 3, 2015; August 6, 2015; December 4, 2015, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	July, November, February annually
Advisory Council Review	October, January, May annually
Earliest Start Date	December, April, July annually
Expiration Date	December 5, 2015
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (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

Recent technological innovations in high throughput screening (HTS), chemical synthesis, and cheminformatics have allowed rapid discovery of novel, small-molecule probes for the study of disease related biological processes and mechanisms in academic environments. This provides an unprecedented opportunity for investigators to translate knowledge about diseases into tangible tools for translational research. This announcement aims to encourage investigators to form collaborations with a funded HTS/chemical probe discovery facility that has the requisite resource to implement an HTS-ready assay for the discovery and development of small molecule chemical probes. Through this announcement, 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.

The FOA will provide applicants who have established a partnership with an HTS/chemical probe discovery facility with a diverse small molecule library, resources, and capacity to support a joint research collaboration to discover chemical probes (e.g., the NIH Chemical Genomics Center), with access to NIH resources for HTS/chemical probe discovery at no cost. The X01 mechanism may be suitable for the investigators who seek to access the Center's resources at no-cost and no additional funding (e.g., those of NIH intramural labs, disease foundations, private industries, etc.).

Investigators who are interested in seeking funds to support the HTS/chemical probe discovery facility are encouraged to apply under PAR-12-058, PAR-12-059, and PAR-12-060.

Investigators who are interested in seeking funds to partner with HTS screening facilities to discover chemical probes are encouraged to apply under PAR-13-135 (R03).

Note: For investigators in the infectious diseases field, the Division of Microbiology and Infectious Diseases (DMID), a component of the National Institute of Allergy and Infectious Diseases (NIAID), would encourage the investigators to access a comprehensive set of preclinical services as listed: http://www.niaid.nih.gov/LABSANDRESOURCES/RESOURCES/DMID/Pages/default.aspx.

The research scope may encompass:

1. HTS implementation. The proposed screening facility should have the capability to optimize and automate biochemical-, cellular-, or whole organism-based assays to screen a large library of compounds with adequate diversity and representation of chemical space. The projects submitted to this announcement are expected to already have an implementable HTS assay and a large collection of compounds to be screened. Some assay adaptation may be performed with the aim of optimizing parameters such as reagent preparation/consumption, assay readout, and automation in parallel or multiplex screening format. Such adaptation work will be accomplished through a joint effort between the assay submitting investigator and the proposed screening facility responsible for implementing the assays. Some complementary research including biology-oriented chemical synthesis of screening compounds and virtual screening may also be conducted to improve the screening success likelihood.

2. Hit validation. When HTS is complete, fresh compound samples of initial hits will be selected (cherry-picked) for further confirmation. The investigators will implement secondary assays that are orthogonal to the primary assay to remove false positives. This provides additional verification that the hits are acting on the target/pathway of interest. In addition, the investigators will conduct advanced cheminformatics analysis and medicinal chemistry inspection to prioritize the hit set. It is expected that the investigators will test powder samples of hit compounds and commercially available analog compounds during the hit validation stage. Investigators should verify the structure of hits using a combination of analytical methods and, if possible, re-synthesis of select hits. Additional follow-up assays may also be conducted to characterize mode and mechanism of action of the validated hits.

3. Hit-to-probe optimization: To optimize initial screening hits, the chemists at the HTS/chemical probe discovery facility will work together with the assay provider through iterative cycles of synthesis and testing of new compounds to improve properties such as potency and selectivity. New compounds for testing during 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 desired probe criteria. In those instances, the HTS/chemical probe discovery facility needs 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 HTS/chemical probe discovery facility 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. 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.

For the preparation of a grant submission, the screening facility may provide advice such as identification and selection of commercial HTS assay reagents, and suitable HTS assay format and readout. In addition, the screening laboratory may be able to provide assistance in adapting assays to an HTS format (e.g., 1536-well or 384-well microplate) and performing a pilot screen of a small library of compounds (e.g., the Library of Pharmacologically Active Compounds (LOPAC) collection, the NIH Clinical Collection, etc.) to generate sufficient preliminary assay data to support a grant application submission. Further, the researchers might seek advice from the screening laboratory about orthogonal assays to validate the screening hits, and advice on chemical improvement of the initial hits via structure-activity relationship (SAR) study.

Other technical resources about HTS assay development include the online comprehensive guidebook Assay Guidance Manual, HTS assay protocols deposited on PubChem BioAssay data base, ASSAY and Drug Development Technologies, a peer-reviewed bimonthly journal, and the Journal of Biomolecular Screening.

1. Compound collection. A large library of compounds (e.g., NIH Molecular Libraries Small Molecule Repository collection) should be used for HTS to cover adequate chemical space. In certain cases, it may be advantageous to utilize focused libraries of compounds with specific considerations for the assay targets, privileged scaffolds, representative diversity sets, drug repurposing, and/or the ease of follow-up synthetic chemistry for SAR expansion. The compounds in such a collection are expected to be maintained under strict storage conditions and meet a set of quality control restrictions on purity, solubility, a number of reactive groups, and compound size.

2. 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, LOPAC1280, 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%.

3. Follow-up assay. A cascade of follow-up assays need to be in place to efficiently and effectively remove false positives because the primary HTS assay may typically generate hundreds to thousands of hits, of which most may be false positives or chemically intractable. 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.

A Chemical Probe Development Plan (CPDP) is expected to be developed at the beginning of the project based on the awarded research application by a team composed of the screening/chemical probe discovery facility staff, the assay submitter, and an NIH program staff. The CPDP outlines the projected probe development path 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. The CPDP discussion should include an updated assessment of prior art of chemical probes, probe definition, assay responsibilities, hit selection criteria, planned follow-up assays, structure-activity relationships of bioactive compounds, and a flowchart to summarize critical path to the probe discovery.

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 the 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 and achieve the goals of this program, assay data, assay protocols, and chemical structures of compounds tested are expected to be made publicly available.

For the purpose of this FOA, the following data generated or developed under this FOA are expected to be released to PubChem, consistent with achieving the goals of this program: (1) primary assay data from high throughput screening (HTS), (2) data generated in the follow-up assays, (3) assay protocols, (4) the chemical structure of compounds tested, and (5) chemical synthesis protocols.

Applications in response to this FOA should include a statement of willingness to deposit the aforementioned data to PubChem within the Data Sharing section of the application.

Projects awarded under this FOA are subject to oversight and review by each of the following entities.

The participating NIH ICs will be responsible for making the award according to their respective missions to support basic and clinical research. For each awarded research project, the participating IC will delegate a program staff to join meeting discussions on the Chemical Probe Development Plan and participate in planning of the screening project.

NIH Project Team: The NIH Project Team composed of the participating IC staff will serve as the governing body that oversees the data deposition to PubChem.

NIMH - The NIMH is especially interested in applications for novel, clinically-relevant targets with the goal of transforming target discovery into therapeutic treatment of mental disorders such as depressive disorder, bipolar disorder, schizophrenia, anxiety disorders, panic disorder, autism, etc. Proposed projects should be relevant to NIMHs mission of supporting basic science discoveries and translating these discoveries into new therapeutic interventions that will relieve the suffering of people with mental disorders. NIMH encourages cross-disciplinary collaboration among NIMH-funded existing research, such as Psychopharmacology, Neuropharmacology, Molecular Pharmacology Research, and Genetic Basis of Mental Disorders Programs. If a screening campaign yields promising bioactive chemical probes, investigators are encouraged to consider the following funding opportunities: Drug Discovery for Nervous System Disorders PAR-13-048 and PAR-13-049.

NIAAA - NIAAA is interested in applications for novel clinically-relevant targets with the goal of transforming target discovery into treatment of alcohol dependence. NIAAA is also interested in the development of novel ligands to be used as tools for investigating biological processes contributing to alcohol dependence. Alcohol dependence is a complex disorder involving many neurotransmitter receptors and transporters, ion channels, neuromodulators, hormones, and intracellular signaling networks. This provides a number of potential target sites for which new pharmaceutical agents may be developed. Examples of interest include: effectors of opioid, glutamate, GABA, cannabinoid, and adenosine receptors, modulators of neuropeptide systems (e.g., NPY, CRF, substance P, orexin), agents that alter signal transduction pathways (such as protein kinase effectors, protein phosphatase inhibitors, G-protein regulators and calcium signaling disruptors), and modulators of neuroimmune and neuroinflammatory pathways.

NICHD - NICHD is interested in high throughput screening that will lead to discovery of chemical probes of developmental targets relevant to pregnancy and pediatric-related conditions. Potential applicants are encouraged to review the NICHD mission at http://www.nichd.nih.gov/about/overview/mission/ and vision at http://www.nichd.nih.gov/vision/ and to contact NICHD program staff listed in Section VII prior to submitting an application.

NIDA - NIDA is particularly interested in assays for novel targets that may lead to the development of pharmacotherapeutics for drug addiction and/or chronic pain. NIDA is also interested in assays to identify compounds that are selective for or against reported human genetic or epigenetic variants of known targets for drug addiction, where the variant is associated with risk for or protection against dependence or addiction. If a screening campaign yields promising bioactive chemical probes, investigators are encouraged to consider the following funding opportunities: Drug Discovery for Nervous System Disorders PAR-13-048 and PAR-13-049.

Funding Instrument	Other: A mechanism that is not a grant or cooperative agreement. Examples include access to research resources or pre-applications
Application Types Allowed	New Resubmission The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	Not Applicable. Funds are not awarded via this X01.
Award Project Period	The total project period may not exceed two years.

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

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• Eligible Agencies of the Federal Government - NIH Intramural Program

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

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

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

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 PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (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 that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Yong Yao, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7182B, MSC 9641
Bethesda, MD 20892-9641
Rockville, MD 20852 (for express/courier service)
Telephone: 301-443-6102
Email: yyao@mail.nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirement:

• For this specific FOA, the Research Strategy section is limited to 6 pages.

The forms package associated with this FOA includes all applicable components, required 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 instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Facilities & Other Resources: Provide a detailed description of existing resources of the HTS/chemical probe discovery facility and resources available to the applicants, following the instructions in the SF424(R&R) Application Guide. The information provided is of major importance in establishing the feasibility of the research aims. Describe only those resources that are directly applicable to the proposed work. Describe any special facilities used for working with biohazards or other potentially dangerous substances. (Note: Information about select agents must be described in the Research Plan, Select Agent Research section).

This information is used to assess the capability and the resources available to perform HTS, hits validation, and chemical optimization efforts.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Letters of Support: Attach all appropriate letters of support, including letter(s) necessary to indicate that the HTS/ chemical probe discovery facility will be capable of completing HTS and chemical optimization without additional funding. Save this information in a single file in a location you remember.

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:

• For the purpose of this announcement, the following data generated or developed under this FOA are expected to be released to PubChem, consistent with achieving the goals of this program: (1) primary assay data from high throughput screening (HTS), (2) data generated in the follow-up assays, (3) assay protocols, (4) the chemical structure of compounds tested, and (5) chemical synthesis protocols.

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-U.S.) 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 applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the 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 SF424 (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 SF424(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. See Section III of this FOA for information on registration requirements.

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 System for Award Management. 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.

For this particular announcement, note the following:

The X01 Resource Access Program invites eligible institutions to seek access to NIH research resources. This includes programs where institutions will request access to the resource (e.g., high throughput screening assays). Important factors in the peer review of X01 applications are the need for, and potential benefit of, gaining access to the resource, specifications for any assays proposed, timelines for completion and plans for follow-on studies.

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

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/PI, 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 there are known small molecule modulators 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? Is the compound library adequate for screening? Is the HTS assay well designed to minimize false positives and false negatives? Is there sufficient preliminary data to support assay readiness for HTS? Is there 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?

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?

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? Does the applicant demonstrate evidence of a previous collaboration, or commitment to a joint collaborative research project with the proposed HTS/chemical probe discovery facility? Is there evidence of a commitment of the facility to provide the resources and support to implement the proposed collaborative HTS campaign, including access to a large, diverse collection of small molecules, and chemical resources to optimize the screening hits without additional funding?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

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 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).

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),in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center Following initial peer review, recommended applications will receive a second level of review by the appropriate National Advisory Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Any application awarded in response to this FOA will be subject to the DUNS, SAM 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 annual Non-Competing Progress Report (PHS 2590 or RPPR) 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.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Phone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

Yong Yao, PhD
National Institute of Mental Health (NIMH)
Telephone: 301-443-6102
Email: yyao@mail.nih.gov

Changhai Cui, PhD
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-1678
Email: changhai.cui@nih.gov

Katerina Tsilou, MD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-6287
Email: tsiloue@mail.nih.gov

Rao Rapaka, PhD
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1304
Email: rrapaka@mail.nih.gov

Ajit Jadhav
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-217-5716
Email: ajadhav@mail.nih.gov

J. Thomas Peterson, PhD
Center for Scientific Review (CSR)
Telephone: 301-408-9694
Email: petersonjt@csr.nih.gov

Rebecca Claycamp, M.S., CRA
National Institute of Mental Health (NIMH)
Telephone: 301-443-2811
Email: rclaycam@mail.nih.gov

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301- 443-4704
Email: jfox@mail.nih.gov

Bryan S. Clark, M.B.A
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: clarkb1@mail.nih.gov

Suezette Epps
National Institute on Drug Abuse (NIDA)
Telephone: 301-617-3882
Email: eppss@mail.nih.gov

Jenelle Wiggins
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0843
Email: JWiggins@mail.nih.gov

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.