Department of Health and Human Services
Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Mental Health (NIMH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Allergy and Infectious Diseases (NIAID)
National Cancer Institute (NCI)
National Institute of General Medical Sciences (NIGMS)
National Institute on Drug Abuse (NIDA)
National Institute on Aging (NIA)
The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Funding Opportunity Title

Development of Assays for High-Throughput Screening for Use in Probe and Pre-therapeutic Discovery (R01)

Activity Code

R01 Research Project Grant

Announcement Type

Reissue of PA-10-213

Related Notices
  • June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number

PAR-13-364

Companion Funding Opportunity

None

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.242,93.865; 93.866; 93.855; 93.856; 93.273; 93.847; 93.859; 93.279; 93.399; 93.396; 93.395; 93.394; 93.393

Funding Opportunity Purpose

The participating NIH Institutes and Centers invite Research Project Grant (R01) applications to develop assays for high throughput screening (HTS) for use in Probe and Pre-therapeutic Discovery. Through this FOA, NIH wishes to stimulate research in 1) developing assays for specific biological targets and disease mechanisms relevant to the mission of participating NIH Institutes with the intent to screen for small molecule compounds that show potential as probes for use in advancing knowledge about the known targets, identifying new targets, or as pre-therapeutic leads; and 2) establishing collaboration with screening centers that have the requisite expertise and experience needed in implementation of HTS assays for the discovery and development of small molecule chemical probes. This FOA seeks to establish a stream of scientifically and technologically outstanding assays for screening by the NIH Molecular Libraries Production Centers Network (MLPCN) in the Molecular Libraries Program (MLP) and other academic centers. One important criterion for this initiative is novelty, so applicants are therefore encouraged to avoid focusing on areas and approaches that have been extensively targeted in other settings. Assays should be relevant to the scope of research in at least one of the participating NIH Institutes.

Key Dates
Posted Date

September 27, 2013

Open Date (Earliest Submission Date)

January 5, 2014

Letter of Intent Due Date(s)

Not Applicable

Application Due Date(s)

Standard dates apply, 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)

Standard AIDS dates apply, 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.

Scientific Merit Review

Standard dates apply

Advisory Council Review

Standard dates apply

Earliest Start Date

Standard dates apply

Expiration Date

January 8, 2017

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.


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Table of Contents

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

Part 2. Full Text of Announcement


Section I. Funding Opportunity Description

Research Objectives

The purpose of this Funding Opportunity Announcement (FOA) is to stimulate the development of high throughput screening (HTS) assays which are relevant to processes and diseases specific to the missions of the participating Institutes and Centers (ICs) at the National Institutes of Health (NIH). This FOA seeks to apply new knowledge and screening technologies to assays developed around novel targets and pathways. New discoveries in the field of novel and/or understudied targets will contribute to development of useful tools necessary for basic and clinical research, leading to the development of potential pre-therapeutic leads. 

Through this FOA, NIH wishes to stimulate research in 1) developing assays for specific biological targets and disease mechanisms relevant to the mission of participating NIH Institutes with intent to screen for small molecule compounds that show potential as probes for use in advancing knowledge about the known targets, identifying new targets, or as pre-therapeutic leads; and 2) establishing collaboration with screening centers that have the requisite expertise and experience needed in implementation of HTS assays for the discovery and development of small molecule chemical probes.

The overall goal of this FOA is to establish a stream of scientifically and technologically outstanding HTS-ready assays ultimately suitable for implementation at NIH-funded or other academic screening centers and to be used in further studies of relevant new biology.

Background Information

High-throughput screening (HTS) comprises the screening of large chemical libraries for activity against biological targets via the use of automation, miniaturized assays and large-scale data analysis. Since its beginning about 10–15 years ago, lead discovery by HTS has evolved into a mature scientific discipline in modern drug discovery and is now also being used for basic and translational research in academia as a crucial source of chemical starting points for Probe and Pre-therapeutic Discovery. HTS is defined by the number of compounds tested in the range of 10,000–100,000 per day. Current probe and lead discovery rely upon a massive screening of chemical libraries against various extracellular and intracellular molecular targets to find novel chemotypes with the desired mode of action.

Since 2005, the National Institutes of Health (NIH) has been in a major effort to broaden the access of HTS technologies, and the information produced by such approaches to a wider range of researchers in academia, government, and non-profit institutions. The NIH Common Fund’s Molecular Libraries and Imaging Program (MLP) offers biomedical researchers access to the large-scale screening capacity necessary in the identification of small molecules that can be optimized as chemical probes used to study the functions of genes, cells, and biochemical pathways in health and disease. Probes may also be used by researchers in the public and private sectors to validate new drug targets, which may then move into the drug-development pipeline.

Requirement for an Assay Development Research Application

1. Novelty: This FOA seeks to apply new knowledge and screening technologies to assays developed around novel targets and pathways. New understandings of these targets will contribute to the translation of new discoveries into useful tools for basic and clinical research, thus leading to the development of potential pre-therapeutic leads. Other targets might be associated with rare and neglected diseases; an area of focus for the National Center for Advancing Translational Sciences (NCATS). One important criterion for this initiative is novelty, so the proposed assays should avoid focusing on areas and approaches that have already been extensively targeted in other settings.

2. Biological Relevance: Proposed primary assays should be relevant to the scope of the research within at least one of the participating NIH ICs focusing on specific diseases or on relevant basic physiology, cell biology, or developmental processes. The applications should primarily emphasize assays which provide new insights into key targets. For example, assays with targets tangentially related to a disease are also relevant if they are able to provide insight into the biology of that disease. The application should aim to use the assay to screen and develop small molecule probes with selectivity and specificity against targets for use both in academic research and as pre-therapeutic leads.

3. Research Plans: Aims/milestones appropriate for this FOA may include, but are not limited to the following:

      1) Assay development: develop primary HTS assay and hit follow-up assays.

      2) Pilot screen: complete pilot screen against a compound collection of 100-10,000 compounds.

      3) Hit validation: perform initial characterization of active compounds.

Examples of relevant research approaches include but are not limited to:

Given the highly focused nature of assay development, project periods are limited to three years. At the end of that time, the assays should be sufficiently developed for HTS at an NIH-funded (or other) facility and used for further innovative studies focused on the discovery of new biology.

Technical Specifications

Experiments proposed in response to this FOA need not initially include the use of assays in high-throughput screens or even the final stages of miniaturization for HTS. Rather, the emphasis can be on designing and validating creative approaches to assaying biological and disease processes that can potentially be used for chemical probe and drug discovery. To increase the overall likelihood of a successful project, applicants are encouraged to consider incorporating following suitable topics into their applications.

1) Demonstration of highly predictable and reproducible responses to known compounds or other control conditions and of a clear threshold between positive and negative responses. Assays should aim for high S:B ratios and good measures of reproducibility and reliability(e.g. Z’ scores).

2) Demonstration of suitability and reproducibility of the assay for HTS using a diverse and significant number compounds, such as a collection of FDA approved drugs or other bioactive molecules to verify reproducibility and reliability.

3) Demonstration of the availability and suitability of secondary and counter screen assays for a HTS screening campaign.

4) Demonstration of the availability of reagents necessary to perform HTS, such as enzyme indicators, chemicals necessary for reagent readout, and the capacity to generate sufficient reaction substrates (DNA, RNA, protein, or enzyme substrates).

Related Funding Initiatives

At the end of the project periods, successful projects supported by this FOA may lead to screening assays that are ready for HTS implementation, and these assays will be submitted to HTS facilities.  Investigators who already have ready-to-go HTS assays are encouraged to apply for FOAs " High Throughput Screening (HTS) to Discover Chemical Probes": PAR-12-058 (R01), PAR-12-059 (R21), PAR-13-135 (R03), PAR-13-134 (X01, Resource Access Award) and Fast Track access program (http://grants.nih.gov/grants/guide/notice-files/NOT-RM-09-011.html), one of several routes through which access may be gained to the MLPCN, the Common Fund’s Molecular Libraries and Imaging program.

General Guidance for High Throughput Screening Assays

Utilization of Related Resources

Institute and Center Interests

Applicants are encouraged to contact the Scientific/Research Contacts listed in Section VII of this FOA to discuss areas of scientific interest for particular Institutes. With respect to specific conditions or populations, individual Institutes at the NIH may have distinct research priorities. Institute-specific interests are listed below:

NIMH: The NIMH supports neuroscience research on the causes of and treatments for mental disorders. NIMH is especially interested in developing high-throughput screen (HTS) assays 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, and autism, etc. Proposed projects should be relevant to the NIMH mission of supporting basic science discoveries and translating these discoveries into new therapeutic interventions that will relieve the suffering of people with mental disorders. Further information on NIMH research priorities can be found in the NIMH Strategic Plan, Strategic Research Priorities, and Interventions Workgroup Report. Applications should particularly focus on assay development using new targets emerging from genetic and proteomic research in model systems and in human diseases. Also appropriate are applications to discover molecular tools or probes for elucidating the basic genetic, molecular, and cellular mechanisms underlying the action of neuropsychopharmacological agents in vitro and in vivo. In order to identify small molecules that either perturb the system or yield molecular information, the application should use biological systems and measurements that are suitable for automated HTS. Targets of emphasis may include, but not limited to: 1) target-based biochemical assays and receptor-ligand binding assays such as those for enzymes, CNS receptors, G-protein coupled receptors (GPCRs), orphan GPCRs, ion channels, transporters, nuclear receptors; 2) cell-based assays could include functional assays, reporter gene assays and phenotypic assays for cellular processes and pathway analysis; and 3) non-traditional targets of interest include transcription factors, nucleic acids, multimeric proteins, membrane proteins, and polymorphic gene products; and subcellular processes such as molecular trafficking and translocation, post-transcriptional editing or splicing of gene products, and protein or RNA stabilization. Finally, NIMH encourages cross-disciplinary collaboration among NIMH-funded existing research, such as Psychopharmacology, Neuropharmacology, Molecular Pharmacology Research, and Genetic Basis of Mental Disorders Programs (http://www.nimh.nih.gov/about/organization/dnbbs/index.shtml).

NIDDK: NIDDK is particularly interested in proposed assay development projects that are relevant to the mission of NIDDK, which includes obesity, diabetes, diabetic complications, endocrine disease, liver and digestive diseases, nutrition, kidney and urological diseases, hematology, and inborn errors of metabolism. Alternatively, applications may focus on NIDDK-relevant basic physiology, such as glucose and lipid homeostasis, insulin sensitivity and resistance, intestinal inflammation, gastrointestinal transport, nutrient metabolism and absorption, host-microbial interactions in the gastrointestinal tract, liver injury and repair, cell biology, or developmental processes. For additional information on disease areas of interest to the NIDDK, please see http://www2.niddk.nih.gov/Research/. It is expected that there is a significantly novel approach utilized in applications focused on primary assay development such as, but not limited to, a new molecular target, a novel phenotypic readout, or an innovative assay technology expected to permit identification of new compounds. Finally, applications may propose interaction with NIDDK-funded existing research consortia, such as the Beta Cell Biology Consortium (www.betacell.org), the Nuclear Receptor Signaling Atlas (www.nursa.org), the Diabetic Complications Consortium (www.diacomp.org), the Mouse Metabolic Phenotyping Centers (www.mmpc.org), the Intestinal Stem Cell Consortium (iscc.coh.org), or the GenitoUrinary Development Molecular Anatomy Project (www.gudmap.org).

NIA: NIA is interested in assays that are relevant to diseases and conditions involved in normal aging in a variety of tissues. Examples include Alzheimer’s disease and other dementias of aging, osteoporosis, sarcopenia and other age–related changes that occur during the human lifespan. NIA is particularly interested in assays that will stimulate the discovery of small molecular probes that will be useful in identifying new therapeutic targets and, novel therapeutic and imaging agents.

NIAAA: NIAAA is interested in applications proposing to develop high-throughput screen (HTS) assays for novel clinically-relevant targets with the goal of transforming target discovery into therapeutic treatment of alcohol dependence, as well as development of ligands to be used as tools for investigation biological processes contributing to compulsive drinking. Aspects of alcohol consumption and alcohol-seeking are modulated through the actions of neurotransmitter receptors and transporters, ion channels, neuromodulators, hormones, and intracellular signaling networks. Thus, there are a number of potential target sites for which new pharmaceutical agents may be developed, such as effectors of opioid, serotonin, dopamine, 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, protein phosphatase, G-protein and calcium signaling pathways), and modulators of neuroimmune and neuroinflammatory pathways.

NIDA: NIDA solicits applications to develop ligand assays relevant to the understanding and treatment of drug addiction to opiates, methamphetamines, cocaine, heroin, tobacco, marijuana, and other psychoactive substances.  The initial targets for most drugs of abuse are known and have been shown to be predominantly either G-protein coupled receptors, such as the dopamine receptor, an indirect site of action for cocaine and amphetamine, or ligand gated ion channels, such as the nicotinic cholinergic receptors (nAChRs), a target for nicotine. Drug addiction also involves activation of intracellular signaling proteins that can affect the response to drugs of abuse, and there is clear evidence for the involvement of numerous, specific neurotransmitter systems in addiction.  Genetic polymorphisms are likely to lead to variation in the biological activity in many of these protein targets, which may be relevant to individual variability in response to drugs of abuse and, ultimately, to vulnerability to addiction. High throughput screening assays may include, but are not limited to:  small molecule modulators of various known and orphan membrane GPRCs, small molecule and peptide ligands which modulate GPCR-interacting proteins, such as arrestins, and regulators of G protein signaling, small molecule modifiers of various channels, pores, and transporters, modifiers of histone, modifiers of endolipids or their metabolizing enzymes, and probes of chromatin remodeling complexes. Assays of additional interest are those identifying ligands targeting signaling pathways, synaptic transmission, cognition, learning, and memory. Applicants are encouraged to consult the http://www.drugabuse.gov/sites/default/files/files/ATDPGuide.pdf for high priority targets.

NCI: Assays pertinent to the mission of NCI should be justified in the application as relevant to cancer. The NCI is interested in development of assays to identify or evaluate small molecules for use in elucidating molecular, cellular, or in vivo mechanisms or processes of probable or known importance to cancer biology, and for use in developing strategies for cancer prevention, diagnosis, treatment or clinical monitoring of treatment. Assays proposed may be biochemical, cellular or model organism-based, and may be useful for discovering small molecule probes, preventive or therapeutic drug leads, or imaging agent leads. Applicants may find the NCI Developmental Therapeutics Program (http://dtp.nci.nih.gov) resources to be helpful. Collaborations between laboratories with screen development capabilities and laboratories with small molecule synthesis capabilities are encouraged.

NHLBI: The NHLBI would like to stimulate the development of assays that are pertinent to its mission to advance understanding and treatment of heart, lung, and blood diseases. Assays can focus on diagnosis, prognosis, treatment, or biological processes relevant to heart, lung, or blood diseases.  Applicants may propose to develop biochemical, cellular, or model organism-based assays.  Applicants are also encouraged to align their assay development with NHLBI’s on-going translational research programs, clinical trial networks, and community resource programs (http://www.nhlbi.nih.gov/resources/index.htm).

NIAID: NIAID is particularly interested in applications directly addressing infectious or immune-mediated disease or basic immunology. Applications may focus on assays targeting etiologic agents of human infectious disease including, but not limited to, potential ages of biodefense (categories A, B, and C), as well as other newly emerging infectious agents. Pathogens with abnormally high global burdens of disease such as HIV, tuberculosis, and malaria, as well as toxins or arthropod vectors of infectious agents as targets will also be included. Additionally, applications may focus on augmenting immune responses towards infectious agents, including early innate immune responses and the induction or prolongation of immunological memory to vaccination. Also of prime interest is the prevention, amelioration, or reversal of immune-mediated diseases by small molecules. Targets relevant to asthma, allergy, inflammatory diseases, transplant rejection, and all types of autoimmune diseases may be proposed. Assays that facilitate studies on basic immunological mechanisms are also appropriate.

NIGMS: NIGMS welcomes assays that are relevant to the Institute's mission: basic scientific research that increases understanding of life processes and lays the foundation for more applied advances in disease diagnosis, treatment, and prevention. NIGMS-funded researchers seek to answer important scientific questions in fields such as cell biology, biophysics, genetics, developmental biology, pharmacology, physiology, biological chemistry, bioinformatics, computational biology, selected aspects of the behavioral sciences, and specific cross-cutting clinical areas that affect multiple organ systems.

NICHD: NICHD is interested in developing high throughput screening assays that will lead to discovery of new chemical probes and novel therapeutic targets with the ultimate goal the development of new treatment modalities for pediatric as well as pregnancy induced/related conditions. Assays proposed may be biochemical, cellular or model organism-based. Areas of interest include but are not limited to biophysics, genetics, developmental biology, developmental pharmacology, physiology, biological chemistry, models of neurodevelopment, pregnancy drug targets, new drug targets that do not overlap with fetal/developmental ones,  identification of targets for treatment of mental health conditions in pregnant women. Potential applicants are encouraged to review the NICHD mission http://www.nichd.nih.gov/about/overview/mission/ and vision http://www.nichd.nih.gov/vision/ and to contact NICHD program listed on this FOA prior to submitting an application.

Section II. Award Information
Funding Instrument

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed

New
Resubmission
Revision

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

Application budgets are not limited, but need to reflect the actual needs of the proposed project.

Award Project Period

Given the highly focused nature of assay development, project periods are limited to three 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.

Section III. Eligibility Information


1. Eligible Applicants


Eligible Organizations

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

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.

Required Registrations

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.

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.

Eligible Individuals (Program Director/Principal Investigator)

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.

2. Cost Sharing

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

3. Additional Information on Eligibility


Number of Applications

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:

Section IV. Application and Submission Information


1. Requesting an Application Package

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.

2. Content and Form of Application Submission

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.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Required and Optional Components

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.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R or Modular Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: Provide Specific Aims for the Research Project.

Research Strategy: Start each section with the appropriate section heading—Significance, Innovation, Approach. Clearly describe the project's objectives and explain its relevance to the mission of the participating institute.  Specify the biomedical significance of the work proposed. As part of the Research Strategy, include information on preliminary studies, data, and/or prior experience pertinent to this application. Organize the Research Strategy using the instruction provided below:

1) Assay development: Include preliminary data from primary HTS assay studies on how well the assay will perform, e.g. evidence of reproducible; dose-dependent responses to a small collection of pharmacologically active standards and/or reaction substrates or inhibitors; knowledge of control parameters such as time, temperature and protein concentration dependencies; information as to tolerance to the effect of DMSO at 0.1-1%; reproducibility between plates and day-to-day experiments. The application should include plan to develop (as needed) or use existing secondary screens to confirm compounds active in the primary screen as reproducible hits, and rule out artifacts (to include dose-ranging experiments, and assays which measure a different activity than employed in the primary assay). Plan to develop (as needed) and use counter-screening assays should also be described that allow prioritization of these hits for further testing (e.g., on the basis of selectivity or potential toxicity). Overall, the application should show that secondary and counter-screen assays are available, or will be developed and characterized within the project period.

2) Pilot screen:  Provide a plan for a pilot screen and discussion of the anticipated results. For many screens it is likely that a few hundred active compounds may be identified in a primary HTS effort; therefore the plan for a pilot screen should show that an evaluation of these hits is feasible. Provide recommendations of appropriate test concentrations, together with concentration cut-offs to be used in selecting compounds active in the primary, secondary and counter-screening assays, as well, information describing reagent availability, equipment used in configuring the assays.

3) Hit validation: Include a plan to perform initial characterization of active compounds. It is expected that preliminary data will be provided in the application demonstrating that the proposed assay(s) can be developed, configured and validated within the project period. In addition, experimental plans aimed at providing validation data supporting a HTS strategy for molecular probe development at the end of project period should provide answers to the essential questions, such as, Are the proposed screening assays feasible in HTS format?  Is the screening plan complete?  Are key reagents required for execution of the HTS project available?  What is the current availability of pharmacological probes to the proposed target, mechanism or phenotype?

Letters of Support: Provide letters of support specific to the Research Project.

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 modification:

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.

Planned Enrollment Report

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide. 

PHS 398 Cumulative Inclusion Enrollment Report

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide. 

Foreign Institutions

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.

3. Submission Dates and Times

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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

6. Other Submission Requirements and Information

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.

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact NIH program staff at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Section V. Application Review Information


1. Criteria

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.

Overall Impact

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).

Scored Review Criteria

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 use of the HTS or HCS assay developed, either to screen for small molecule compounds that show potential as probes for use in advancing knowledge about the known targets, identifying new targets, or as pre-therapeutic leads?

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 HTS or HCS assay development and the process of screening compound libraries? Are the investigators reasonably knowledgeable and experienced to conduct follow-up assays to validate screening hits?  

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 development project for a novel biological target (or pathway)? 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 pathway)? Will the innovation in assay design lead to better success likelihood of a ready-to-go HTS or HCS assay?

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 preliminary data sufficient to support that the proposed assay(s) can be developed? Is there a small compound library, or other bioactive molecules proposed for pilot screening? Is there adequate plan for an assay performance parameter to be generated and calculated, such as Z'-factor? Is the assay well designed to minimize false positives and false negatives? Are non-commercial reagents required for this assay? If so, how are they characterized for purity and activity? Are there adequate plans for secondary 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?  Is there a plan to establish collaboration with academic screening centers, such as the NIH MLPCN centers, that have the requisite expertise and experience in development and implementation of HTS or HCS assays for the discovery and development of small molecule chemical probes?

Additional Review Criteria

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 Guidelines for the Review of Human Subjects.

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 Guidelines for the Review of Inclusion in Clinical Research.

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

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

Additional Review Considerations

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s )convened by the CSR, 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:

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:

3. Anticipated Announcement and Award Dates

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.

Section VI. Award Administration Information


1. Award Notices

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, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

3. Reporting

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. 

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Application Submission Contacts

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 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 TelepPhone: 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 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

Scientific/Research Contact(s)

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

Dr. Aaron Pawlyk
National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK)
Telephone: 301-451-7299
Email: pawlykac@mail.nih.gov

Lorenzo Refolo, PhD
National Institute on Aging (NIA)
Telephone: 301-594-7754
Email: refolol@nia.nih.gov

Martin John Rogers, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3359
Email: mr92i@nih.gov

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

Suzanne Forry-Schaudies, PhD
National Cancer Institute (NCI)
Telephone: 240- 276-5922
Email: forryscs@mail.nih.gov

Miles A. Fabian, Ph.D.
National Institute of General Medical Sciences (NIGMS)
Telephone 301-594-3827
Email: fabianm@mail.nih.gov

Kristopher Bough, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-9800
Email: boughk@mail.nih.gov

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

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

Theresa Jarosik
National Institute of Mental Health (NIMH)
Telephone: 301-443-3858
Email:  tjarosik@mail.nih.gov

Todd Le
National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone:  301-594-7794
Email: toddle@mail.nih.gov

Ryan Blakeney
National Institute on Aging (NIA)
Telephone: 301-451-9802
Email: blakeneyr@mial.nih.gov

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4707
Email: jfox@mail.nih.gov

Victoria Connors
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-402-5065
Email: connorsv@niaid.nih.gov  

Shane Woodward
National Cancer Institute (NCI)
Telephone: 301-496-8791
Email: Woodwars@mail.nih.gov

Lisa Moeller
National Institute of General Medical Sciences (NIGMS)
Telephone:  301-594-3914 
Email:  Lm236j@nih.gov

Suezette Epps
National Institute on Drug Abuse (NIDA)
Telephone:  301-490-7431
Email:  eppss@mail.nih.gov

Bryan S. Clark, MBA
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-402-0915
Email: clarkb1@mail.nih.gov

Section VIII. Other Information

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.

Authority and Regulations

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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