National Institutes of Health (NIH)
National Institute of Mental Health (NIMH)
National Cancer Institute (NCI)
National Eye Institute (NEI)
National Institute on Aging (NIA)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute on Deafness and Other Communication Disorders (NIDCD)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute on Drug Abuse (NIDA)
National Institute of Neurological Disorders and Stroke (NINDS)
High Throughput Screening (HTS) to Discover Chemical Probes (R01)
R01 Research Project Grant
Reissue of PAR-12-058
93.242, 93.865, 93.273, 93.173, 93.867,93.395, 93.394, 93.853, 93.279, 93.866, 93.847, 93.846
This Funding Opportunity Announcement (FOA) encourages investigators to form collaborations with an established academic, nonprofit, or commercial high throughput screening (HTS) facility that has the requisite expertise and experience to implement HTS-ready assays for the discovery and development of small molecule chemical probes.
Through this FOA, NIH wishes to stimulate research in 1) discovery and development of novel, small molecules for their potential use in studying disease treatments 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 projects that provide new insight into important disease targets and processes.
July 17, 2014
September 5, 2014
30 days prior to the application due date
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.
September 8, 2017
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.
There are several options to submit your application to the agency through Grants.gov. You can use the ASSIST system to prepare, submit and track your application online. You can download an application package from Grants.gov, complete the forms offline, submit the completed forms to Grants.gov and track your application in eRA Commons. Or, you can use other institutional system-to-system solutions to prepare and submit your application to Grants.gov and track your application in eRA Commons. Learn more.
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
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 (see Academic Screening Facilities Directory, http://www.slas.org/screeningFacilities/facilityList.cfm). This provides an unprecedented opportunity for investigators to translate knowledge about diseases into tangible tools for translational research. This Funding Opportunity Announcement (FOA) aims to support investigators to form collaborations with an academic, nonprofit, or commercial HTS screening facility that has the requisite expertise and experience to implement an HTS-ready assay for the discovery and development of small molecule chemical probes. Through this FOA, NIH wishes to stimulate research in 1) discovery and development of novel, small molecules for their potential use in studying disease treatments 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 projects 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 and health.
This program intends to support mainly the following two stages of discovery research:
1. HTS implementation. The screening facility should have the capability to optimize and automate biochemical-, cellular-, or whole organism-based assays to screen a library of compounds with adequate diversity and representation of chemical space. The projects submitted to this FOA are expected to already have an implementable HTS assay and an adequate 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 screening facility responsible for implementing the assays.
The HTS may include the following several primary assay configurations: (1) a biochemical or cell based assay against a large collection of compounds; (2) a whole animal (e.g., zebrafish, mouse, etc.), organoid, or 3-D culture based primary assay against a focused collection of compounds; (3) a high-value primary cell or tissue sample based primary assay against a focused collection of compounds; (4) an array of biochemical or cell based primary assays against a focused collection of compounds; (5) an affinity based primary assay of multiple protein targets against a very large library of compounds (e.g., DNA encoded compound library, etc.).
Complementary research including virtual screening may also be conducted to improve the screening success likelihood and cost effectiveness.
HTS assay development is beyond the scope of the FOA. Investigators who are interested in the development of HTS assays are encouraged to apply under PAR-13-364 - Development of Assays for High-Throughput screening for use in Probe and Pre-therapeutic Discovery (R01). 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 facility 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 a structure-activity relationship (SAR) study.
Other technical resources about HTS assay development include the online comprehensive guidebook Assay Guidance Manual (http://www.ncbi.nlm.nih.gov/books/NBK53196/), HTS assay protocols deposited on PubChem BioAssay data base (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pcassay), ASSAY and Drug Development Technologies, a peer-reviewed bimonthly journal, and the Journal of Biomolecular Screening.
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.
A substantial amount of screening campaigns may yield validated hits that can be further optimized via medicinal chemistry work. However, extensive medicinal chemistry optimization is beyond the scope of the FOA. Investigators of a successful screening project are encouraged to consider further funding opportunities that would support medicinal chemistry optimization of the validated hits, i.e., PAR-14-279 (Discovery of in vivo Chemical Probes) or other funding opportunities as listed below in the section "Institute Interests."
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, assay data, assay protocols, and chemical structures of compounds tested are expected to be made publicly available, consistent with achieving the goals of this program.
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) protocols for assays implemented, and (4) the chemical structure of compounds tested.
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. Investigators who are interested in developing novel, robust analytical platforms using in vitro assays to reveal changes in neuronal and/or glial function may apply to the following funding opportunity: Scalable Assays for Unbiased In Vitro Analysis of Neurobiological Function (R21/R33) PAR-11-319 and future reissues of this FOA. In case a screening campaign yields promising bioactive hits, investigators are encouraged to consider the following funding opportunities: Drug Discovery for Nervous System Disorders PAR-13-048 (R01) , PAR-13-049 (R21). High-quality and reproducible studies that are reported to the scientific community in a transparent manner are an essential cornerstone of the research enterprise. Attention to principles of study design and transparency is essential to enable reviewers, the scientific community, and NIH to assess the quality of scientific findings. In support of this important goal, investigators are strongly encouraged to implement rigorous study designs and reporting. Examples of the critical elements of a well-designed study are summarized at http://www.nimh.nih.gov/research-priorities/policies/enhancing-the-reliability-of-nimh-supported-research-through-rigorous-study-design-and-reporting.shtml.
NCI: High throughput screens that are pertinent to the mission of NCI should be justified in the application as relevant to cancer. The NCI is interested in high throughput screens intended to identify 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. Screens may be biochemical, cellular or model organism-based. High throughput screens for targets that address unmet needs in cancer prevention, treatment or diagnosis are encouraged. Validated hits identified by HTS may be appropriate for entry in the NCI Experimental Therapeutics Program (NExT) for further development to clinical candidate status and testing in clinical trial. See http://next.cancer.gov/ for the NExT application process. Applicants may also find the NCI Developmental Therapeutics Program (http://dtp.nci.nih.gov) resources to be helpful.
NEI: The NEI is especially interested in applications to develop novel, clinically-relevant targets, which can be transformed into therapeutics for treatment of visual diseases and disorders. Appropriate research areas include, but are not limited to, inflammatory, vascular, and degenerative diseases of the eye, such as diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, glaucoma, ocular infections, corneal wound healing, and dry eye syndrome. Proposed projects should be relevant to NEI’s mission of supporting basic science discoveries and translating these discoveries into new therapeutic interventions that will lead to sight-saving treatments, reduce visual impairment and blindness, and improve the quality of life for people of all ages.
NIA: NIA is interested in HTS assays and chemical probes that are relevant to the process of normal aging (including normal cognitive aging) and age-related diseases and conditions in a variety of tissues. Examples include Mild Cognitive Impairment (MCI), Alzheimer’s disease and other dementias of aging, progeroid syndromes, osteoporosis, sarcopenia, and other age–related changes that occur during the human lifespan. NIA is particularly interested in assays and chemical probes that will be useful in identifying new therapeutic targets and, novel therapeutic and imaging agents. NIA is also interested in assays to screen for compounds that affect protective factors or processes that may contribute to slowing or reversing the progression of age-related adverse molecular, biochemical, genetic, cellular, or physiological changes that contribute to multiple age-related diseases, and which hence could contribute to longer health span.
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. In case a screening campaign yields promising bioactive hits, investigators are encouraged to consider the following funding opportunities: Drug Discovery for Nervous System Disorders PAR-13-048 (R01) , PAR-13-049 (R21).
NIAMS: NIAMS is interested in discovery and development of novel small molecules that can be used to treat diseases or understand disease mechanisms in the areas of arthritis and musculoskeletal and skin diseases. Potential applicants are encouraged to review the NIAMS mission (http://www.niams.nih.gov/About_Us/Mission_and_Purpose/mission.asp) and the NIAMS long-range plan (http://www.niams.nih.gov/About_Us/Mission_and_Purpose/long_range.asp) for more information.
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 http://www.nichd.nih.gov/about/overview/mission/ and vision http://www.nichd.nih.gov/vision/ and to contact NICHD Scientific/Research staff listed on this FOA 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. In case a screening campaign yields promising bioactive hits, investigators are encouraged to consider the following funding opportunities: Drug Discovery for Nervous System Disorders PAR-13-048 (R01) , PAR-13-049 (R21).
NIDCD: The NIDCD is interested in the development of high throughput screens to assess and identify putative analogs that might have potential therapeutic value in the treatment, protection or prevention of communication disorders, including hearing, balance, smell/taste, voice, speech and language. Applications could include, but are not limited to, identification of clinically-relevant targets that might lead to translatable therapeutics in hearing/balance areas of otoprotection, regeneration, otitis media, tinnitus, and normal/abonormal development; chemosensory abnormalities such as they relate to serious diseases of obesity, diabetes, Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis; disorders involving voice speech, language, including swallowing, aphasia or dysarthria, and laryngeal replacement. Potential applicants are encouraged to review the NIDCD mission http://www.nidcd.nih.gov prior to submitting an application.
NIDDK: The NIDDK is particularly interested in proposed HTS campaigns that are relevant to the mission of NIDDK, which includes obesity, diabetes and related aspects of endocrinology and metabolism, digestive diseases, liver diseases, nutrition, kidney and urological diseases, hematology, bone endocrinology, and specific aspects of cystic fibrosis. For additional information on disease areas of interest to the NIDDK, please see http://www.niddk.nih.gov/research-funding/research-programs/Pages/default.aspx. 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. It is expected that there is a significantly novel approach utilized in the assay to be screened 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 Human Islet Research Network, 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).
NINDS: The NINDS is exclusively interested in applications for the discovery of chemical probes for novel therapeutic targets that are relevant to the mission of the NINDS, which is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. The disease indication should be a neurological disease within the NINDS mission, for which NINDS serves as the lead NIH Institute. Investigators considering applying to this FOA are strongly encouraged to consult the NINDS Scientific/Research staff listed below to determine if the project falls within the mission of NINDS. There is increasing awareness among neurological disease communities that to assess the predictive value of preclinical research, sufficient information must be available about study design, execution, analysis, and interpretation. Examples of the critical elements of a well-designed study are summarized on the NINDS website (http://www.ninds.nih.gov/funding/grant_policy.htm).
Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Application budgets are not limited but need to reflect the actual needs of the proposed project.
The total project period may not exceed 3 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
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
Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.
Applicant organizations must complete 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. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. 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.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:
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, including Supplemental Grant Application Instructions 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:
The letter of intent should be sent to:
Yong Yao, Ph.D.
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.
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.
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.
All instructions in the SF424 (R&R) Application Guide must be followed.
Applicants need to justify the actual needs of the proposed costs associated with HTS, post-HTS follow-up assays, and other probe discovery 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, with the following additional instructions:
Research Strategy: In the Research Strategy applicants should address the following topics as they pertain to the research project proposed:
1. Compound collection. Applicants are expected to provide a rationale for the size and selection of the library of compounds to improve the HTS success likelihood and cost effectiveness. In certain cases, it may be advantageous to utilize focused libraries of compounds with specific considerations for the assay targets, known bioactivities, privileged scaffolds, representative diversity sets, drug repurposing, and/or the ease of follow-up synthetic chemistry for SAR expansion. The compounds for HTS are expected to be maintained under strict storage conditions and meet a set of quality control restrictions on 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.
The application is expected to include preliminary data on the primary assay performance most often in microtiter plate format (96-, 384- and 1536-well plates). A scatter plot obtained from a pilot screen of a small collection of structurally diverse small molecules (e.g., NIH Clinical Collection at http://www.nihclinicalcollection.com/, LOPAC1280 at http://www.sigmaaldrich.com/chemistry/drug-discovery/validation-libraries.html, etc.) may provide an overview of the assay performance. In general, an acceptable lower limit of Z’ factor is 0.5 for a robust single-concentration HTS that corresponds to a combination of Signal-to-Basal Ratio (S/B) of 4 with a Coefficient of Variation (CV) of 10%. The assay robustness will improve in case multiple compound test concentrations or kinetic recordings are used in HTS.
3. Follow-up assay. The application is expected to include a cascade of follow-up assays 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.
4. Probe criteria. The application should (1) define the specific criteria that a compound must meet to be considered a probe for the project, and (2) provide a thorough literature and informatic analysis about prior art of chemical probes.
5. Critical path. The application should include a flow diagram to outline all critical steps in sequential and/or parallel manners with appropriate benchmarks and timelines, including but not limited to the primary HTS assay to be implemented, alternative assay or approach (e.g., computational docking) to ensure success of the screening, hit selection criteria, cheminformatic analysis, chemical tractability assessment, all follow-up assays to validate screening hits, study of structure-activity relationships, assay responsibilities of each party involved, etc.
6. Future plan. The application should also include a plan to briefly describe existing and potential follow-up assays to develop chemical probes in the future.
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.
When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.
When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report 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.
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 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.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.
Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.
Reviewers will provide an overall impact 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.
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 important and well-defined goals for the use of chemical probes identified with the proposed assays, either as research tools or for therapeutics development?
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?
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? ? Is this assay project for a novel biological target or cellular process? Does the application address whether or not known small molecule modulators are available for this biological target? Is there a need for better small molecule modulators against the target or cellular process? Will the innovation in assay design and compound assembly enhance success rate of the screening?
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
If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?
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 the assay performance adequate, 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?
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact 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 human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
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.
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.
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.
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.
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) convened by Center of Scientific Review, 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. Following initial peer review, recommended applications will receive a second level of review by the appropriate National Advisory Council or Board. The following will be considered in making funding decisions:
After the peer review of the application is completed, the PD/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.
If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this 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
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)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Grants.gov Customer Support (Questions
regarding Grants.gov registration and submission, downloading forms and
Contact CenterTelephone: 800-518-4726
GrantsInfo (Questions regarding application instructions and
process, finding NIH grant resources)
National Cancer Institute (NCI)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Aging
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.
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