Expired PAR-13-364: Development of Assays for High-Throughput Screening for Use in Probe and Pre-therapeutic Discovery (R01)

Part 1. Overview Information

Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Mental Health (NIMH) National Institute on Alcohol Abuse and Alcoholism (NIAAA) 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	March 9,2016 - Notice of NIDDK's Withdrawal from Participation in PAR-13-364. See Notice NOT-DK-16-012. NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) 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.

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:

Assays for molecular chaperones or molecules that improve the post-translational targeting, folding, or assembly or proteins, especially involving mutant proteins responsible for inborn errors of metabolism, metabolic disorders, cancers, or rare diseases.
Screens involving immunological targets, especially in the context of research that focuses on autoimmune diseases or areas where specific antibodies stimulate or inhibit relevant processes.
Model organism-based assays, such as those using bacteria, yeast, Drosophila, C. elegans, zebrafish, etc. that have relevance to the research areas of the sponsoring Institutes. There is particular interest in projects that aim to significantly improve on the automation of imaging analysis and whole organism handling.
Assays for compounds that identify multi-protein signaling complexes, or that modify the function of signaling complexes, regulatory networks, and sorting machinery.
Assays to identify highly specific molecular markers that might be useful for identifying or tracking a particular cell or function.
Biochemical or cell-based assays of activity, behavior, or interaction of proteins (e.g. protein-protein interaction or protein-chromatin interaction) and other molecules of interest.
Assays of cellular or molecular phenotypes such as subcellular imaging ( high-content screening , HCS), offers the potential to identify the effect first and to isolate the target later.
Modulation of expression of genes of interest, including effects on transcription factors, transcription, translation or RNA splicing.
Assays that biochemically incorporate an entire metabolic or macromolecular biosynthetic pathway from an organism.
Whole cell assays that employ engineered cells rendered hypersensitive to a targeted pathway.

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.

Proposed work should include assay development plans sufficient to demonstrate reproducibility in a low-to-moderate throughput setting and should be feasible for adaptation to an automated, high-throughput screening approach. It is expected that the awardee(s) will establish a ready-to-go HTS assay during 3-year funding period, including:

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).

There are a number of characteristics that make an assay suitable for HTS approaches. The assay should be robust, reproducible, and have a simple readout that is amenable to automated analysis. At the end of the project period, successful assays would be able to be miniaturized into formats such as 96-, 384-, or 1536-well automated screens. A broad range of models share these features, including molecular and biochemical assays, cellular models, cell based assays, and simple model organisms.
If achievable, pilot screening for target validation from a small compound library, or other bioactive molecules (e.g., NIH Clinical Collection at http://www.nihclinicalcollection.com /, LOPAC1280 at http://www.sigmaaldrich.com/chemistry/drug-discovery/validation-libraries.html , etc.) should be performed as a highly desirable validation step for translation of the assay to HTS. Alternatively, dose-ranging studies for a limited set of agents having known interaction with the proposed target should be proposed. The intent of this characterization is to demonstrate the ability of the assay to pharmacologically distinguish structurally diverse ligands.

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 (https://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

Primary HTS assay: Assays developed for HTS may be target-, pathway-, and phenotype-based assays. Some examples include: a) target-based biochemical or cellular assays that measure activities of enzymes, receptor-ligand bindings, protein-protein interactions, ion channels, transporters, nuclear receptors and other transcription factors, and other new targets emerging from genetic and proteomic research in model systems and in human diseases; b) cell- or organism-based assays that detect phenotypic changes that may involve unidentified molecular targets; and c) non-traditional targets of interest such as nucleic acids, protein folding, polymorphic gene products, post-transcriptional editing or splicing of gene products, and protein or RNA stabilization. The assay detection methods may include fluorescence, luminescence, absorbance, fluorescence resonance energy transfer (FRET), time-resolved fluorescence resonance energy transfer (TR-FRET), fluorescence polarization, flow cytometric measurements, fluorescence imaging, bioluminescence resonance energy transfer (BRET), AlphaScreen, scintillation proximity assay (SPA), electrophysiological assay, biophysical assay, etc. In general, the proposed HTS assay should adopt an adequate detection principle that results in a sensitive detection of even weak binders with expected low rates of false positives and false negatives. Assays that require only addition of reagents (i.e., mix and measure or homogeneous assays) and endpoint measurements are preferable. Assays that require long-time kinetic recordings, high content imaging, multiple washing and aspiration steps, whole organism preparations, reagents of exceedingly high cost, and radioactive materials may be re-configured using alternative assay technologies to simplify the process.
Follow-up assays: A cascade of follow-up assays need to be in place to efficiently and effectively remove false positives because the primary HTS assay may typically generate hundreds to thousands of hits, of which most may be false positives or chemically intractable. The post-HTS follow-up assays include: a) an assay that is essentially an HTS assay with orthogonal detection scheme (e.g., switching light detection mode or wavelength to avoid intrinsic compound interference); b) a target-minus assay (e.g., coupling enzymes in the absence of the assay target enzyme, parental cell line without the assay target protein, etc.); c) an assay that is different in biological context and process (e.g., protein functional assay vs. protein binding assay, RT-PCR and Western assay vs. reporter gene assay, cell-based assay vs. biochemical assay, etc.); d) cytotoxicity assay; (e) target selectivity assays; (f) specificity assays to distinguish biological activities of chemical entities among orthologous targets across organism species through kingdoms (e.g., yeast vs. mammalian cell targets, parasite vs. host targets); (g) mode of action assays (e.g., allosteric vs. orthosteric, competitive vs. noncompetitive or uncompetitive); and (h) target identification assays. The assays farther downstream may also include cellular and tissue models pertaining to the relevant physiology or pathophysiology.
Assay Performance and Robustness: Assays should be robust, reproducible, and meet minimum statistical thresholds for robotic screening. Performance characteristics of an assay should be suitable and reliable for automated HTS. Robustness is a measure of the capacity of the assay to remain unaffected by small changes in method parameters and provides an indication of its reliability during normal run conditions. The Z-factor, a calculated parameter, is commonly used to quantify assay performance, and it accounts for both the signal-to-background and the amount of variability in the assay. Assays with Z parameters >0.5 are typically HTS-compatible assays. For example, a signal-to-background ratio of at least 5 and a coefficient of variation (CV) below 10% (determined, for example, from measurements across an entire plate), and the statistical parameter Z has an acceptable lower limit of 0.5.
Assays Suitable for Automation: Assays should be developed not only toward acceptable statistical quality (Z'-value) but also toward the most sensitive detection of weak inhibitors to maximize the potential of finding new chemical series or scaffolds. Assays should be simple enough for automated handling and steps such as centrifugation, filtration and extraction should be avoided to increase automation for an HTS platform.
Diversity of Assay types: Assays developed for HTS can be roughly characterized as target-based or phenotypic assays. A biological target is a macromolecule or a set of macromolecules in a biochemical pathway. Phenotypic assays measure a signal which corresponds to a complex response such as cell survival, proliferation, localization of a protein, nuclear translocation, etc. The molecular target is not assumed in a phenotypic assay. Many of the in vitro biological and disease models currently used to study the effects of specific compounds or molecular perturbations can be adapted to HTS formats. A large number of ion channels, transporters, transmembrane receptors, protein protein interactions, protein DNA, and protein RNA interactions, perhaps even RNA/DNA itself might form innovative targets for modulation via low molecular weight compounds.

Utilization of Related Resources

"Assay Guidance Manual" published in May 2012 on NIH NCBI Bookshelf provides guidance to investigators who are interested in developing assays useful for the evaluation of collections of molecules to identify probes that modulate the activity of biological targets, pathways, and cellular phenotypes. These probes may be candidates for further optimization and investigation in drug discovery and development.
Applicants are encouraged to take advantage of the resources provided by the NIH Molecular Libraries Production Centers Network (MLPCN) that provide access to a unique compound library of >350,000 compounds, robotics to carry out assays, informatics to interpret results, and synthetic and medicinal chemistry resources which can optimize the small molecule compounds with the desired properties as probes and pre-therapeutic leads. Descriptions of the network screening and chemistry centers are available at: http://mli.nih.gov/mli/.

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

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

State Governments
County Governments
City or Township Governments
Special District Governments
Indian/Native American Tribal Governments (Federally Recognized)
Indian/Native American Tribal Governments (Other than Federally Recognized)
Eligible Agencies of the Federal Government
U.S. Territory or Possession

Other

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

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.

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

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

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

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:

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

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