Department of Health and Human Services


Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute on Drug Abuse (NIDA)

Funding Opportunity Title

Functional Genetics, Epigenetics, and Non-coding RNAs in Substance Abuse (R21)

Activity Code

R21 Exploratory/Developmental Research Grant

Announcement Type

Reissue of FOA PA-11-034

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

PA-14-013

Companion Funding Opportunity

PA-14-014, R01 Research Project Grant

Number of Applications

See Section III. 3. Additional Information on Eligibility.

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

93.279 

Funding Opportunity Purpose

Genetic and genomic studies have identified genes and gene variants that potentially modulate the fundamental biological mechanisms underpinning addictive processes.  Discovery of these genes/variants, while extremely valuable, is only a first step in understanding molecular mechanisms of addiction. This Funding Opportunity Announcement encourages basic functional genetic and genomic research in two areas:  1. functional validation to determine which candidate genes/variants/epigenetic/non-coding RNA features have an authentic role in addictive processes, and 2. detailed elucidation of the molecular pathways and processes modulated by candidate genes/variants, particularly for those genes with an unanticipated role in addiction.

Key Dates
Posted Date

December 5, 2013

Open Date (Earliest Submission Date)

January 16, 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 by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Scientific Merit Review

Standard dates apply

Advisory Council Review

Standard dates apply

Earliest Start Date

Standard dates apply

Expiration Date

January 8, 2017

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.


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Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement


Section I. Funding Opportunity Description


Purpose

Genetic and genomic studies have identified genes and gene variants that potentially modulate the fundamental biological mechanisms underpinning addictive processes.  Discovery of these genes/variants, while extremely valuable, is only a first step in understanding molecular mechanisms of addiction. This Funding Opportunity Announcement (FOA) encourages basic functional genetic and genomic research in two areas:  1. functional validation to determine which candidate genes/variants/epigenetic/non-coding RNA features have an authentic role in addictive processes, and 2. detailed elucidation of the molecular pathways and processes modulated by candidate genes/variants, particularly for those genes with an unanticipated role in addiction.

Background

Genes.  Addiction to, or dependence on, drugs of abuse (including prescription drugs, nicotine, methamphetamine, cannabis, opioids, stimulants, and inhalants) is a major public health and economic problem.  Candidate genes/variants that play a role in addictive processes have been identified using methods such as human or animal genome-wide association scans, QTL characterization, gene expression profiling, forward or reverse genetic screens, proteomics, or through epigenomic analyses.  Genes and variants identified by these methods are priority targets for functional validation.  Other candidate genes/variants include genes relevant to co-occurring psychiatric disorders and social behaviors relevant to drug addiction, as well as genes relevant to other areas of NIDA’s mission, including pain and HIV/AIDS susceptibility and progression.

Functional Validation.  The most desirable functional validation would be demonstration of an epigenetic or genetic variant’s effect on a human phenotype relevant to addiction.  Effects of copy number variation, modified chromatin states, methylation patterns, higher order chromatin structure, transcriptional regulation  and how these changes are influenced by genetic variation are of interest.   An epigenetic or genetic variant could manifest itself phenotypically at the level of a molecular pathway, cell, circuit, organism, or social interaction, leading to phenotypic differences in protein function, cell morphology, neural connectivity, behavioral responses to an addictive drug, or behavioral responses to social cues.  Validation studies are encouraged at any of these levels to identify phenotypic differences relevant to addictive processes and further elucidate the driving molecular pathways that converge to elicit biobehavioral changes.  Some human functional validation studies may not be feasible or ethical, necessitating the use of in vivo animal models or in vitro strategies. 

Resources.  There are numerous public and private resources available to facilitate functional validation of genes/variants involved in addiction.  NIDA promotes the mining of databases (containing information such as model organism phenotypes, physically interacting proteins, Roadmap Epigenomics Program and ENCODE datasets, eQTL data, and gene expression levels with respect to brain anatomy) to obtain insight into the molecular mechanisms of epigenetic or genetic variant function in addictive processes.  Publicly available mutants in yeast, C. elegans, Drosophila, zebrafish, mouse, and other models can be used for functional tests.  For example, to test hypotheses about gene function and addiction, the Knock Out Mouse Project (KOMP) provides ES cells that can be used to generate knockout animals.  Reagents for RNA knockdown of genes are available for functional validation studies.  Researchers may also exploit iPS cells, human tissue banks, and post-mortem tissue collections for validation studies.   For many available resources see Neuroscience Information Framework (http://www.neuinfo.org/).

Potential Research Areas and Approaches

Applicants proposing to functionally validate genetic findings or to elucidate functional mechanisms for putative substance abuse relevant genes are encouraged to apply to this FOA.  Applicants proposing high risk/high payoff exploratory/developmental research projects with limited preliminary data are encouraged to submit an R21 grant application through this FOA, while applicants proposing discrete projects with substantial preliminary data are encouraged to submit an R01 grant application using the companion FOA.  Applicants proposing to discover new genes or gene variants involved in substance abuse may also apply using the related NIDA FOA "Discovering Novel Targets:  The Molecular Genetics of Drug Addiction and Related Co-Morbidities."  Applications to this FOA can vary greatly in depth and breadth of analysis.  They may investigate a single high priority epigenetic or genetic variant in detail (e.g. using transgenic mouse approaches) or test several hundred genes/variants rapidly (e.g. using high throughput RNA knockdown). 

NIDA seeks to understand addiction to abused substances such as prescription drugs, nicotine, methamphetamine, cocaine, cannabis, opioids, and inhalants.  Applicants should therefore focus on one or more NIDA-relevant substances of abuse.  Applicants proposing to investigate alcohol in concert with one or more NIDA-relevant drugs may also submit their CRAN-related project to this FOA, since NIDA is a member of the Collaborative Research Activity on Addiction at NIH (CRAN).  Applicants investigating only the effects of alcohol should submit using an appropriate NIAAA FOA.

The following list highlights some areas of functional genetic/genomic research that would be of interest. 

Human Studies.  Functional validation studies could use human DNA samples from phenotypically well-characterized individuals to correlate a gene variant with a particular phenotype and/or endophenotype.  Similarly, post-mortem tissue could be used for allele-specific gene expression, epigenomic mapping, or other studies.  Researchers performing assays that measure epigenomic or somatic genomic features are encouraged to focus on tissues directly relevant to the disease being investigated.  Some applicants may wish to propose epigenomic investigations of blood to identify potential biomarkers for chronic exposure to abused substances or as a potential indicator of addiction trajectory.  For blood studies, it may be prudent to propose to collect multiple samples over time from the same individual and to consider assaying only the most relevant cell type(s) contained within the sample.  Induced pluripotent stem cells (iPS cells) and neurons or other cell types derived from these cells may be useful for investigating the function of a genetic variant. 

Comparison of Wild type and Gene Variant Functions.  The molecular alteration associated with a gene variant frequently does not reveal whether the function of a particular gene is increased, decreased, or leads to unexpected functional consequences.   Yet this information is critical if one wishes to exploit a gene variant to develop a therapeutic approach.  Approaches using in vivo transgenes, in vitro biochemical assays, or other validation methods that can address these issues will help to identify the most promising molecular targets for therapeutic interventions to treat addictions. 

Addictive behavior.  Approaches that can ascribe a functional role to an epigenetic and/or genetic variant with respect to a particular aspect of addictive behavior (e.g. drug reinforcement, tolerance, withdrawal, craving, reinstatement) are of great interest, as are strategies to identify epigenetic and/or genetic variant effects on behavioral responses to other drugs or addictive stimuli, stress, changes in social situations, food, other natural rewards, or other environmental stimuli.  In general, applicants are advised to carefully consider their selection of a behavioral model of drug exposure or addiction and to justify why this behavioral model is the most compelling choice for the proposed aims of their application.  

Genetic Models.  Established genetic models (such as yeast, C. elegans, sea slug, Drosophila, zebrafish, mouse, and primate) as well as emerging genetic models (such as rat) can be used to examine in vivo epigenetic and/or genetic variant function.  Strategies could include exploitation of available genetic knockouts or other mutants, knockin of gene variants, or conditional reduction or overexpression of wild type and variant alleles.  Since some model organism genomes (e.g. C. elegans and Drosophila) do not encode obvious opioid or cannabinoid receptors, functional validation studies involving these pathways would need to use genetic models such as zebrafish or mouse.  Cross-species validation of functional alleles is encouraged, as are studies investigating sex differences with respect to epigenetic and/or genetic variant function.  Functional validation approaches that could lead to the development of in vivo models of addictive processes or could facilitate future screening for therapeutic agents are of great interest. 

Genomic Manipulation.  Depletion of candidate gene mRNAs in cells, tissues, brain regions, or whole organisms using RNA interference or related approaches can be used to discover or validate phenotypes.  These phenotypes could range from the cellular (e.g. changes in morphology or function of synapses, dendritic spines, or neurons) to the organismal (e.g. changes in behavioral responses to drugs).  Similarly, applicants may wish to exploit locus-specific genome editing approaches such as the use of TALE, CRISPR or related strategies to address genetic or epigenetic function.  Strategies to investigate the effects of genetic or epigenetic variants in specific cell types or during specific temporal windows using opto-epigenetic or chemo-epigenetic approaches are also encouraged. 

Epigenetics and Epigenomics.  Identification of cell type-specific epigenomic features associated with addictive processes as well as functional validation of epigenetic mechanisms of gene regulation in the context of neuroscience or addiction biology are encouraged as are studies aiming to discover or better characterize histone or DNA modifications important for neuronal signal transduction or regulation of gene expression.  Exploitation of chromatin structure assays (e.g. Hi-C, ChIA-PET) or microscopy techniques to explore chromatin dynamics in response to substances of abuse are also of interest. 

Somatic Genomic Variation and Regulatory Elements.  Studies investigating somatic genomic variation and its regulation and function in the nervous system and in response to drugs of abuse (including the role of repetitive DNA, retrotransposons, and other sources of somatic genomic variation as well as their potential functional effects on gene expression, alternative splicing, or chromatin state) are encouraged.  Studies exploiting artificial somatic genomic variation such as DNA barcoding to tag brain cells for cell censuses, connectivity studies, or functional characterization are also of interest.  Studies to assign drug abuse-related function to variants in non-coding RNAs, microRNAs, gene regulatory elements, transposable elements, or other putative non-protein coding regions of the genome are appropriate.  

Non-coding RNAs and RNA Modifications.  Studies to identify and characterize non-coding RNAs relevant to neuroscience and addictive processes are encouraged.  Applicants might wish to investigate the role of miRNA regulation in substance abuse, especially the identification of miRNA targets and associated mechanistic pathways.  Investigations into novel and poorly understood classes of regulatory non-coding RNAs such as circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), or RNAs associated with chromatin are of great interest.  Applications investigating the potential functional roles of RNA modifications in mRNAs or regulatory RNAs in the nervous system are also encouraged. 

Systems-level Approaches.   Bioinformatic resources can be mined to identify causal genes or gene variants or to generate testable hypotheses concerning the function of candidate genes and groups of genes.  Some data types that could be used include:  gene expression, epigenomic, transcription factor binding information, proteomic, metabolomic, interactome, functional genomic, in silico mapping data, connectome, or neuroanatomical expression.  Studies could test to see if sets of candidate disease genes are co-expressed in a particular brain region or cell type, or function together in a signal transduction cascade. 

Cellular or Circuit-level Approaches.  Studies comparing epigenetic and/or genetic variant functional consequences at the cellular and circuit levels, especially with respect to drug challenge are encouraged.  Such outcomes may include, but are not limited to, studies of differences in neurotransmission, intracellular trafficking of proteins or RNAs, neurophysiology, signal transduction, as well as synaptic and dendritic physiology or morphology.  Functional responses to changes in the neural environment due to steroid hormones, cytokines and chemokines, neuropeptides or neurotransmitter imbalance are also sought. 

Developmental and Transgenerational Studies.  Investigations into the functional effects of genes/variants on organism development in the context of drug exposure and addiction pathways are also of great interest.  Approaches investigating epigenetic and/or genetic variant roles in neuronal differentiation, brain patterning, circuit formation, plasticity of brain circuitry during adolescence, gene x environment, gene x development, or gene x environment x development functional effects are all appropriate. In addition, there are some indications that parental exposure to certain drugs of abuse may lead to transgenerational phenotypic effects.  Studies exploring these effects, including whether or not these effects are inherited through epigenetic or non-epigenetic mechanisms, are encouraged. 

Imaging Strategies.  Studies to identify in vivo human or animal gene/variant/epigenetic effects on neuronal activity or brain functions relevant to addiction are appropriate.  These may include specific behaviors associated with addictive processes that are influenced by neurocircuitry or neuroconnectivity that may be assessed by imaging techniques such as fMRI, DTI, MRS, or PET.  Studies in live, behaving animals that examine brain function in response to commonly abused drugs are encouraged, especially in animal models of adolescent drug exposure. 

Brain Energetics.  Studies investigating the functional interplay between molecular regulation of brain energy utilization and brain and/or behavioral changes resulting from chronic exposure to abused substances are of interest. 

Extracellular Vesicles.  Secreted extracellular vesicles (EVs) such as exosomes and microvesicles play an important role in many biological processes.  EVs appear to play several interesting roles in the nervous system and may function in 1. neuronal-glial communication, 2. synaptic plasticity, and 3. immune surveillance.  Potential studies could include:  1. the functional role of EVs and their cargoes in the nervous system, particularly with respect to neuroplastic processes and substance abuse exposures, 2. whether or not EVs in serum, cerebral spinal fluid, or other body fluids might be useful biomarkers for substance abuse exposure or addiction trajectory, and 3. whether or not EVs might have therapeutic utility for cell-specific treatment of substance abuse. 

HIV/AIDS.  Functional genetic and genomic studies relevant to HIV/AIDS infection and/or progression, including molecular regulation of HIV latency are encouraged.

Translational.  The use of functionally validated gene variants, RNAs, or proteins for clinical applications or as validated biomarkers to predict phenotypes are of interest, as is the development of cell-type specific targeting approaches to deliver DNA, RNA, protein or other potentially therapeutic cargoes.

Special Considerations

HIV/AIDS Counseling and Testing Policy for the National Institute on Drug Abuse:  In light of recent significant advances in rapid testing for HIV and in effective treatments for HIV, NIDA has revised its 2001 policy on HIV counseling and testing.  NIDA-funded researchers are strongly encouraged to provide and/or refer research subjects to HIV risk reduction education and education about the benefits of HIV treatment, counseling and testing, referral to treatment, and other appropriate interventions to prevent acquisition and transmission of HIV.  This policy applies to all NIDA funded research conducted domestically or internationally.  For more information see http://grants.nih.gov/grants/guide/notice-files/NOT-DA-07-013.html.

National Advisory Council on Drug Abuse Recommended Guidelines for the Administration of Drugs to Human Subjects:  The National Advisory Council on Drug Abuse (NACDA) recognizes the importance of research involving the administration of drugs with abuse potential, and dependence or addiction liability, to human subjects.   Potential applicants are encouraged to obtain and review these recommendations of Council before submitting an application that will administer compounds to human subjects.  The guidelines are available on NIDA's Web site at http://www.drugabuse.gov/funding/clinical-research/nacda-guidelines-administration-drugs-to-human-subjects

Points to Consider Regarding Tobacco Industry Funding of NIDA Applicants: The National Advisory Council on Drug Abuse (NACDA) encourages NIDA and its grantees to consider the points it has set forth with regard to existing or prospective sponsored research agreements with tobacco companies or their related entities and the impact of acceptance of tobacco industry funding on NIDA's credibility and reputation within the scientific community.  Please see http://www.drugabuse.gov/about-nida/advisory-boards-groups/national-advisory-council-drug-abuse-nacda/council-statements/points-to-consider-regarding- for details.

Data Harmonization for Substance Abuse and Addiction via the PhenX Toolkit:  NIDA strongly encourages investigators involved in human-subjects studies to employ a common set of tools and resources that will promote the collection of comparable data across studies and to do so by incorporating the measures from the Core and Specialty collections, which are available in the Substance Abuse and Addiction Collection of the PhenX Toolkit (www.phenxtoolkit.org).  Please see NOT-DA-12-008 (http://grants.nih.gov/grants/guide/notice-files/NOT-DA-12-008.html) for further details.

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
Renewal
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

Direct costs are limited to $275,000 over a two-year period, with no more than $200,000 in direct costs allowed in any single year. Application budgets should reflect the actual needs of the proposed project.

Award Project Period

The maximum project period is two years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information


1. Eligible Applicants


Eligible Organizations

Higher Education Institutions

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are  eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are  eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are  allowed.

Required Registrations

Applicant Organizations

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

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

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

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

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

3. Additional Information on Eligibility


Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

Section IV. Application and Submission Information


1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.

Page Limitations

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

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R or Modular Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

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.

Appendix:  Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report

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

PHS 398 Cumulative Inclusion Enrollment Report

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

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

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

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

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

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

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

Post Submission Materials

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

Section V. Application Review Information


1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this FOA, please note the following:

The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

Overall Impact

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

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?  

Investigator(s)    

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

If the project involves 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?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Additional Review Criteria

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

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children 

When the proposed project involves 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.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

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

Renewals

For Renewals, the committee will consider the progress made in the last funding period.

Revisions

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

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

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

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information


1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.      

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

3. Reporting

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement. 

Section VII. Agency Contacts

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

Application Submission Contacts

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

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

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

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-435-0714
TTY: 301-451-5936
Email: GrantsInfo@nih.gov

Scientific/Research Contact(s)

John Satterlee, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1020
Email: satterleej@nida.nih.gov

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Cheryl Nathaniel
National Institute on Drug Abuse (NIDA)
Telephone: 202-526-0108
Email: nathanic@nida.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.


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