Expired PA-13-337: Neuroscience Research on Drug Abuse (R21)

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	Neuroscience Research on Drug Abuse (R21)
Activity Code	R21 Exploratory/Developmental Research Grant
Announcement Type	Reissue of PA-10-269
Related Notices	January 9, 2017 - This PA has been reissued as PA-17-112. 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	PA-13-337
Companion Funding Opportunity	PA-13-338, R01 Research Project Grant PA-13-336, R03 Small Grant Program
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.279
Funding Opportunity Purpose	Substance abuse results in widespread changes in brain structure and function, and research is needed to explain these changes and how they affect behavior. The goals of the research areas described in this Neuroscience of Drug Abuse FOA are to understand the neurobiological mechanisms underlying drug abuse and addiction, with special emphasis on changes that occur during chronic drug use, withdrawal and relapse. An understanding of the basic mechanisms underlying drug addiction can help to identify targets for prevention and treatment interventions. Research utilizing basic, translational, or clinical approaches is appropriate.

Key Dates

Posted Date	August 26, 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 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
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

Background

Licit and illicit drug use places a large burden on the nation’s health care systems and the economy, costing billions of dollars each year. According to the 2011 National Household Survey, about 22.5 million Americans, ages 12 or older, or about 8.7 percent of the population, were current users of illicit drugs and nearly 22 percent of the population used tobacco products. Drug use often begins during adolescence and its effects are more long-lasting and resistant to treatment than when initiation occurs during adulthood. Additionally, drug use is a risky behavior that occurs with high frequency among those with HIV/AIDS and often co-exists with other psychiatric disorders. Substance abuse and addiction are serious national health issues and understanding their neurobiological and behavioral mechanisms would enable us to develop strategies for effective treatment and prevention.

Addiction is a chronic, relapsing neurobehavioral disorder that is characterized by the compulsive self-administration of abused substances despite their negative consequences. NIDA-supported research has made significant progress in identifying the receptors and some mechanisms of action for each major drug of abuse. In addition, there is a reasonable understanding of the changes that occur in the brain as a result of acute exposure to drugs, but there is a need to know more about the changes that occur during and after chronic exposure. Similarly, we need to understand how pharmacological, behavioral, or other therapeutic interventions affect the brain and which mechanisms the brain uses to protect itself from the deleterious effects induced by abused drugs. The research encouraged by this FOA should lead to improved understanding of drug abuse and its consequences.

Research Scope

The evolution and vitality of the biomedical sciences require a constant infusion of new ideas, techniques, and points of view. These may differ substantially from current thinking or practice and may not yet be supported by substantial preliminary data. By using the R21 activity code, the NIH seeks to foster the introduction of novel scientific ideas, model systems, tools, agents, targets, and technologies that have the potential to substantially advance biomedical research.

The R21 activity code is intended to encourage new exploratory and developmental research projects. For example, such projects could assess the feasibility of a novel area of investigation or a new experimental system that has the potential to enhance health-related research. Another example could include the unique and innovative use of an existing methodology to explore a new scientific area. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on a field of biomedical, behavioral, or clinical research.

Applications for R21 awards should describe projects distinct from those supported through the traditional R01 activity code. For example, long-term projects, or projects designed to increase knowledge in a well-established area, will not be considered for R21 awards. Applications submitted to this FOA should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications.

This FOA encourages basic neurobiological studies in in vivo and in vitro model systems as well as studies in humans. The topic of study may range from that of a single protein or gene, to that of the entire organism. The level of analysis may be at one or more levels, and studies that incorporate changes over time across multiple scales (e.g., gene to behavior, abuse to dependence, adolescent to adulthood) are sought. Multi- and inter-disciplinary studies are especially encouraged. Studies should incorporate analyses on sex-differences when appropriate. Studies that examine the role of drug abuse in exacerbating the effects of HIV infection, especially HIV-associated neurocognitive disorder (HAND) are of interest. Topics that would be appropriate to this FOA are described below, but they are not intended to be exhaustive or exclusionary.

Developmental Approaches

This FOA encourages the conduct of neurodevelopmental studies throughout life, such as:

Research that characterizes neural development and its interaction with abused substances during sensitive developmental periods, such as the peripubertal period.
Research during aging, particularly on interactions of drugs of abuse with therapeutic pharmaceuticals.
Research on the effects of abused drugs, as well as those that are potential treatments for drug abuse, on neurogenesis, cell differentiation, proliferation, migration and survival in young and adult animals,
Assessments of the consequences and reversibility of such alterations.
Examinations of the influence of addictive substances on the interactions between stem/progenitor cells and their microenvironment.

Cellular, Molecular, and Genetic Approaches

NIDA encourages the use of cellular and molecular approaches to identify and understand the mechanisms underlying addiction. Studies encompassing human genetics, molecular genetics, epigenetics, and pharmacogenetics are of interest. Research questions may include, but are not limited to:

The study of neural plasticity engendered by abused drugs, therapeutic agents and behavior.
Identification of neuroadaptations that can lead to persistent changes in the brain and arise both to protect and potentially repair neurons that are damaged or dysregulated by exposure to drugs, or toxic cytokines associated with neuroAIDS.
Functional studies of novel receptor-receptor interactions (homo- and hetero- dimerization of receptor subunits, or receptor mosaics) and their response to drugs.
Functional studies of the effects of novel receptor-protein interactions, including those with scaffold, RGS, kinase, arrestin, GPCRs, TRP ion channels, and PDZ proteins.
Identification and validation studies for novel targets or ligands on neurons and glia
The use of patient- and disease-specific inducible pluripotent stem cells as a model system for the study of unique cellular and molecular events that occur in drug-abusing individuals for the purpose of developing therapeutic agents or screening drug toxicity.
Studies of the interactions of drugs with genes at different stages of CNS maturation.
Studies may employ or develop novel genetic tools to map circuits critical to the understanding of drug abuse. These may include tools such as spatial-temporal, or conditional knockouts, receptor- or subtype-selective antagonists that can demonstrate conclusively the site, developmental stage, and the receptor type(s) involved in the action of drugs of abuse.
Studies may include functional comparisons of populations of subjects with different gene dosing, whether naturally-occurring (such as comparison of different strain along a dimension) or manipulated experimentally.
Genetic and epigenetic screening and analysis of addiction variations and genetic mechanisms using novel cellular systems, such as induced pluripotent stem cell (iPSC) derived from addicts.
Use of systems-level approaches to understand the effects of drugs on the biology of glia and neurons.
Additional areas of interest include, but are not limited to, replication and validation studies in molecular genetics, genomics, and proteomics.

Circuit-level Approaches

Applications using circuit-level approaches are encouraged, especially to understand chronic exposure to drugs, different drug administration regimens, or withdrawal. These might include in vivo or in vitro studies of normal and drug-exposed tissues from humans and animals to determine the effects of abused substances on neurophysiology, changes in distributions of receptors, or delineation of circuits through the use of neuroimaging techniques such as optogenetics, two-photon imaging, or in vivo spectroscopy, PET- or BOLD imaging. Such studies might include, but are not limited to:

Development and application of novel technologies that that can manipulate (e.g., activate and silence) and track neural activities (excitability and inhibition) in freely moving animals, with spatiotemporal precision.
Examination of the temporal course of the addictive process on dendritic spine development and retraction in na ve, drug-treated, and drug-withdrawn tissues within specific brain regions and circuits, linked to their physiological and behavioral outcomes.
Modulation of neural systems by the neurochemical environment, including steroid hormones and peptides, trophic factors and cytokines/chemokines, and by patterns of neural activity (i.e., tonic vs phasic activity).
The interaction of abused substances with the neuronal-glial interface, the study of glial-derived inflammatory and protective factors (neuroimmunology), and the linkage of the anatomy and physiology with outcomes.
Neurobiological, physiological and behavioral adaptations expressed by understudied classical neurotransmitter systems such as GABA and glutamate.
Identification of the circuitry linking brain regions involved in the components of the addictive process and the corresponding changes in gene or protein expression or neurochemistry or cognitive function that occur as a result of drugs of abuse.
Studies of compensatory changes that occur within neurotransmitter systems as a result of drug exposure, especially drug self-administration, and their functional consequences.
Comparison of the neural circuits and behaviors that are central to non-drug reward processes with those directly linked to drug-induced reward, including obesity and co-morbid mental disorders.
Drug-induced modifications of glia that impact the function of the neural circuit, including synaptic excitability, alterations of neurotransmission, or the formation of synapses and/or synaptic elements such as spines.

Behavioral Approaches

NIDA is committed to the support of studies of the behavioral neuroscience of substance abuse in humans and in animals, including the development and use of preclinical behavioral models of drug abuse and addiction that are faithful to their clinical counterparts. Such studies might include, but are not limited to:

Neural control of cognitive and affective processes such as craving, attention, memory, decision-making, impulse control, etc.
Identification of neurobiological processes critical in resilience or vulnerability to drug abuse and the development of models of compulsive drug-taking or other forms of behavioral dysregulation.
Development of animal models that expand traditional paradigms to incorporate a wide range of subject and environmental variables so as to enhance their translational potential for prevention and treatment
Since drug abuse and addiction may signal the operation of pathological learning processes, the mechanisms of learning and memory pertaining to drug abuse are relevant.
Influence of the environmental context, including the roles of cues, novelty, and environmental enrichment and impoverishment on the course of addiction.
Standardization of experimental measures to allow comparisons between humans and non-human primates.

Development of Tools and Reagents for the Study of Neuroscience and Substance Use

The study of the genetic, molecular, cellular, behavioral, and circuit-based mechanisms involved in substance abuse and addiction, and the development of associated therapeutic strategies will benefit from methods, tool, and reagent development research and approaches as well. There is a need for:

Improved neuroimaging techniques as well as novel, innovative molecular probes/ligands for receptors, transporters, enzymes, and other neurobiological targets that permit non-invasive deep imaging of neuronal activity at the level of the single cell.
Development and application of genetically encoded voltage sensors to map neural activity with circuits involved in addiction and neuroplasticity.
Development and use of high throughput screening methods and application of associated technologies to discover new endogenous ligands and critical biomarkers of known drug effects.
Development of innovative technologies in the service of behavioral and neurobiological assessments and the assessment of novel therapeutic regimens aimed at producing favorable neuroadaptations.
Classification of cell types by genetic and/or protein complement and activity before and after chronic exposure to/withdrawal from abused substances or therapeutics aimed at mitigating drug use.
Single cell analysis-based approaches to study heterogeneities of the neurons that form identified circuits that underlie learning and motivation.
Develop novel behavioral screens or computational models to predict treatment response between drugs of abuse and medications.

Computational Modeling and Secondary Data Analysis

Development of computational models of neural function in the presence and absence of drug to integrate structural and behavioral neurobiology.
Methods for manipulating and interpreting large data sets (preclinical and clinical data) related to substance abuse and its treatment.
Secondary data analysis for molecular, preclinical and clinical data.
Collection and interpretation of pharmacogenetic data with respect to its relationship to drug targets or clinical utility.
Development of computational models that identify patterns of neural activity and synaptic activation.

Additional Areas of Interest

HIV/AIDS and drug abuse: there is a need to characterize the interaction of addictive drugs with proteins and the morphological changes in the central nervous system that are involved in the development and expression of HIV/AIDS, particularly neuroAIDS.
Chronic Pain: studies aimed at understanding the underlying neurobiological mechanisms of pain including the changes that occur in response to chronic pain and exposure to treatments for pain; mechanisms that underlie the sex differences in the response to pain; and the development of non-addicting analgesics for the control of pain. For example, the development of novel therapeutics or studies that combine different classes of drugs with opiates for the control of pain (and the reduction of tolerance) may be considered.
Pharmacotherapeutic discovery, development, and characterization: there is a need for studies that incorporate models of polydrug use and compare their physiological and behavioral outcomes.
Co-morbidity: research aimed at elucidating the neurobiological mechanisms involved in the comorbidity between substance abuse and other psychiatric disorders. The high incidence of such comorbidity is well documented, but the reasons for this association remain obscure. Preclinical and clinical studies could further our understanding of the extent to which these disorders share a common neurobiological etiology.

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 https://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 (https://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 Resubmission Revision
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 Maximum of $275,000 over two years with no more than $200,000 in either year.
Award Project Period	The maximum period is 2 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