Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute on Alcohol Abuse and Alcoholism (NIAAA) National Institute on Drug Abuse (NIDA)
Funding Opportunity Title	Mechanisms of Alcohol and Nicotine Co-Addiction (R21)
Activity Code	R21 Exploratory/Developmental Research Grant Award
Announcement Type	Reissue of PA-09-098
Related Notices	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 3, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same. August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications. May 30, 2013 (NOT-OD-13-074) - NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013. April 24, 2013 - See Notice NOT-DA-13-025. Notice of NIDA's Participation.
Funding Opportunity Announcement (FOA) Number	PA-13-193
Companion Funding Opportunity	PA-13-194, R01 Research Project Grant
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.273; 93.279
Funding Opportunity Purpose	This FOA encourages R21 applications from institutions/organizations that propose to study neurobiological and behavioral mechanisms contributing to concurrent alcohol and nicotine co-addiction.

Posted Date	April 12, 2013
Open Date (Earliest Submission Date)	September 16, 2013
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.
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	September 8, 2016
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.

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

By using the R21 mechanism, the NIAAA 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. Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. 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 under this mechanism should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) encourages grant applications to examine mechanisms contributing to concurrent alcohol and nicotine dependence. Co-occurring alcohol and nicotine dependence is common. Research suggests that alcohol dependence and nicotine dependence have similar genetic, neurochemical and behavioral characteristics. It is not well understood, however, whether common mechanisms underlie the comorbidity of alcohol and nicotine use and dependence. The purpose of this funding opportunity announcement is to promote research to study neurobiological and behavioral mechanisms of dependence and how alcohol and nicotine use interact through these mechanisms to promote dependence. Such an understanding is essential to guide the development of better prevention and treatment strategies for alcohol and nicotine co-abuse.

Alcohol and nicotine are the most commonly misused non-therapeutic drugs in the United States. Nearly 50 million Americans smoke cigarettes; almost 20 million Americans are alcohol dependent or regularly drink alcohol in harmful quantities. These are not mutually exclusive populations. As many as 88% to 96% of alcoholics are also smokers, and approximately 60% of smokers binge drink or consume significant amounts of alcohol. Individuals who co-abuse alcohol and nicotine have worse clinical outcomes than individuals who use either drug alone. Thus, there is a need to better understand neurobiological and behavioral mechanisms underlying alcohol and nicotine co-dependence.

Human twin studies and studies using selected strains of laboratory animals suggest a shared genetic predisposition to develop alcohol and nicotine dependence. In addition to seeking further research on common genetic determinants of alcohol and nicotine dependence, we also seek proposals to examine how genetic factors contribute to the development of common intermediate traits (e.g., risk taking, novelty seeking, and sensitivity to stress) that predispose one to alcohol and nicotine dependence. Furthermore, studies of how these common intermediate phenotypes impact alcohol and nicotine dependence are encouraged.

Human and animal studies have found that alcohol and nicotine exert both synergistic and antagonistic effects on behavior which may contribute to their concurrent use. For example, preclinical studies have shown that nicotine’s stimulant effects may offset alcohol’s acute sedative effects and cognition-impairing effects. Early postnatal exposure to alcohol enhances nicotine’s analgesic and reinforcing effects in adolescent rats, suggesting that early exposure to alcohol influences the strength of subsequent reinforcing effects of nicotine in later developmental stages. In humans, alcohol pretreatment increases cigarette smoking and craving as well as self-reported subjective rewarding effects of nicotine. A transdermal nicotine patch enhanced alcohol’s subjective rewarding and pharmacological effects in humans. The mechanism underlying such effects, and whether the combination of alcohol and nicotine has a greater effect than either drug alone have not been thoroughly investigated.

Role of nicotinic acetylcholine receptors in alcohol and nicotine co-addiction

One of the most probable targets for alcohol and nicotine to interact is nicotinic acetylcholine receptors (nAChRs). Several different types of nAChRs are involved in nicotine addiction. For example, cigarette smoking resulted in nearly complete occupancy of alpha4/beta2 nAChRs and was accompanied by a reduction in cigarette craving, indicating involvement of alpha4/beta2 nAChR in nicotine’s reinforcing effects. Alcohol enhances alpha4/beta2 nAChR function, but inhibits the activity of alpha7 nAChRs in vitro. By potentiating or inhibiting the function of different nAChRs, alcohol affects nicotine’s affinity for these receptors. A recent study using alpha4 nAChR knock-out (KO) mice points to a direct involvement of alpha4 nAChRs in modulating alcohol reward. In addition to alpha4, other studies have implicated alpha7 nAChRs in mediating alcohol’s (but not nicotine s) ability to disrupt contextual learning. It remains to be determined whether and how nicotine and alcohol interactions at nAChRs contribute to their co-dependence.

Neurobiological mechanisms underlying alcohol and nicotine co-addiction

Nicotine and alcohol ultimately affect common neural circuits that support motivational and hedonic processes. Both drugs exert their reinforcing effects through complex interactions with many neurotransmitters including gamma-aminobutyric acid (GABA), glutamate, dopamine (DA), serotonin, opioid, cannabinoid, and acetylcholine. For example, drugs that block nAChRs reduce alcohol drinking suggesting that nicotine’s primary receptor target plays a role in supporting alcohol ingestion. Pharmacological blockade of nAChRs in the ventral tegmental area (VTA) and nucleus accumbens (NAcc) attenuates alcohol consumption in rats. Varenicline, an alpha4/beta2 nAChR partial agonist, reduces alcohol drinking without affecting sucrose intake in rats. These interactions may be mediated by mesolimbic dopaminergic function. Further, naltrexone, an opioid receptor antagonist approved for treating alcohol dependence, decreases the number of cigarettes smoked daily by humans as well as self-reported satisfaction experienced during smoking, suggesting the role for endogenous opioid systems in smoking and drinking. Given the wide range of receptor systems through which alcohol and nicotine interact, additional research is needed to delineate specific contributions of these systems in mediating concurrent alcohol and nicotine dependence. Studies of other molecular adaptations (e.g., CREB and delta FosB) and their functional roles in alcohol and nicotine co-abuse are also encouraged.

Unlike mesocorticolimbic pathways, the habenulo-interpeduncular pathway has recently received much attention for its role in absence of reward in humans and monkeys. Nicotine activates this pathway through alpha5 nAChRs, triggering an inhibitory motivational signal that limits nicotine intake. Thus, nicotine’s action in the habenulo-interpeduncular pathway is the opposite of the mesocorticolimbic reward pathway. The involvement of this pathway following acute and/or chronic alcohol treatment as well as combined alcohol and nicotine use, and how such use translates into subsequent alcohol and nicotine intake remains to be determined.

Cross-tolerance may also play a role in co-occurring alcohol and nicotine use. For example, chronic administration of alcohol to mice induced tolerance to behavioral effects of alcohol as well as cross-tolerance to the hypothermic and bradycardiac effects of nicotine, and vice versa. This relationship may be especially important during adolescence in that adolescent nicotine exposure might facilitate alcohol use in adulthood. Further research examining nicotine and alcohol cross-tolerance across developmental stages is needed.

Role of conditioned and discriminative stimuli in alcohol and nicotine co-addiction

Cues associated with drugs can elicit feelings of craving and often trigger unintended relapse episodes in people trying to maintain abstinence. Alcohol and nicotine have well-defined stimulus properties. Thus, during alcohol and nicotine co-use, one drug may serve as a cue for the expectancy of the other. After abstaining from one drug, cues associated with ingesting the other, such as interoceptive discriminative stimulus effects, may precipitate craving and relapse. This possibility has received very little experimental attention, but may have important implications for designing treatment plans. Alternatively, in operant behavior studies, when two behaviors are consistently reinforced concurrently in the same environment, as is the case with concurrent smoking and drinking, discontinuing one reinforcer (e.g., smoking) can trigger the resurgence of behaviors directed toward the other reinforcer (e.g., drinking). Additional experimental research is needed to examine the consequences of discontinuing or administering one drug (i.e., either alcohol or nicotine) on reinstating the ingestion of the other.

Role of neuroimmune factors in alcohol and nicotine co-abuse

Recent studies support the idea that a complex communication network exists between the central nervous and immune system. The interplay between these diverse systems occurs through a complex set of neurotransmitters, cytokines and hormones that act to modulate inflammation and restore homeostasis. Nicotine exposure exerts anti-inflammatory and immune modulatory effects in vivo, underscoring roles of nAChRs in CNS inflammatory and autoimmune responses. Chronic alcohol, on the other hand, is known to cause neurodegeneration and neuroinflammation. A recent study demonstrated a direct link between Toll-like receptor 4 (TLR4), an innate immune system molecule that contributes to the inflammation, and GABA(A) receptor in brains of heavy-drinking rats. Silencing the genes for TLR4 and GABA(A) receptor in the central amygdala inhibited binge drinking in rats, an effect that lasted for two weeks. These findings suggest a role for neuroimmune factors in modulating a variety of neuronal functions associated with alcohol and/or nicotine exposure. Additional research is needed to examine how neuroimmune factors regulate neurotransmitter and neuropeptide systems involved in alcohol and nicotine co-abuse, or vice versa, how alcohol and nicotine co-use influences neuroimmune factors and associated signal transduction pathways in targeted brain regions.

Neuroadaptive mechanisms of alcohol and nicotine co-abuse

As alcohol and nicotine use transitions from initiation to occasional, habitual and compulsive use, it is important to explore whether and how either of these drugs produce mutual transition to dependence. In rats, repeated cycles of alcohol intoxication and withdrawal promote neuroadaptations in many neural circuits leading to hyperexcitability and to long-lasting changes in measures of stress and anxiety once alcohol administration is discontinued. Dysregulation of CRF neurons in the central nucleus of the amygdala mediates elevated drinking in post-dependent animals. Similarly, intermittent exposure to unlimited access to nicotine produced large and rapid intake of nicotine in rats. Many of the underlying neuroadaptive changes in response to chronic nicotine exposure remain unclear. Given that neuroadaptation is a key element in development of drug dependence and vulnerability to relapse, its role in conjoint alcohol and nicotine abuse needs further examination.

Appropriate topics for investigation under this FOA include, but are not limited to:

• Elucidation of genetic factors that underlie the joint vulnerability to alcohol and nicotine dependence (e.g., gene-gene interactions; gene-environment interactions). For example, study how genetic variance contributes to risk of alcohol and nicotine co-abuse.
• Studies of how common intermediate phenotypes such as risk taking, novelty seeking and sensitivity to stress impact alcohol and nicotine co-abuse.
• Identification of common brain circuitry and molecular pathways underlying alcohol and nicotine co-dependence. For example, what neural substrates are implicated in cognitive deficits induced by combined use of alcohol and nicotine? Further, study the role of habenulo-interpeduncular pathway in alcohol-nicotine co-abuse.
• Determining whether drug reinforcement induced by the combination of alcohol and nicotine is additive or synergistic in nature.
• Elucidation of nAChRs and their role in concurrent alcohol-nicotine use. For example, how chronic alcohol and nicotine use alone or in combination modulates expressions of different nAChRs?
• Determination of the functional roles of glutamate, opioid and cannabinoid receptor systems as well as transcription factors in concurrent alcohol and nicotine dependence.
• Elucidation of the role of cross-tolerance as a common mechanism underlying alcohol and nicotine co-dependence. For example, study the involvement of adolescent nicotine use in induction of tolerance to alcohol and facilitation of alcohol use in adulthood. Further, study how nicotine (or alcohol) exposure leads to development of cross-tolerance to reinforcing effects of alcohol (or nicotine) and subsequent increase in alcohol (or nicotine) use.
• Individuals that do not initiate alcohol and/or tobacco use prior to adulthood very rarely ever become dependent on either alcohol or nicotine. Studies of mechanisms during the early initiation of drinking and smoking that would lead to subsequent predisposition to either alcohol or nicotine abuse or their combination.
• Determination of the role of conditioned cues and their interactions in concurrent alcohol and nicotine dependence and elucidation of relevant receptor and neural mechanisms.
• Examination of discriminative stimuli for alcohol and nicotine and how these stimuli interact to promote alcohol and nicotine use and relapse.
• Examination of how neuroimmune factors regulate neurotransmitter and neuropeptide systems involved in alcohol and nicotine co-abuse, or vice versa, how alcohol and nicotine co-use influences neuroimmune factors and associated signal transduction pathways in targeted brain regions.
• Determining whether neuroadaptive mechanisms (e.g., neuropeptides involved in post-dependent stress and anxiety responses) contributing to concurrent alcohol and nicotine dependence are additive or synergistic in nature.
• Determination of the optimal timing of alcohol and smoking cessation in treatment programs (i.e., concurrent vs. separate treatment)

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	The combined budget for direct costs for the two year project period may not exceed $275,000. No more than $200,000 may be requested in any single year.
Award Project Period	The total project period may not exceed 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.

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)

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

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

Applicant Organizations

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.

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

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

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

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

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.

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

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, 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.

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

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.

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

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.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115,

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 particular announcement, 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.

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

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

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 clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

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?

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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

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

Biohazards

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

Resubmissions

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

Renewals

Not Applicable

Revisions

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

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

Applications from Foreign Organizations

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

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

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

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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

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

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

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

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

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

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

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

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

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Phone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]

Ivana Grakalic, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
Telephone: 301-443-7600
Email: [email protected]

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

Ms. Judy Fox
National Institute on Alcohol Abuse and Alcoholism
Telephone: 301-443-4704
Email: [email protected]

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

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