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 Alcohol Abuse and Alcoholism (NIAAA)

Funding Opportunity Title

Unconventional Roles of Ethanol Metabolizing Enzymes, Metabolites, and Cofactors in Health and Disease (R21)

Activity Code

R21 Exploratory/Developmental Research Grant

Announcement Type

Reissue of PA-12-234

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)

Funding Opportunity Announcement (FOA) Number


Companion Funding Opportunity

PA-15-058, R01 Research Project Grant

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


Funding Opportunity Purpose

The purpose of this FOA is to provide support for integrated, innovative research on the novel and unconventional contributions of ethanol metabolizing pathways, their metabolites, cofactors, and interactions with synergizing biological pathways in the development of alcohol- induced diseases and end organ injuries. It is anticipated that research supported under this FOA will generate data that lead to breakthroughs in identification and understanding of key cellular and molecular components in the initiation, progression and maintenance of the diverse medical disorders caused by excessive or long term alcohol consumption. This knowledge is critical for the diagnosis, treatment and management of vulnerable patient populations debilitated by the vast array of alcohol-induced pathologies and will enable clinicians to improve disease outcomes and, consequently, public health.

Key Dates

Posted Date

December 8, 2014

Open Date (Earliest Submission Date)

January 16, 2015

Letter of Intent Due Date(s)

Not Applicable

Application Due Date(s)

Standard dates apply, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.

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 dates apply, by 5:00 PM local time of applicant organization. All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on these dates.

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

Advisory Council Review

Earliest Start Date

Expiration Date

January 8, 2018

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

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description


Alcohol is the most frequently abused drug for many societies and is an important causative factor or contributing agent in numerous human diseases. For many of these diseases, ethanol metabolism plays a key role. Ethanol is primarily absorbed by the intestine and mainly metabolized in the liver, hence these are two organs that are most affected by excessive alcohol consumption. An increase in intestinal permeability caused by excessive alcohol use, resulting in a "leaky gut" is implicated in much of the downstream organ damage including alcoholic liver disease. Metabolism of ethanol in other organs, although quantitatively less important than liver is nonetheless important in the development of various pathologies including alcoholic cardiomyopathy, neurodegeneration, acute and chronic pancreatitis and kidney failure among others. Alcohol metabolism by microorganisms in the oral cavity and gastrointestinal tract has been implicated in carcinogenesis, and may also play a role in other health effects of alcohol.

Alcohol also impairs the liver’s capacity for activation and utilization of certain nutrients and vitamins and detoxification of chemicals. Unlike other drugs of abuse, alcohol is a source of energy that sometimes accounts for more than half of an alcoholic’s caloric intake. As a result, it displaces normal nutrients, leading to malnutrition and vitamin deficiencies including folate, thiamin, vitamin A and others. Secondary malnutrition can result from deficient absorption and digestion of nutrients due to ineffective digestive enzymes and other gastrointestinal complications. Deranged liver metabolism and liver-brain-gut interactions along with diet choice further aggravate ethanol associated malnutrition.

The primary enzymes of alcohol metabolism are alcohol dehydrogenase (ADH), cytochrome p450 (CYP2E1) and, to a lesser extent, catalase. These enzymes reside primarily in the cytoplasm, the endoplasmic reticulum (ER) and the peroxisome, respectively. ADH and CYP2E1 constitute the two major pathways of ethanol oxidation and both produce highly reactive acetaldehyde. Acetaldehyde in turn is further converted to acetate by aldehyde dehydrogenases (ALDH). In addition to generating acetaldehyde, both reactions reduce NAD+ to NADH. Furthermore, ethanol metabolism by CYP2E1 also generates several reactive oxygen species (ROS) species. Acetaldehyde is highly toxic, forming protein and DNA adducts, directly inhibiting key enzymes that lead to protein transport defects, protein misfolding, ER stress and marked reduction in oxygen utilization by the mitochondria. Acetaldehyde promotes cell death by depleting the GSH reserve, inducing lipid peroxidation and increasing the level of free radicals.

Excess NADH causes a number of metabolic disorders including hyperlactacidemia, and hyperuricemia. NADH also opposes gluconeogenesis, leading to hypoglycemia, elevation of alpha-glycerophosphate level and inhibition of fatty acid oxidation. Inhibition of fatty acid oxidation favors steatosis and hyperlipidemia paving the way to the development of alcoholic liver disease (ALD). Acetaldehyde-protein adducts promote collagen production and contribute to fibrosis in the alcoholic liver.

Canonical ethanol metabolizing enzymes have been extensively studied, but our understanding of concomitant changes in the oxido-reductive cellular milieu and epigenetic status, effects on global energy homeostasis, interactions with synergizing biological pathways, and their overall contribution to alcohol-induced diseases is lagging. Recently several lines of investigations provided convincing evidence that cellular changes accompanying ethanol metabolism may themselves regulate growth, development, and cellular homeostasis and induce organ pathologies. Notably, the enzymatic breakdown of ethanol affects the generation of several metabolites and cofactors that play seminal roles in epigenetic gene regulation: NAD+, acetate, S-adenosylmethionine (SAM), and zinc. Fluctuations in the levels of these four critical compounds also cause energetic imbalance that may contribute to alcohol induced organ pathologies. Additionally, the consequences of ethanol-induced gene expression changes due to reductive stress (decreased NAD+/NADH ratio), perturbation of 1-carbon metabolism (SAM), acetate and zinc utilization pathways in organ pathologies are largely unexplored.

Research Objectives

A major goal of this FOA is to stimulate research that will broaden our understanding of how alcohol metabolism causes tissue damage, by considering not only the metabolic products of ethanol itself, but all of the biochemical changes resulting from alcohol metabolism in different cell types. The long-term goal is a comprehensive understanding of how alcohol metabolism impacts cellular function and end-organ disease, which has important implications for therapeutics development.

Ethanol and NAD+

Ethanol oxidation is accompanied by NAD+ reduction to NADH that generates a highly reductive cytoplasmic environment in cells and tissues where ADH and CYP2E1 are active. This mechanism has been best studied in hepatocytes, but may be relevant in other cells as well. In mammals three major enzyme families are capable of cleaving NAD+: sirtuins, ADP-ribosyltransferases including PARP, and cyclic ADP (cADP)-ribose synthase, two of which (sirtuins and PARPs) are also chromatin-modifying enzymes.

One major consequence of the decreased NAD+/NADH ratio in mammalian cells is the reduced activity of the NAD+ dependent SIRT1 histone deacetylase activity, an orthologue of S. pombe Sir2 histone deacetylase, which links cellular metabolism status to transcriptional silencing. SIRT1 requires NAD+ for its activity and has essential functions in regulating circadian genes, caloric restriction and obesity pathways and consequently affects longevity in every organism studied so far. Members of the mammalian sirtuin family of histone deacetylases (HDAC III) comprise seven homologues (SIRT1-7) with ubiquitous expression and diverse subcellular localization. Their functions affect a wide range of biological processes including tubulin deacetylation (SIRT2), adaptive thermogenesis, mitochondrial function, energy homeostasis, survival during genotoxic stress (SIRT3), genomic DNA stability and DNA repair (SIRT6). These considerations strongly suggest a role for SIRTs in alcohol-induced tissue injuries (e.g. Alcoholic Liver Disease, Fetal Alcohol Spectrum Disorders, ethanol-induced cancers) but their involvement has not been systematically investigated.

NAD+ dependent inhibition of SIRT HDACs increases global histone acetylation, as well as acetylation of key transcription factors and metabolic enzymes including SREBP-1c (Sterol Regulatory Binding Protein 1c), HSF1 (Heat Shock Factor 1) and Long-Chain Acyl Coenzyme A Dehydrogenase (LCAD). Collectively, these changes lead to metabolic disturbances and loss of protective capacity of the Heat Shock Response, contributing to ethanol-induced tissue injury. Therefore, understanding of the organ specific "histone code" resulting from ethanol consumption, and the regulatory roles of protein acetylation are vital to successfully combat diverse alcoholic disorders.

Poly-ADP ribose polymerases (PARPs), which are the most abundant ADP-ribosyl transferases in mammalian cells, consist of a superfamily of up to 17 members. These enzymes are characterized by the highly conserved PARP domain that is the active site of the catalytic center. The best studied members are PARP 1 and 2: these ubiquitous zinc finger proteins are localized in the nucleus and are involved in chromatin maintenance and DNA repair by binding to single and double stranded breaks generated by genotoxic stress. Thus, PARPs may play a significant role in alcohol promoted cancers invoked by DNA damage of acetaldehyde. PARPs are the main modulators of intracellular NAD+ level, which in turn may indirectly control sirtuin functions through NAD+ availability. Changes in ADP-ribosylation of histone and other PARP target proteins brought about by ethanol consumption are unknown and require further investigation. Furthermore, clarification of the functional interrelationship between SIRTs and PARPs mediated through NAD+ availability is needed. Conceivably, zinc deficiency, which is a well described consequence of excess ethanol ingestion, may affect PARP function, but this question has not been addressed experimentally.

Pioneering studies argue that an excessively reductive environment itself can induce "reductive stress" and lead to potentially lethal cardiomyopathy in a transgenic mouse model and in human patients. This novel pathway may be operational in other tissues where reductive intracellular environment is generated by the shift induced by alcohol ingestion. The fundamental principles of this process are unclear and require further investigations.

Ethanol and acetate

As noted above, the two principal pathways of ethanol oxidation by ADH and CYP2E1 both yield highly reactive acetaldehyde that is further converted to acetate. Alcohol consumption can elevate acetate levels as much as 20-fold. Free acetate, the end product in the liver, is used to generate Acetyl-Coenzyme A (Acetyl-CoA) catalyzed by cytosolic Acetyl-CoA synthase 1 (AceCS1) and mitochondrial Acetyl-CoA synthase 2 (AeCS2) in extrahepatic tissue. Acetyl-CoA is utilized ubiquitously in histone acetylation, in the Krebs cycle, and in fatty acid synthesis, as well as in post-translational acetylation of transcription factors, metabolic enzymes, cell motility factors, and other proteins. Acetylation and methylation are the best characterized posttranslational modifications of histone tails. Acetylation of various lysine residues of histones is associated with a transcriptionally permissive state. The neutralization of the positive charge of histones, decrease in the interaction of the histone tails with the negatively charged phosphate groups of DNA and coincident chromatin opening leads to increased accessibility and transcription and thus enhanced gene expression. Hyperacetylation of chromatin due to ethanol has been documented both in tissue cultured cells and in different animal models of alcohol consumption, but the mechanism of hyperacetylation orchestrated by ethanol is largely unknown. Several mechanisms have been hypothesized including increased substrate availability (Acetyl-CoA), increased enzymatic activity of AceCS1 and AceCS2 and modulation of histone acetyl transferases (HAT) and histone deacetylases (HDAC). Most studies have addressed the effect of alcohol at the global level and detected increased acetylation profiles, but studies analyzing specific genes affected by alcohol metabolism are just beginning to emerge. It is interesting to note that alcohol consumption seems to preferentially target certain histone lysine residues for acetylation, while others are unaffected. Understanding the mechanistic basis of this phenomenon is important for understanding how alcohol affects gene expression. Further investigations are needed to decipher the global alcohol and organ specific "histone code" under specific ethanol drinking paradigms. Regulatory effects of acetylation of numerous metabolic enzymes and transcription factors that are modified by alcohol drinking remain obscure and require further investigation.

Ethanol and SAM

SAM, the second most widely used co-factor in nature is synthesized in the liver from methionine and ATP by methionine adenosyltransferase (MAT) in the one-carbon metabolism pathway. SAM is the primary methyl donor in cells and is required for methylation of histones and other protein targets, DNA, RNA, biogenic amines, and phospholipids. This reaction, which can be carried out by a broad class of over a hundred methyltransferases, yields S-adenosylhomocysteine (SAH). Because SAH is a potent inhibitor of methyltransferases, it needs to be rapidly eliminated from the cells by SAH hydrolases. SAM plays a fundamental role in epigenetic gene regulation by methylation of DNA, histones, enzymes, co-repressors, and co-activators of methylation pathways. Additionally, SAM is a precursor of glutathione, a small molecular weight endogenous antioxidant and a scavenger of ROS. Changes in the intracellular concentration of SAM, SAH and other downstream metabolites due to ethanol consumption have been associated with alcoholic liver injury. Although the mechanism of ALD due to SAM depletion is not fully understood, GSH deficiency and increased ROS availability, activation of the Unfolded Protein Response (UPR) in the endoplasmic reticulum by hyperhomocysteinemia, and hypomethylation of histones and DNA are hypothesized to contribute. Although generally believed to be repressive, methylation of histone tails exhibits position specific effects at individual gene promoters: some result in silencing (e.g. H3K9), while others are activating (e.g. H3K4). How histone methylases are specifically recruited to a particular position on individual promoters to convey an "ethanol signature" is unclear and require further investigation. This notion also applies to the generation of alcohol induced hypomethylation signatures on promoter DNA. Compared to other post-translational modifications histone and DNA methylations are relatively irreversible epigenetic marks. Surprisingly, histone and DNA demethylases have been identified only recently and their reaction mechanisms appear to be quite complex and diverse. Among the three histone demethylases jumonji-domain containing (jmjC) demethylases are 2-oxoglutarate (2-OG) and Fe(II)-dependent dioxygenases, the lysine-specific demethylase 1 (LSD1) is a flavine adenine dinucleotide (FAD)-dependent amine oxidase, while peptidyl arginine deiminase 4 (PAD4/PADI4) capacity as a demethylase is still questioned.

An exciting development in recent years has been the identification of 5-hydroxymethyl-cytosine (5-hmC) in mammalian DNA. The TET1 enzyme, product of an acute myeloid leukemia-associated gene, was recently identified as a 5-meC hydroxylase. Elegant studies demonstrated that TET1 is a 2-OG and Fe(II)-dependent dioxygenase that oxidizes 5-mC to 5-hmC, in a reaction similar to the jmjC histone demethylases. 5-hmC thus represents a new class of epigenetic modification with currently unknown function or may prompt DNA demethylation through an oxidative demethylation pathway. Since ethanol exposure modulates SAM and SAH level via changes in the NADH/NAD+ redox change, ethanol may also impact 5-hmC levels in different tissues as well. This mechanism and its possible role in alcohol-induced disease need further studies.

Ethanol and zinc

As an essential trace element, zinc plays a critical role in diverse biological processes including protein and carbohydrate metabolism, digestion, glucose control, immune system, wound healing, fertility, and growth. These effects are brought about by zinc’s modulation of gene expression, redox homeostasis and DNA repair, as it is a co-factor of about 300 different enzymes. Of particular importance, two groups of chromatin modifying enzymes require zinc for proper function: 1.) types I, II and IV histone deacetylases; and 2.) histone demethylases; both of these are inextricably associated with epigenetic gene regulation. Zinc deficiency is observed in ~50% of alcoholics due to decreased intestinal absorption, increased urinary excretion, and insufficient dietary zinc intake and this deficiency is commonly observed in different stages of alcoholic liver disease (ALD). Recent studies clearly demonstrated a direct effect between zinc deficiency and histone acetylation level, but the molecular underpinnings of this process remain unclear. Both the recently identified LSD2 and jumonji-type histone demethylases also contain a zinc finger domain, which is hypothesized to be dramatically affected by zinc deficiency leading to the epigenetic landscape and associated pathology observed in chronic and heavy alcohol users. Zinc depletion may indirectly affect methyl group utilization by the inhibition of the zinc metalloenzyme betaine-homocysteine S-methyl transferase that leads to general cellular hypomethylation. Further research is needed to extend our understanding of how ethanol induced zinc deficiency contributes to the pathological gene programs and their phenotypic manifestation.

Endogenous Substrates and Functions of Alcohol Metabolizing Pathways: Regulation of Growth, Development, and Disease

Mammals, including humans, have numerous highly elaborate and dynamic enzymatic pathways to break down ethanol and generate energy. Recently several lines of investigation have provided convincing evidence that these enzymes may have additional functions beyond metabolizing exogenous alcohols, as they may have endogenous substrates that regulate cellular growth, development, and homeostasis. Ubiquitous, highly reactive endogenous aldehydes may induce DNA damage, a prelude to cancer, or perturb developmental processes leading to fetal damage e.g. fetal alcohol syndrome (FAS). Aldehyde dehydrogenase 2 (ALDH2) also provides cardioprotection. Consequently, genetic deficiencies in ALDH2 activities, and possibly in other alcohol metabolizing enzymes, predispose the carriers to a variety of genetic and developmental abnormalities including cardiovascular disease, bone marrow dysfunction, cancer and FAS. Understanding the molecular underpinnings of these cellular processes will provide opportunities to prevent or treat alcohol-induced organ damage and other alcohol related disorders.

Research in any of the areas described above in detail or in the following key areas will help our understanding of the molecular underpinnings of these cellular processes and provide opportunities to prevent or treat alcohol-induced organ damage. Examples of research that might be supported under this FOA include, but are not limited to studies of the following:

  • The role of endogenous aldehydes and ALDH's in DNA damage, cancer, and development (e.g. FAS)
  • The contribution and functional interplay of ALDH's with DNA damage and cancer pathways
  • The mechanism for the protective functions of ALDH2
  • The development of safe and effective ALDH2 activators (Alda) and inhibitors (Aldi) for treatment and/or prevention of alcohol induced pathologies
  • The effect of decreased NAD+/NADH ratio on NAD+ consuming enzymes: sirtuins, ADP-ribose transferases (PARP) and cyclic ADP (cADP)-ribose synthases and their effect of chromatin gene regulation
  • The development of sensitive and reliable in vivo assays to monitor NAD+ concentration in different sub-cellular compartments
  • The mechanism of how the cellular NAD+ pool is shared by NAD+ consuming enzymes
  • The development of "reductive stress" as a potential new paradigm in ethanol-related organ pathology
  • Regulation of SIRT1 targets by deacetylation: transcription factors, coactivators, and their effects on metabolic pathways by ethanol consumption (e.g., PGC-1alpha, FOXOs)
  • The changes of Ac-CoA levels and increase histone acetylation as a consequence of alcohol metabolism and acetate accumulation
  • The interplay of the NAD+ and Ac-CoA energy sensor in reprogramming of metabolic pathways
  • The mechanism by which alcohol alters the methionine pathway and leads to reduced SAM level and methylation in cells
  • Alcohol induced zinc deficiency and inhibition of chromatin modifying enzymes
  • The effect of alcohol metabolism on the NAD+/NADH ratio, and subsequent impact on sirtuins-related pathways in different organs and cell types
  • Understanding the mechanistic basis of how alcohol metabolism affects the epigenome, including 5-methyl cytosine and 5-hydroxy-methyl cytosine.
  • The effect of alcohol metabolism in various tissues at different stages of development, including in utero, fetal and embryonic development
  • Alcohol’s effects on the redox state and its impact on metabolism of lipids and carbohydrates and on overall energy balance
  • Development of suitable in vitro and in vivo experimental systems to model the diverse ways in which different cell types in the body are exposed to and metabolize ethanol
  • Elucidation on the role of genetic variation in the susceptibility to tissue injury, including carcinogenesis, resulting from alcohol metabolism
  • The effects of alcohol metabolism on the epigenome in different cells and organs, using either genome-wide or hypothesis-driven candidate gene approach
  • Mechanisms by which alcohol metabolism contributes to carcinogenesis in various organs
  • Role of central and peripheral circadian rhythms on alcohol-metabolism
  • Bioinformatics, computational, and mathematical modeling to understand and integrate experimental information on alcohol metabolism
  • Development of more effective biomarkers of alcohol metabolism
  • Therapeutic targets for alcohol metabolism
  • Studies of the mechanisms by which alcohol metabolism in the liver affects the function of other organs in the body
  • Alcohol metabolism by the oral and colonic microbiome, as well as the effects of alcohol and its metabolites on the composition and function of the microbiome
  • Humanized animal models for studies of alcohol metabolism

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.

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




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 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.

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)


  • 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


  • 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.
  • 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 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.
  • – Applicants must have an active DUNS number and SAM registration in order to complete the registration.

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

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

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.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

  • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
  • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
  • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

  • 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

2. Content and Form of Application Submission

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

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

Page Limitations

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

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.

R&R Subaward 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 as provided in the SF424 (R&R) Application Guide, with the following modification:

  • All applications submitted for the January 25, 2015, due date or after are expected to comply with the NIH Genomic Data Sharing Policy as detailed in NOT-OD-14-111, as applicable.

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 (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 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 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. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues.

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 and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Post Submission Materials

Applicants are required to follow our Post Submission Application Materials policy.

Section V. Application Review Information

Important Update: See NOT-OD-16-006 and NOT-OD-16-011 for updated review language for applications for due dates on or after January 25, 2016.

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 particular announcement, 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.


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


Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?


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?


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?


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.


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


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


Not Applicable


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) Genomic Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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) convened by NIAAA, 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 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 National Advisory Council on Alcohol Abuse and Alcoholism. 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.

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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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 Research Performance Progress Report (RPPR) annually 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 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 Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online:
Email: Customer Support (Questions regarding registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-945-7573

Scientific/Research Contact(s)

Andras Orosz Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-2193

Peer Review Contact(s)

Ranga V Srinivas, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-451 2067

Financial/Grants Management Contact(s)

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704

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.

NIH Office of Extramural Research Logo
Department of Health and Human Services (HHS) - Home Page
Department of Health
and Human Services (HHS) - Government Made Easy
NIH... Turning Discovery Into Health®