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)
National Cancer Institute (NCI)

Funding Opportunity Title

Mechanisms of Alcohol-associated Cancers (R21)

Activity Code

R21 Exploratory/Developmental Research Grant Award

Announcement Type

Reissue of PA-06-270

Related Notices

  • June 3, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
  • 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.

Funding Opportunity Announcement (FOA) Number

PA-12-147

Companion FOA

PA-12-146, 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, 93.396 

FOA Purpose

This Funding Opportunity Announcement (FOA) issued by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Cancer Institute (NCI) invites applications from researchers with broad ranges of expertise to study the mechanisms by which alcohol increases cancer risk.

Alcohol has been classified as carcinogenic to humans by the International Agency for Research on Cancer (IARC).  Target sites for alcohol-related carcinogenesis include the oral cavity, pharynx, esophagus, larynx, breast, liver, and colon.  A better understanding of the molecular basis by which alcohol increases cancer risk could lead to improved therapeutic approaches and preventative strategies and would provide guidance on safe levels of alcohol consumption.  The goal of this program announcement is to stimulate a broad range of research into the mechanisms by which alcohol contributes to carcinogenesis.

Key Dates
Posted Date

March 29, 2012

Open Date (Earliest Submission Date)

May 16, 2012

Letter of Intent Due Date

Not Applicable.

Application Due Date(s)

Standard dates apply, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Standard dates apply

Scientific Merit Review

Standard dates apply

Advisory Council Review

Standard dates apply

Earliest Start Date(s)

Standard dates apply

Expiration Date

September 8, 2015

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.


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Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

This Funding Opportunity Announcement (FOA) issued by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Cancer Institute (NCI) invites applications from researchers with broad ranges of expertise to study the mechanisms by which alcohol increases cancer risk.

Alcohol has been classified as carcinogenic to humans by the International Agency for Research on Cancer (IARC).  Target sites for alcohol-related carcinogenesis include the oral cavity, pharynx, esophagus, larynx, breast, liver, and colon.  A better understanding of the molecular basis by which alcohol increases cancer risk could lead to improved therapeutic approaches and preventative strategies and would provide guidance on safe levels of alcohol consumption.  The goal of this program announcement is to stimulate a broad range of research into the mechanisms by which alcohol contributes to carcinogenesis. 

Related Funding Opportunity: Investigators interested in proposing more highly developed projects based upon strong preliminary data should submit applications in response to the partner FOA of identical scientific scope (PA-12-146), which uses the NIH Research Project Grant (R01) funding mechanism.

Background

1. Epidemiology of alcohol-related cancers:  Worldwide, 3.6% of all cancers are attributable to alcohol, totaling 390,000 cases annually.  Cumulative epidemiological evidence supports the conclusion that certain cancers are associated with alcohol consumption, with the relative risk of cancer often varying with the amount of alcohol consumed. 

Upper aerodigestive tract cancers

Cancers of the upper aerodigestive tract (UADT), sometimes referred to as head and neck cancers, include pharynx, larynx, esophagus and the oral cavity.  The relative risk of UADT cancers is increased slightly with consumption of two drinks per day, but rises to 4-6 fold with heavier drinking.  The risk of developing UADT cancer when alcohol and tobacco are used in combination is much higher than the additive risk of smoking or of alcohol intake separately.  Genetic variations in alcohol metabolizing enzymes have a profound effect on UADT cancer risk, implicating alcohol or its metabolites in the development of these cancers.

Hepatocellular carcinoma

Multiple risk factors contribute to the genesis of hepatocellular carcinoma, including alcohol consumption, viral infections, obesity and diabetes.  Fully twenty-five per cent of hepatocellular carcinoma cases are associated with alcoholic liver disease. While much is known about the progression of alcoholic liver disease, from steatosis or fatty liver to steatohepatitis to fibrosis to cirrhosis, much more remains to be learned about the progression to hepatocellular carcinoma and how alcohol influences this process.  In addition, hepatitis B virus (HBV) and hepatitis C virus (HCV) are major contributors to the incidence of hepatocellular carcinoma in East and Southeast Asia.  The combined insults of HBV or HCV and alcohol increase cancer incidence synergistically.

Breast cancer

Alcohol consumption in post-menopausal women raises the risk of breast cancer up to three-fold in a dose dependent manner.  However, the picture in pre-menopausal women is more subtle.  Meta-analyses suggest that there is a linear correlation between the amount of alcohol consumed and breast cancer incidence in women, with an average of even one drink per day increasing breast cancer incidence by 7%.  However, surveys of alcohol consumption are based on self-report, and often fail to distinguish moderate drinking from binge drinking.  This is important because different patterns of alcohol consumption may have significantly different biochemical consequences.  In addition, recent evidence suggests that specific sub-types of hormone receptor positive breast cancer correlate with alcohol consumption.  Thus, more careful analysis of the pattern of alcohol consumption linked to elevated breast cancer risk, and of the molecular characteristics of the alcohol-associated cancers may prove to be informative. 

Colon cancer

A significant fraction of colon cancers is attributable to alcohol, with men more affected than women.  Understanding the mechanism of colon cancer development would help to distinguish whether the greater incidence in men is due simply to higher alcohol consumption or to gender-related physiological differences.  More importantly, identifying the molecular perturbations caused by alcohol may provide a target for therapeutic intervention.

Thyroid cancer

Intriguingly, moderate alcohol consumption is associated with a slight reduction in the incidence of thyroid cancer.  The mechanistic basis for this observation is not yet known.

2.  Cellular and molecular processes altered by alcohol

Alcohol may influence cancer incidence by modulating the initiation, promotion, progression or metastasis of tumors.    Characterization of the cellular and molecular processes that are disrupted by exposure to alcohol is necessary to understanding its pathological effects. Alcohol alters biological function by direct interaction with cellular components and due to the effect of alcohol metabolism (and metabolites) on the systemic oxidative and inflammatory state. 

2A. Mutagenic potential of alcohol and alcohol metabolism

Metabolites of alcohol may contribute to the initiation of cancer.  Acetaldehyde, the first metabolite of alcohol, has also been designated by the IARC as a human carcinogen.  Several lines of evidence support a role for acetaldehyde in cancer initiation. Acetaldehyde is reactive, forming DNA-acetaldehyde adducts that can incorporate into the genome, leading to mutagenesis, and transformation of healthy cells into tumor cells. Genetic evidence also supports a role for alcohol metabolism in cancer risk, particularly in esophageal cancer, since variants in alcohol and aldehyde metabolizing enzymes increase susceptibility to cancer after alcohol consumption.

In addition, alcohol metabolism results in the production of reactive oxygen (ROS) and reactive nitrogen species, resulting in oxidative stress.  Oxidative stress and consequent inflammatory environments are damaging to healthy host tissue, and have been linked to the development of cancer through mutagenesis.   Chronic alcohol consumption leads to systemic and tissue localized chronic inflammation.  In addition, chronic alcohol consumption results in the induction of cytochrome P4502E1 (CYP2E1), which, in addition to metabolizing ethanol, generates  reactive oxygen species, which can directly damage DNA, and can also generate lipid peroxidation products capable of forming mutagenic DNA adducts.  CYP2E1 can also convert procarcinogens to carcinogens. 

2B. Alcohol interactions with oncogenes and tumor suppressor pathways

In addition to the mutagenic potential of alcohol metabolism, it is also possible that alcohol, its metabolites or the oxidative stress and inflammation created by alcohol metabolism may subvert or alter oncogenic pathways or other cellular regulatory or metabolic signaling pathways.  Alcohol has been shown to modify signal transduction at multiple sites, by interacting directly with cell membranes as well as with signaling proteins and ion channels.   Modification of the function of receptors and intracellular signaling molecules, either by genetic mutation or by interaction at the protein level, leads to altered function of multiple signaling pathways that mediate essential processes.  A few examples of known interactions of alcohol with oncogene pathways are presented here.  Others, reported or as yet undiscovered, are also of interest.

Oncogenic pathways can be involved in initiation, promotion, or progression and are possible targets of alcohol or its metabolites.  For example, activating mutations of the Ras oncogene occur in many cancers, and activating mutations of K-ras have been seen preferentially following alcohol exposure.  The activating K-ras mutation in esophageal squamous cell carcinoma correlates strongly with alcohol exposure.  Ras operates through the MAPK pathway which regulates growth in response to extracellular factors.

The retinoblastoma (Rb) gene, primarily involved in cell cycle control, is considered a tumor suppressor.  p16INK4A is one of the regulators of Rb; impaired p16INK4A protein expression is associated with alcohol consumption in head and neck carcinoma.  Further, duration of exposure to alcohol predicts the homozygous deletion of p16INK4A in esophageal cancers in long-term alcohol consumers.  Commonly, hepatocellular carcinoma associated with excessive alcohol consumption displays at least one alteration in the Rb pathway, including, in addition to p16INK4A, p15INK4B promoter methylation, RB1 alteration, or cyclinD1 amplification.   

In addition, hepatocellular carcinomas also commonly display mutations in the p53 gene.  In nearly half of the hepatocellular carcinomas linked to alcohol consumption, mutations in both the Rb and p53 pathways occur.  Mutations of p53 correlating with alcohol consumption also occur in head and neck squamous cell carcinoma.  P53 is a tumor suppressor that prevents cells from proliferating after DNA damage, by triggering apoptosis. 

2C. Alcohol interaction with other signal transduction pathways

Other signal transduction pathways involved in metabolic or developmental processes or exerting regulatory control are altered in the presence of alcohol.  Modification of many of these same pathways is associated with carcinogenesis.  A single example is presented.

The constitutive activation of the hedgehog (Hh) pathway in some cancers may promote cell growth and survival and maintain cancer stem cells.  A potential role for Hh in the development of alcohol-associated hepatocellular carcinoma is supported by the following observations.   Hh pathway activation has been observed in both mouse and human alcoholic liver disease and there is evidence for disruption of the Hh pathway at several stages of alcoholic liver disease.  Hh signaling mediates the transition of hepatic stellate cells to the myofibroblast phenotype prior to cirrhosis, due to the fact that Hh regulates the epithelial to mesenchymal transition.  Whether alcohol modification of the epithelial to mesenchymal transition leads directly to hepatocellular carcinogenesis is not yet clear.  In addition, in some hepatocellular carcinomas, Hh promotes viability and protects from apoptosis.

2D. Mechanisms of alcohol-induced alterations of gene transcription

Signal transduction leads ultimately to activation or repression of the expression of a specific set of genes, setting a cellular activity, such as proliferation, differentiation, or host defense, into motion.  The regulation of gene transcription occurs as a result of the translocation of the transcription factor machinery to the nuclear chromatin.

In contrast, epigenetic changes provide a more global means of regulating gene expression.  Many environmental factors for disease, including alcohol exposure, are known to cause epigenetic alterations.  DNA methylation, histone modification and RNA-mediated gene silencing are all types of epigenetic modification, and alcohol is known to modulate all three. 

DNA methylation

Alcohol affects DNA methylation in at least two ways; first, by its interference with one carbon metabolism, and second, by alteration of the methylation of specific promoters.  Chronic alcohol consumption is associated with poor folate absorption, reduction in methionine and S-adenosylmethionine availability and a general disruption of one-carbon metabolism.   Folate deficiency by itself is linked to the damage of several specific oncogenes or signaling pathways important for tumorigenesis, and has been implicated in multiple cancer types.  Multiple enzymes involved in the methionine cycle are inhibited by alcohol, ultimately disrupting the substrate availability for DNA methylation reactions.  The effect of chronic alcohol ingestion on DNA methylation is complex, linked to greater methylation by some measures and demethylation of specific genes in other cases.

Histone modifications

Epigenetic modifications that involve histones include methylation, phosphorylation, acetylation, or ubiquitination. Each of these covalent modifications occurs on specific amino acids located in histone tails, with specific consequences for gene expression.   Alcohol increases histone acetylation at H3K9 sites, which alters the state of chromatin in a tissue-specific manner, allowing access of the gene transcription machinery to the DNA.  Another mechanism by which alcohol modifies acetylation involves the alteration of the NAD+: NADH+ ratio due to oxidative alcohol metabolism.  Since SIRT histone deacetylases are NAD+-dependent, the altered NAD+ reduces the deacetylase activity of SIRT enzymes, potentially preventing the down-regulation of cancer-related genes.  By these methods, alcohol may affect processes or signaling pathways that contribute to tumorigenesis.

MicroRNAs

Micro RNAs (miRNAs) are non-protein coding RNAs that influence cell cycle regulation, differentiation, immune cell development and organogenesis.  Most cancer-related signaling pathways are under regulation by miRNAs, and altered miRNA expression is linked to a broad assortment of cancers.   miRNA modulation has been shown to mediate some alcohol-induced disorders.  For example, alcohol-associated alterations of the levels of specific miRNAs have been shown to moderate tolerance to alcohol, gut leakiness and neural stem cell proliferation.  Thus, modification of miRNA activity by alcohol is a potential mechanism for alcohol-induced carcinogenesis. 

Several reports of miRNA expression profiles in hepatocellular carcinoma identify significant increases or decreases in the expression of a small number of miRNAs that constitute miRNA signatures.  In one case, the miRNA signature distinguishes between HCC (increase in miR-21, 10b, 222) and non-HCC (decrease in miR 200c) containing livers.   A separate signature differentiates alcohol-associated HCC (decrease in miR-126) from hepatitis B virus-associated HCC (increase in miR-96).  In addition to providing mechanistic insights into whether alcohol-induced miRNA changes mediate cancer initiation and progression, these signatures may be useful as diagnostic biomarkers or as therapeutic targets.

Retinoic acid

Retinoic acid (RA) exerts widespread, if not global, effects on gene transcription, through its activation of a family of nuclear RA-specific receptors that form heterodimers, each activating unique expression profiles.  RA receptors thus regulate broad and diverse phenotypic effects, ranging from proliferation to differentiation.  Alcohol metabolism can compete with retinoid metabolism in complex and tissue-specific ways, altering RA availability, and potentially disrupting cell fate decisions.   Significantly, RA signaling is disrupted in most of the alcohol-associated cancers.  In addition, altered retinoid metabolism causes changes in lipid metabolism and inflammation, two other processes that are the subject of investigation in mechanisms of tumorigenesis. 

3. Local and systemic factors affecting tumor formation and maintenance

The tumor microenvironment plays a significant role in tumor survival.  Tumors are populated by a diversity of tumor cells and stromal cells.  The stroma includes fibroblasts, multiple classes of leukocytes and lymphocytes, classes of immature cells capable of differentiation, and in more advanced cases, vascular endothelial cells.  The interaction between the tumor and its stroma plays an important part in tumor development and maintenance.  Many components of the tumor niche can be influenced by alcohol.  Since alcohol’s cancer-promoting properties are unique to certain organs, the tissue-specific factors that make the organs more susceptible to alcohol’s effects are of interest.

3A. Alcohol effects on stem cells and cancer stem cells

Alcohol effects on adult stem cells and cancer stem cells may explain the association of alcohol with the development of cancer in specific target organs.  Each tissue is likely to have characteristic stem cells that repopulate the tissue during natural turnover.  The unique characteristics of the healthy adult stem cells of each tissue, or the tissues’ unique niches, may dictate vulnerability to damage by alcohol. Alternatively, if alcohol impacts promotion or progression rather than initiation, then the cancer stem cell, bearing one or more oncogenic mutations, may be more sensitive to alcohol’s possible disruption of signaling or cell cycle controls.  Possible effects of ethanol on self renewal and differentiation are of interest.

3B. Alcohol and inflammation in cancer development

Clinical and molecular genetic evidence support a role for chronic inflammation in tumor initiation and progression.  For example, chronic infection and autoimmune disease, two conditions characterized by chronic inflammation, are associated with cancers of various organs.  In addition, polymorphisms in inflammatory mediator genes are associated with increased risk of lung and liver cancer.  Inflammation is an acute response of the host to threats, in which innate immune cells release mediators to recruit and activate other immune cells to eliminate the threat, whether a pathogen or damaged host tissue.  In the course of acute inflammation, pro-inflammatory cytokines initially trigger the production of ROS that destroy target cells but also harm healthy tissue.  The simultaneous expression of anti-inflammatory cytokines exerts feedback inhibition to extinguish the inflammatory cascade in due course.   When the feedback mechanisms fail, inflammation becomes chronic.  The persistent presence of inflammatory mediators has local and systemic impact on host tissue.

Chronic alcohol consumption is associated with chronic inflammation.  This is due to leakage of bacteria and bacterial products, predominantly lipopolysaccharide (LPS), from the gut into the liver and the bloodstream.  LPS triggers innate immune cells to release pro-inflammatory cytokines and ROS.   Sustained oxidative stress damages host tissue, and may be involved in the initiation of tumors.  Thus, chronic inflammation associated with chronic alcohol consumption may mediate alcohol-related cancers.

Alcoholic liver disease, a frequent complication for chronic alcoholics, is a strong predictor for hepatocellular carcinoma.  Inflammatory conditions resulting from LPS leakage support the progression of liver disease.  Chronic inflammation is a central component of alcoholic liver disease arising from two distinct etiologies: alcohol-associated hepatocellular carcinoma and hepatitis B virus-related hepatocellular carcinoma.  

Alcohol affects the inflammatory mediator IL-6, which is an important growth factor for various cell types, and its systemic elevation may support proliferation.  In non-malignant alcoholic liver disease, fibrosis results from the subversion of normal repair processes; a similar aberration may contribute to compensatory proliferation, hyperplasia and malignancy in other organs.  The epithelial to mesenchymal transition plays a role in alcoholic liver disease and fibrosis.  The potential effect of alcohol on the epithelial to mesenchymal transition in other niches remains to be determined.

3C. Alcohol and immune surveillance

Through the process of immune surveillance, immune cells detect cancerous tissues and act to eradicate them.  Innate and adaptive immune mechanisms cooperate during the process of immune surveillance.  In spite of host anti-tumor strategies, tumors sometimes evade immune surveillance.  Failures of immune surveillance occur when mutations within the tumor allow it to escape detection or to subvert immune regulation, inactivating the anti-tumor focus of the immune response.   The tumor microenvironment is enriched with immune cells, and the composition of the immune cell infiltrate has clinical relevance.  The presence of cytotoxic CD8+ T cells and markers of Th1 polarization in human colorectal cancer have a favorable prognosis for the patient, while Treg infiltrates predominate in late stage tumors and confer a negative prognosis.  Tumor associated macrophages have different characteristics than most tissue-resident macrophages. While classically activated macrophages (M1) are pro-inflammatory, alternatively activated macrophages (M2) in tumors tend to be immune suppressive and to support tumor growth and tumor survival.  Myeloid derived suppressor cells (MDSCs) are another class that supports tumor growth. 

Alcohol consumption has profound effects on innate and adaptive immunity, suggesting that alcohol has the potential to disrupt immune surveillance at multiple sites.  Well-regulated immune interactions are necessary for maintaining the correct balance so that inflammation that is protective to the host occurs, but is quelled before it becomes chronic.  In addition to intrinsic immune regulation, crosstalk between neural and hormonal systems with immune cells also regulates the extent and nature of the immune response.  Alcohol’s effect on the balance between pro-inflammatory and anti-inflammatory, and between immune stimulating and immune suppressive influences may have a profound effect on immune surveillance, and is of great interest.

3D. Alcohol and angiogenesis

As tumors grow, tumor volume precludes oxygen diffusion to the center of the tumor, so vascularization of tumors is essential to survival and further growth.  Vascular endothelial growth factor (VEGF), which mediates the process of vascularization, is up-regulated by alcohol exposure in a mouse model, and VEGF expression correlates with increased tumor volume.  Thus, alcohol may support the progression of established tumors in humans by supporting angiogenesis.

3E. Potential hormonal effects on alcohol-induced cancers

Alcohol-associated cancers of the upper aerodigestive tract, liver and colon occur at higher levels in men than in women.  Since men drink more alcohol, smoke more often and are more likely to be infected by HBV or HCV than women, the simplest explanation for the greater cancer incidence in men may be a greater exposure to the risk factors.  However, biological and endocrine differences may also account for the differences in prevalence of these cancers in men and women. 

Also of interest are possible interactions between alcohol and estrogens in the development of breast cancer.  Both estrogen availability and intracellular estrogen signaling are potential targets for alcohol effects.  Circulating estrogen levels are altered by alcohol consumption in both pre-menopausal and post-menopausal women, potentially fueling hormone-dependent tumors.  At the cellular level, epidemiological and experimental evidence implicate estrogen signaling in alcohol-associated cancers of the breast.  Alcohol’s potential to modulate estrogen signaling at multiple points, including at the ligand, receptor and transcriptional levels, warrants further investigation and may provide potential avenues of therapeutic intervention.

Significance

Two thirds of adults in the United States consume alcohol at some level.   Current guidelines for moderate drinking address alcohol intake that is beneficial to cardiac health, but even a moderate level of consumption may increase the risk of other diseases, specifically breast cancer.  Educating the public about the relative risks and benefits of alcohol consumption requires sound scientific evidence.  In addition to alcohol as a single risk factor, it also interacts synergistically with other risk factors, including viral hepatitis B and C, smoking and obesity to increase cancer incidence.  Expanding insights into these cancer mechanisms, separately and in combination, will not only provide a basis on which the general public can make rational decisions about their alcohol consumption, it will also be useful for developing preventative or protective strategies by providing molecular targets for therapeutic approaches.  In particular, clarification of the molecular processes affected by alcohol leading to cancer in breast tissue could provide the basis for women’s informed choices on frequency and volume of alcohol consumption.

Areas of Research Interest

The focus of this FOA is to encourage investigation into the mechanism(s) by which alcohol contributes to the development, initiation, promotion, progression or metastasis of cancer.  Since alcohol’s cancer-inducing properties are unique to certain organs, the tissue-specific factors that make the organs more susceptible to alcohol’s effects are of interest.  Investigators are encouraged to employ models of cancers that have been convincingly linked to alcohol consumption in humans, including UADT cancers such as oral cavity and pharynx, esophagus, larynx, as well as liver cancer, breast cancer and colon cancer.   This FOA encourages research activities into the molecular, cellular, hormonal, immunological, and physiological factors that contribute to alcohol-induced cancer.   Research topics of interest include, but are not limited to:

Investigation of the effects of alcohol on metastasis including, but not limited to, alterations in signaling pathways, matrix metalloprotease function, cell adhesion processes, or factors that affect tumor cell motility and seeding at secondary sites

This FOA is intended to attract research proposals that use comprehensive approaches to address mechanistic questions about alcohol’s effect on cancer development.  Genomic, proteomic, metabolomic, lipidomic techniques and systems biology approaches are welcome.  Collaborations using existing surveys, repositories and genomics databases to clarify alcohol contributions to cancer development are encouraged.  Study designs exploiting established preclinical cancer models for studying alcohol-related carcinogenesis are also encouraged.

Section II. Award Information
Funding Instrument

Grant

Application Types Allowed

New
Resubmission
Revision

The OER Glossary and the SF 424 (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 (2) year project period may not exceed $275,000. No more than $200,000 may be requested in any single year.

Award Project Period

The maximum project period is two (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

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

Foreign Institutions

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

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

Required Registrations

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

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 PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.   

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed. Resubmission applications may be submitted, according to the NIH Policy on Resubmission Applications from the SF 424 (R&R) Application Guide.

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

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

Required and Optional Components

The forms package associated with this FOA includes all applicable components, mandatory 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.

Page Limitations

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

PHS 398 Research Plan Component

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 Institutions

Foreign (non-US) 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 in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via 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.

Applicants are responsible for viewing their application 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 SF 424 (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 SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD(s)/PI(s) Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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 Central Contractor Registration (CCR). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

Post Submission Materials

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

Section V. Application Review Information

1. Criteria

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

For this 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.

Overall Impact

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

Scored Review Criteria

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

Significance

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

Investigator(s)    

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

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/priority 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.

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/priority score.   

Applications from Foreign Organizations

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

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

Applications will be assigned on the basis of established PHS referral 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 advisory council or board. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

2. Administrative and National Policy Requirements

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) 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 www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement. 

Section VII. Agency Contacts

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

Application Submission Contacts

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

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

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Scientific/Research Contact(s)

M. Katherine Jung, PhD
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 2021
Rockville MD 20852
Telephone: 301-443-8744
Fax: 301-594-0673
Email: jungma@mail.nih.gov

Sharon Ross, PhD
National Cancer Institute (NCI)
6130 Executive Blvd, EPN Room 3157
Rockville MD 20852
Telephone: 301-594-7547
Fax: 301-480-3925
Email: rosssha@mail.nih.gov

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

Ms. Judy Fox
Chief, Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 3023
Rockville, MD 20852
Telephone: 301-443-4707
FAX: 301-443-6077
Email: jfox@mail.nih.gov

Alice C. Wong, CRA
Office of Grants Administration
National Cancer Institute (NCI)
6120 Executive Boulevard, EPS Suite 243P
Rockville, MD 20852
Telephone: 301-496-9312
Fax:  301-496-8601 or 301-495-5476
Email: wongalice@mail.nih.gov

Section VIII. Other Information

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

Authority and Regulations

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


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