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

Alcohol impairment of immune function, host defense and tissue homeostasis (R21)

Activity Code

R21 Exploratory/Developmental Research Grant Award

Announcement Type

New

Related Notices

  • 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-12-026

Companion FOA

PA-12-025, 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

FOA Purpose

This Funding Opportunity Announcement (FOA) invites applications from researchers with broad ranges of expertise to study the consequences of alcohol consumption on immune function with the ultimate goal of alleviating infection and reversing alcohol-induced organ damage.

Susceptibility to infection and organ damage are the two most common causes of alcohol-related morbidity and mortality. These consequences of alcohol abuse are closely associated with profound impairment of the host innate and adaptive immune systems. The mechanisms of these immune alterations and their link with alcohol-related medical problems are, in most cases, poorly understood. The goal of this FOA is to attract applications on basic and translational research: 1) to identify how alcohol alters immune function; 2) to establish functional links between immune alterations and alcohol related infections and organ damage; and 3) to develop means for mitigating immune impairment with the goal of alleviating alcohol-induced pathology.

Key Dates
Posted Date

November 18, 2011

Open Date (Earliest Submission Date)

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

Scientific Merit Review

Standard dates apply

Advisory Council Review

Standard dates apply

Earliest Start Date(s)

Standard dates apply

Expiration Date

January 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) invites applications from researchers with broad ranges of expertise to study the consequences of alcohol consumption on immune function with the ultimate goal of alleviating infection and reversing alcohol-induced organ damage.

Alcohol abuse has long been associated with increased susceptibility to opportunistic infections. This association has led to extensive research demonstrating that patterns of alcohol consumption indeed have a profound and negative impact on immune cell function and development of immune defense against pathogens.  Binge alcohol consumption suppresses host innate immune defense.  Chronic alcohol consumption suppresses most immune functions including macrophages’ phagocytic activity and development of adaptive immune defense, yet paradoxically activates chronic inflammation.  Cumulative evidence now supports a role for alcohol-induced immune alterations, in particular inflammation, in a wide range of alcohol related illnesses involving organ or tissue injury. In some cases, interventions against such alcohol-induced immune dysfunctions, for example with anti-oxidant supplements, micronutrients, or probiotics, are found to be effective in improving the clinical outcome. A comprehensive understanding of alcohol-induced immune dysfunctions and the underlying mechanisms is critical for developing effective diagnostic, preventive, and treatment approaches.

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-12-025), which uses the NIH Research Project Grant (R01) funding mechanism.

Background

Overview 

Alcohol abuse was estimated to be the third most common non-genetic cause of mortality in the US in the year 2000. Epidemiological and clinical studies have established that alcohol abuse predisposes individuals to opportunistic infections and to organ and tissue damage, the two most prominent alcohol-related medical complications. Important alcohol-related infections include bacterial pneumonia, tuberculosis, and viral hepatitis. Significant illnesses resulting from alcohol-induced tissue injury have been observed in virtually every organ including liver, lung, pancreas, kidney, cardiovascular and endocrine systems, muscle, and bone. In addition, alcohol abuse worsens tissue injury under co-morbid conditions such as viral hepatitis, trauma, surgical challenge, obesity, diabetes, smoking (in the case of cancer), and HIV/AIDS.  Significantly, cumulative research findings support that immune dysfunction caused by alcohol abuse is a common mechanism underlying not only the increased susceptibility to infection, but also organ and tissue pathogenesis. 

Alcohol-related dysfunction of immune cells

Innate immune cells:

Monocytes and monocyte-derived tissue macrophages are innate immune cells critical for initiating inflammation by producing cytokines and eliminating pathogens and damaged cells by phagocytosis. Acute alcohol feeding in animal models in general inhibits both the phagocytic activity of monocytes and macrophages and their cytokine production in response to inflammation- inducers (most commonly lipopolysaccharides, LPS). Chronic alcohol feeding also inhibits the phagocytic activity of these cells, yet stimulates excessive cytokine expression (especially monocytes and liver macrophages, Kupffer cells) in response to inflammation inducers.  This sensitization of cytokine production and the resulting inflammatory conditions have been causally linked to tissue injury.

Neutrophils are innate immune cells critical for microbe killing by phagocytosis and production of reactive oxygen species (ROS, via the respiratory burst). They are recruited to the site of infection early in an acute inflammation.  Acute alcohol exposure inhibits neutrophil migration in response to bacterial challenge in animal models and reduces neutrophil phagocytic activity. In contrast, increased neutrophil infiltration in the liver after chronic alcohol consumption is a characteristic of alcoholic steatohepatitis; these neutrophils, however, also appear to have reduced phagocytic activity. 

NK cells are innate immune cells that induce apoptosis of virally infected or cancer cells by releasing perforin and granzymes.  Prolonged alcohol feeding in an animal model inhibits the expression of perforin and granzymes in NK cells.  Alcohol’s effect on NK cell activities appears to be complex with differing results from different cohorts, and the functional relevance of these results is poorly understood. In addition, the functional differences due to the origin of NK cells (thymus, bone marrow, spleen or liver) remain to be determined.

NKT cells are T lymphocytes with innate immune cell features. Chronic alcohol exposure in rodents leads to an increase in the number of NKT cells in the liver. NKT cells also have capacity to bridge innate and adaptive immunity, so effects of alcohol on NKT cells may influence the balance of the immune response. 

Dendritic cells, and to a lesser extent, monocytes and macrophages, activate adaptive immune cells by presenting processed antigens and by releasing co-activating cytokines. Acute alcohol exposure inhibits monocyte antigen presenting function, reduces dendritic cell IL-12 production, and decreases expression of co-stimulatory molecules.  Similarly, chronic alcohol exposure reduces the number of dendritic cells and inhibits their output of co-activating cytokine IL-12, impairing antigen-specific induction of T cell proliferation. Furthermore, co-culture of T cells with acute alcohol–treated dendritic cells results in T cell anergy.

The integrity of barrier function is also essential to host defense. Epithelial tissues at mucosal surfaces in the gut, the lung, and at the blood brain barrier are increasingly recognized for their roles in restricting infections and shaping host immune responses.   Barrier dysfunction has been linked to alcohol-related micronutrient deficiencies and oxidative stress resulting from alcohol metabolism. The consequence of this disruption on the host immune system remains to be fully determined.

Adaptive Immune cells:

T cells and B cells of the adaptive immune response mount a more specific and long-lasting defense against infection.  Antibodies specific to the invading antigen are produced by B cells.  CD8+ T cells attack the antigen bearing invader directly, while CD4+ T cells produce cytokines and other factors that direct the immune response.  Memory cells of both B cells and T cells ensure a more rapid response to future infection by the same agent.

Chronic alcohol consumption has a generally immunosuppressive effect on the adaptive immune response, especially cell-mediated immunity by CD8+ T cells.  Reports of the effect of alcohol on lymphocyte abundance vary with the study population, but, in general, host defense is weakened and cytokine expression is altered. Paradoxically, persistent T cell activation and a heightened T cell response to non-specific stimulation have been observed in alcoholics.  In addition, a chronic alcohol-induced shift from a naïve CD8+ T cell phenotype to a memory cell CD8+ phenotype has been observed in both humans and in mouse models.   Alterations in selectins and co-stimulatory molecules by alcohol have also been observed.  Chronic alcohol impairs the primary response of CD8+ cells to specific antigen priming in mice. Thus, the immunodeficiency in the adaptive response of chronic alcoholics results both from impaired antigen presentation as well as from intrinsic defects in the T cells themselves.  The relative contribution of an apparent generalized activation and heightened non-specific T cell response to immunodeficiency is not yet clear.

Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis to release cortisol.  Since glucocorticoids, including cortisol, are generally anti-inflammatory and immune suppressive, it has been hypothesized that immunomodulating effect of alcohol may be mediated through alcohol’s effect on the HPA axis.  Evidence in support of the hypothesis is mixed; modification of the HPA axis in a clinical setting partially corrects the post-surgical immune derangement attributed to alcohol exposure.  However, cortisol levels do not correlate with all cases of alcohol-associated inhibition of pathogen recognition receptor activity.  The involvement of the HPA axis in the mechanism of immunosuppression due to alcohol consumption remains an open question.

Alcohol-related dysregulation of the immune response at cellular and molecular levels

In response to different pathogens, progenitor or naïve immune cells differentially develop into effector cells through a highly regulated process. This process is initiated by innate immune cell sensing of a pathogen, and regulated by immune cell-derived mediators (e.g., cytokines), and by direct interactions among different immune cells.

Innate immune cells use pattern recognition receptors (PRRs) to detect the presence of pathogens and tissue-derived danger signals. Upon sensing of pathogens or tissue damage, these receptors trigger downstream signaling events leading to transcription activation followed by the production of myriad immune mediators. Alcohol abuse causes increased leakiness of gut microflora products, including LPS, which can activate innate immune cells via Toll-like receptor 4 (TLR4). Acute alcohol inhibits and prolonged alcohol sensitizes the activation of TLR4 signaling.

In addition to the indirect effect of alcohol-related inflammation, alcohol also exerts a direct effect on immune cell function via its metabolism-derived oxidative stress. Oxidative stress has been linked to impairment of both proteasome function and autophagy, both of which play important roles in modulating immune function including antigen presentation. Furthermore, alcohol-related oxidative stress has been linked to activation of the immune regulatory transcription factor NF-kB.  Further clarification of the mechanisms underlying the effect of alcohol on these intracellular processes is needed.

Different lineages of helper CD4+ T cells play critical roles in directing pathogen-specific adaptive immune responses. For example, CD4+ T helper1 (Th1) cells are essential for combating intracellular bacterial infections whereas Th2 cells are critical for combating extracellular parasites. Th1 cell-produced cytokines help to sustain an inflammatory response by stimulating macrophages, with feed forward stimulation by macrophage cytokines.  Alcohol-fed animal models with primary infection and human alcoholics undergoing surgery show a significant shift of the Th1/Th2 balance which has been suggested to be critical in the susceptibility to infection. The mechanism underlying this shift of Th1/Th2 balance, especially its relationship with known alterations in the transactivating dendritic cells or macrophages, remains to be determined.

The current understanding of the polarization of immune function has expanded beyond T helper cells to a somewhat analogous diversity of function in macrophages.  While classically activated macrophages (M1) stimulate and maintain inflammation by releasing pro-inflammatory cytokines that influence Th1 development, alternatively activated macrophages (M2) are anti-inflammatory and non-phagocytic, and serve different homeostatic functions.  Potential disruptions of macrophage phenotype by alcohol remain to be investigated, especially in conjunction with obesity.

Recent studies have also shown that alcohol has significant effects on differentiation and lineage commitment in immune progenitor cells including hematopoietic stem cells, naïve T cells, and immature myeloid cells.  For example, chronic alcohol consumption is associated with liver enrichment of neutrophils and lymphocytes (Th17 cells) that produce IL17, a pro-inflammatory cytokine believed to play an important role in liver inflammation and fibrosis. The modification by alcohol of the differentiation of naïve T cells into Th1, Th2, Treg or Th17 cells needs to be investigated.  Overall, the potential effect of alcohol on maturation of specific cell populations is still a new area of research and much remains to be explored. 

Immune cell phenotype is strongly influenced by the local niche, so the effects of alcohol on interactions between immune and non-immune compartments may be very important.  Existing evidence supports disruption by alcohol of the following:  endothelial cell function, impairment of barrier function in both gut and lung, and altered neutrophil recruitment and clearance.

Chronic and systemic inflammation, as manifested by the rise of circulating pro-inflammatory cytokines, is a common feature in alcohol abusers, especially those with liver diseases. This condition is believed to be induced and sustained by a confluence of factors, including long term exposure to alcohol, continued tissue injury in the liver and gut and the resulting impact on the host immune system, increased circulating LPS, and altered neuroendocrine function.  The impact of alcohol-induced chronic inflammation on innate and adaptive immune cell functions, host defense, and tissue homeostasis is still not well understood.

Alcohol-related immune dysfunction and organ injury

Lung

Impairment of pulmonary defense by alcohol is a major contributor to the medical burden due to infections and Acute Respiratory Distress Syndrome (ARDS).  The high incidence of the latter often fatal condition and all respiratory infections in chronic alcohol abusers reflects the fact that alcohol has multiple effects on lung homeostasis.  Both alveolar integrity and pulmonary immune function are compromised by alcohol exposure, and alcohol is known to contribute to oxidative stress in the lung.  In addition, alcohol also disrupts mucociliary clearance in the upper airway.  Antioxidant therapy has shown some promise in restoring pulmonary immune function in preclinical models. 

Alcoholic liver diseases (ALDs)

A number of immune alterations are associated with alcoholic liver diseases.  For example, alcohol abusers with steatohepatitis and cirrhosis have elevated pro-inflammatory cytokines in circulation, and have clinical symptoms of systemic inflammation closely linked to an increased leakage of gut microbial products, e.g., LPS.  Polymorphisms of cytokine genes have been associated with ALDs. Consistently, studies of mouse models have shown that LPS and its host cell sensor TLR4, liver resident macrophages (Kupffer cells), and the pro-inflammatory cytokine TNFα all play a causal role in the early stages of alcohol-induced liver pathology. The use of probiotics in ALD has shown promise as an effective preventive treatment.

Other immune alterations associated with ALD include: 1) autoimmune activity, including liver deposition of IgG and IgA against liver proteins that form adducts with the alcohol metabolite acetaldehyde and the lipid peroxidation product malondialdehyde; 2) enrichment of a proinflammatory effector T cell, Th17 cells, in  patients with ALD; 3) activation of hepatic stellate cells, an event critical for fibrogenesis, by cytokines produced by Kupffer cells; 4) enrichment of neutrophils in the liver; and 5) defective NK cells.  The extent to which these immune alterations interact in the pathogenesis of human alcoholic liver diseases remains to be determined.

Neuropathy

Impairment of cognitive function and structural changes to the brain are common in alcohol abusers. Alcohol-induced brain inflammation is now believed to be an underlying cause. Alcohol administration induces the pro-inflammatory cytokine TNFα in the brains of mice and potentially contributes to neural damage.  In addition, alcohol alters the permeability of the blood brain barrier by oxidative stress and by damaging basement membranes and modifying tight junction proteins.  The disruption of the blood brain barrier allows the accumulation of neutrophils and T cells in the brain, leading to an inflammatory milieu that is harmful to neurons.   Furthermore, binge drinking of alcohol inhibits neurogenesis due to activation of an inflammatory cascade in the brain.  Alcohol-induced gut leakage of LPS may contribute to the neuropathy as well since peripheral use of LPS in mice activates inflammation in the brain and blocks neurogenesis.   

Alcohol-related immune dysfunction in co-morbid conditions

Trauma

In patients who sustain trauma, alcohol exposure contributes to enhanced morbidity and mortality due to sepsis and shock whether alcohol consumption occurs prior to or at the time of injury.  Tissue injury at remote sites leads not only to a systemic inflammatory response, but also affects the immune homeostasis of the lung and the gut.  Consequently, trauma victims are more susceptible to infections after acute or chronic alcohol exposure.  Alcohol’s contribution to a poorer outcome has been observed with fractures, burns, blood loss, and other forms of trauma.  In addition, the incidence of post-surgical complications is greater in alcoholics than in the general population.  Insight into the mechanism by which alcohol exposure increases the likelihood of the systemic inflammatory response progressing to sepsis and ultimately multiple organ failure would be of clinical benefit. 

Pathogenesis of viral hepatitis:

Four million Americans and 175 million people worldwide are infected with hepatitis C virus (HCV). Up to 70-80% of patients with primary infection fail to clear the virus and become chronically infected. Chronic HCV infection, like alcohol abuse, is a major cause of chronic liver disease and hepatocellular carcinoma (HCC).  Alcohol abuse further reduces viral clearance and in addition accelerates the progression of fibrosis and HCC.  Current anti-HCV medications are only partially effective and made even less so by alcohol abuse. One mechanism by which alcohol affects anti-HCV immunity is the impairment of dendritic cell ability to activate Th1 CD4+ cells, an adaptive immune cell type critical for HCV clearance. There is also evidence that alcohol, through its metabolism-induced oxidative stress, can reduce the hepatocyte proteasome activity necessary for viral antigen presentation in the infected cells.

HIV/AIDS

An estimated 1.1 million Americans and more than 30 million people worldwide are living with HIV/AIDS. Prevalent alcohol use in this population is associated with increased mortality.  In animal models with HIV/SIV infection, alcohol feeding increases viral replication and accelerates mortality and morbidities. These medical consequences coincide with alcohol-induced alteration of T cells in the mucosa.  The impact of alcohol on the mucosal immune system is still largely unknown.

As increasing numbers of HIV-infected patients live longer with anti-retroviral medications, non-AIDS defining conditions have become the major causes of mortality and morbidities.  For example, a significant percent of HIV patients have HCV or HBV co-infections and are most likely to develop end-stage liver diseases.  These co-infected patients are particularly vulnerable to the adverse impact of alcohol abuse. Other alcohol affected conditions include neuropathological problems.

Alcohol, Immune Function and Cancer

Alcohol consumption is associated with cancers originating in the upper aerodigestive tract, liver, colon, and breast.  Chronic alcohol consumption leads to chronic inflammation, and a causative link between inflammation and cancer has been postulated.  In addition, disruption of immune function, specifically immune surveillance by alcohol, may contribute to the incidence of cancer at these sites.  Alterations in NK cells and myeloid derived suppressor cells (MDSCs) in alcohol-fed animals have been reported in the context of cancer models.  However, immune surveillance is a complex physiological process likely involving all immune cell types.  The effects of alcohol on anti-tumor immunity remain an underexplored area of research. 

Research Objectives and Scope

Investigation into the effect of alcohol on immune function should take into account recent and ongoing advances in the field of immunology, specifically, the expanding list of immune cell types and sub-types.

In addition, there is increasing evidence that alcohol may disrupt immune regulation globally.  Rather than considering the dichotomy of immune activation and immune suppression, it may be more illuminating to consider that alcohol exposure leads to an altered course of immune activation, by modifying T helper cell commitment, by influencing the range of macrophage function, or by other, as yet unidentified, trends.  Thus, advancing the field also requires insight into the role that alcohol plays in disrupting or dysregulating multiple components of the immune network. 

Research topics of interest include, but are not limited to, the following:

Characterization and mechanistic investigation of alcohol-induced immune dysfunctions. 

Characterization of the intracellular and extracellular milieu in infection, disease, cancer and co-morbid settings using high throughput methodologies such as systems biology, histoimmunological or histochemical approaches.  Collaborations among multiple laboratories with complementary expertise are strongly encouraged.

Translational research on pharmacological or nutritional remedies of alcohol-induced immune dysfunction to increase the resistance to alcohol-associated infection and to ameliorate or reverse alcohol-induced pathogenesis

This FOA is intended to attract research proposals that utilize comprehensive approaches and cutting edge technology to address mechanistic questions about alcohol’s effect on human health.  In view of the complexity of the interactions within the immune system and among immune, neural and endocrine networks, systems approaches are encouraged.  Further, experimental designs incorporating an in vivo component are strongly recommended, including, but not limited to, incorporation of available transgenic models.

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/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

Any application awarded in response to this FOA will be subject to the DUNS, 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
Bethesda MD 20892-9304
Telephone: 301-443-8744
Fax: 301-594-0673
Email: jungma@mail.nih.gov

H. Joe Wang, PhD
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 2029
Bethesda MD 20892-9304
Telephone: 301-451-0747
Fax: 301-594-0673
Email: wangh4@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 

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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