Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (

Components of Participating Organizations
National Institute on Alcohol Abuse and Alcoholism (NIAAA) (

Title:  Stress Pathways in Alcohol Induced Organ Injury and Protection (R01)

Announcement Type

Update: The following updates relating to this announcement have been issued:

Program Announcement (PA) Number: PA-10-093

NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through ( using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide. 


This FOA must be read in conjunction with the application guidelines included with this announcement in for Grants (hereafter called

A registration process is necessary before submission and applicants are highly encouraged to start the process at least four (4) weeks prior to the grant submission date. See Section IV.

Catalog of Federal Domestic Assistance Number(s)

Key Dates
Release/Posted Date: March 17, 2010
Opening Date: May 5, 2010 (Earliest date an application may be submitted to
Letters of Intent Receipt Date(s): Not Applicable
NOTE: On-time submission requires that applications be successfully submitted to no later than 5:00 p.m. local time (of the applicant institution/organization). 
Application Due Date(s):  Standard dates apply, please see  
AIDS Application Due Date(s): Standard dates apply, please see
Peer Review Date(s): Standard dates apply, please see 
Council Review Date(s): Standard dates apply, please see
Earliest Anticipated Start Date(s): Standard dates apply, please see
Additional Information To Be Available Date (URL Activation Date): Not Applicable
Expiration Date: May 8, 2013

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants

    A. Eligible Institutions
    B. Eligible Individuals
2. Cost Sharing or Matching
3. Other-Special Eligibility Criteria

Section IV. Application and Submission Information
1. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
    A. Submission, Review, and Anticipated Start Dates
          1. Letter of Intent
    B. Submitting an Application Electronically to the NIH
    C. Application Processing   
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices

2. Administrative and National Policy Requirements
3. Reporting

Section VII. Agency Contacts
1. Scientific/Research Contact(s)

2. Peer Review Contact(s)
3. Financial/Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives


Alcohol abuse and dependence devastate the life of the affected individuals and often lead to various medical disorders putting enormous economic and public health burdens on our society. These alcohol-induced tissue injuries include alcoholic hepatitis and cirrhosis, pancreatitis, cardiomyopathy, immune system defects, various forms of cancer, endocrine and fetal abnormalities, skeletal muscle loss, and osteoporosis. It is estimated that 18 million adults in the U.S. are alcohol-dependent and the cost to our society is staggering: over 185 billion dollars annually, of which 27 billion is the total cost for alcohol-attributable illnesses. It is crucial to develop effective strategies to treat alcohol-induced diseases, based on better understanding of their underlying mechanisms. In recent years the role of the ancient and evolutionally highly conserved stress pathways in alcohol related tissue injuries, organ pathologies and protection became apparent. In general, alcohol causes protein damage that induces protein quality control mechanisms (PQC) in different cellular compartments: the classic stress response or heat shock response (HSR) in the cytoplasm and the unfolded protein response (UPR) in the endoplasmic reticulum. While acute or repeated low dose alcohol exposure may be beneficial, chronic high dose exposure unequivocally triggers pathological pathways leading to inflammation, oxidative stress, cell death, metabolic derailments and eventual tissue damage in the heart, the liver and various organs. Better understanding of the salutary and pathological characteristics of these pathways is highly desirable since they will provide abundant knowledge for the development of effective preventative and therapeutic applications of alcohol induced disorders.

Classic Stress or Heat Shock Response (HSR)

Hallmarks of the classic stress response include Heat Shock Factor 1 (HSF1) activation by cytoplasmic-nuclear translocation, trimerization to gain high affinity binding to heat shock elements (HSE) embedded in the promoter of heat shock proteins (HSPs), followed by post-translational modifications, primarily phosphorylation, to achieve transcriptional competence and up-regulation of HSP genes. In principle, HSF1 activation in different organs provides protection against proteotoxic insults by alcohol and different noxious stimuli through the increased synthesis and recruitment of chaperone activities of HSPs to improve protein quality control (PQC) and mitigate proteotoxicity. Interestingly, chronic up-regulation of HSPs is also a common feature in many disparate diseases with diverse etiology including cancer, neurodegenerative disorders, protein aggregation cardiomyopathies, chronic inflammation and alcoholic liver disease. Whether, as it is generally believed, the HSF1-HSPs axis plays exclusive protective roles to guard against alcohol induced cellular and proteotoxic stresses, or its dysregulation will predispose organisms to various disorders, is relatively poorly understood.

Acute and chronic alcohol exposure produces changes in the gene expression patterns in various organs via transcription factor binding to alcohol responsive element (ARE) situated in the promoter region of alcohol regulated genes and concomitantly inducing their transcription. Numerous microarray studies of alcohol treatment demonstrated the activation of critical elements of the heat shock pathway leading to the induction of several HSP genes through their master regulator Heat Shock Factor 1 (HSF1). It is intriguing to speculate that alcohol consumption activates key components of the evolutionally conserved heat shock cascade that mediates some of the gene expression changes associated with alcohol uptake and define important beneficial and/or pathophysiological responses to alcohol depending on drinking patterns and volumes. A recent report examining the alcohol responsive gene Gabra4, a ligand-gated ion channel, found that its expression is predominantly regulated by HSF1 that binds to ARE in the Gabra4 promoter region in mouse cortical neurons and may mediate long-lasting physiological and behavioral changes. Moreover, voluminous literature provides evidence that repeated low level heat shock provides protection against subsequent lethal heat shock, a phenomenon called thermotolerance. Similarly, in the heart, repeated short ischemic episodes followed by reperfusion, termed ischemic preconditioning, protect against major ischemic insult experienced during myocardial infarction. Cellular and organ defense can be attributed, at least partially, to the accumulation of heat shock proteins (HSPs) during the preconditioning phase that confers protection against proteotoxic insults by heat and hypoxia via their molecular chaperon activity. Large scale epidemiological and controlled clinical studies of chronic, low to moderate level alcohol consumption showed beneficial effects in cardiovascular diseases. The mechanistic details of cardioprotection by low level alcohol consumption are currently partially understood, but it is tempting to hypothesize that, similar to ischemic cardioprotection, HSPs and their master regulator HSF1 both participate. The scope and contribution of the HSF1- mediated gene expression changes by alcohol in human organ protection and pathologies is largely unknown and requires further investigation.

Heat exposure during gestation or embryonic growth induces massive developmental changes. In Drosophila, heat exposure during embryonic development produces well described homeotic transformations or phenocopies of different phenotypes, while in mammals extreme heat during pregnancy generates neuronal tube defects in humans and in animal models. This situation is in principal reminiscent to the well known Fetal Alcohol Spectrum Disorder (FASD), the most widespread and preventable non-inherited developmental disorder due to maternal alcohol abuse during pregnancy. The most serious manifestation is fetal alcohol syndrome (FAS), a devastating developmental disorder characterized by craniofacial abnormalities, growth and mental retardation, behavioral and attention disorders, speech impairment, cleft palate, and other abnormalities. Intriguingly, loss-of-function studies implicated both HSF1 and HSF2 in brain development that designates them as potential candidate genes in the pathogenesis of FAS, but their precise roles remains enigmatic. Other, much less studied attributes of FAS may also be affected by the stress master transcription factors. Given their role in the regulation of cell growth, cell division and metabolism, dysregulation of normal HSF1 and HSF2 expression and activation patterns by alcohol can lead to growth retardation, and other organ system dysfunctions , which contribute to overall morbidity. The possibility that the heat stress master regulators HSF1, HSF2 and their target genes (HSPs) may play a role in this devastating alcohol related pathology provides an excellent opportunity for future investigation.

Immunomodulatory effects of chronic ethanol use on innate immune cells lead to exaggerated TNF alpha production and liver injury. Regulation of the heat shock response and the immune system is intimately intertwined, and surprisingly, both HSF1 and its target genes HSP70 and HSP90 play important roles in TNF alpha production. Earlier work with knockout mice demonstrated that HSF1, contrary to its well established activator function, is a direct repressor of the TNF alpha gene and down-regulates its expression induced by LPS challenge. Recent work examining the role of in vitro alcohol exposure of monocytes and macrophages demonstrated that HSF1 activation is associated with both acute and chronic treatment. Interestingly, HSP70 is up-regulated only by acute alcohol exposure, while HSP90 level increases with prolonged exposure. HSP90 interaction and with client protein IKKBbeta induced IkappaBalpha degradation, NF-kappaB activation and TNF alpha production. Geldanamycin, a specific small molecular inhibitor of HSP90 ATPase activity, prevented TNF alpha expression by chronic alcohol treatment raising the exciting possibility that HSP90 inhibitors or small molecular inhibitors of the general stress response may become attractive in vivo targets for inhibition of alcohol induced TNF alpha production and alcohol-induced liver injury.

Alcohol is primarily metabolized to acetaldehyde by alcohol dehydrogenase (ADH) in the liver. Ethanol oxidation is accompanied by NAD+ reduction to NADH that generates highly reduced cytoplasmic environment in cells and tissues where ADH is active, predominantly in hepatocytes. One major consequence of the decreased NAD+/NADH ratio is the inhibition of the NAD+ dependent SIRT1 histone deacetylase activity in mammalian cell, which links cellular metabolism status to transcriptional silencing. SIRT1 that exquisitely requires NAD+ for its activity has essential functions in regulating circadian genes, caloric restriction and obesity pathways and consequently affecting longevity in every organism studied so far. A recent surprising discovery links SIRT1 activity to the regulation of the Heat Shock Response (HSR) through deacetylation of a conserved K80 residue in the DNA binding domain of HSF1 that is essential for maintaining a DNA-binding competent state and transcription of HSP genes. This important study puts HSF1 in the hub where cell metabolism, nutritional status, stress and longevity are linked and argues that HSR regulation is intimately intertwined with the cell metabolic demands. At the organism level it is anticipated that diet and nutritional status may influence the regulation of HSF1 target genes and the HSR. It is conceivable that chronic, high level alcohol consumption may compromise the protective capacity of the HSR by shifting the NAD+/NADH equilibrium and inhibiting SIRT1 and ultimately HSF1 activity. This scenario may have far reaching consequences in the development of alcohol related pathologies of the liver and potentially other organs by disengaging the protective functions of the HSR. Pioneering studies argue that excessive reductive environment itself can induce “reductive stress” and lead to potentially lethal cardiomyopathy in a transgenic mouse model and in human patients. This novel pathway may be operational in other tissues where reductive intracellular environment is generated by alcohol-induced shift. The fundamental principles of this process are unclear and require further investigations.

Endoplasmic Reticulum Stress: The Unfolded Protein Response

The endoplasmic reticulum (ER), the largest and essential cellular organelle of all eukaryotic cells, is a membrane-enclosed network of tubular, sack and bag-like sub-cellular structures contiguous with the nuclear envelop that is the venue of folding and post-translational modification of secreted and membrane proteins, synthesis of lipids and sterols, and storage of free Ca2+. Approximately one third of newly synthesized cellular proteins travel through the ER to obtain correctly folded three dimensional structure and post-translational modifications with the help of ER chaperones and subsequently transported to their final destination in various cellular organelles or the cell surface. Ca2+ levels in the ER are several thousand-fold higher than in the cytoplasm, hence the ER functions as dynamic Ca2+ source responsive of extracellular and intracellular signaling pathways, including growth factors, hormones, metabolic-nutritional-energy imbalances and changes in the oxido-reductive milieu. ER chaperon capacity overload due to extreme protein synthesis demands, production of aggregation-prone mutant proteins, Ca2+ depletion, glucose deprivation, altered glucosylation or defects in the protein folding machinery leads to unfolded and misfolded protein accumulation in the ER, a pathophysiological condition referred to as ER stress. To resolve the imbalance in the protein folding homeostasis eukaryotic cells unleash the evolutionally conserved, ER specific unfolded protein response (UPR). This elaborate signaling cascade consists of three independent ER resident stress sensors that work in a highly collaborative manner: IRE1a (inositol requiring 1a), PERK (double-stranded RNA-dependent protein kinase (PRK)-like ER kinase) and ATF6 (activating transcription factor 6). Under non-stressed conditions the ER lumenal domain of the three sensors is associated with intralumenal chaperon GRP78 (glucose regulated protein 78 or BiP). Protein misfolding induces the dissociation of GRP78 to assist refolding and resolution of protein aggregates in the ER and simultaneously activates the ER stress sensors to promote compensatory protective measures. While PERK and IRE-1a are activated by autophosphorylation, ATF6 is transported to the Golgi to undergo regulated intramembrane proteolysis (RIP). To relieve the proteotoxic burden, these signaling cascades up-regulate the synthesis of ER resident chaperones, terminate novel protein synthesis by eIF2a (eukaryotic initiation factor-2a) phosphorylation and inactivation, initiate the transports of excess protein load to the cytoplasm for ER-associated protein degradation (ERAD) by the ubiquitin-proteosome pathway to ensure cell survival. Alternatively, extreme prolonged ER stress that can’t be alleviated by these protective mechanisms induce apoptosis through the up-regulation of several canonical and unorthodox signaling programmed cell death cascades including JNK, procaspase-4, procaspase-12, Ca2+ leakage, and the mitochondria. Exciting new discoveries from diverse research areas suggest that unresolved ER stress is the potential culprit in the development in many devastating human disorders including diabetes, liver injury, neurodegenerative diseases, viral infection, atherosclerosis, inflammation, bacterial pathogenesis, cancer and cardiomyopathy, among others. Ethanol and its first metabolite acetaldehyde are both robust proteotoxic agents and may provoke ER stress. Recent findings strongly suggest that chronic, unresolved ER stress plays causative role in the development, maintenance and progression of alcohol induced tissue injury.

Many mechanisms have been implicated in the development of alcohol-induced liver disease (ALD) that leads to steatosis, inflammation, apoptotic cell death, fibrosis, and cirrhosis, and even hepatocellular carcinoma. Recent studies using the intragastric ethanol feeding mouse model reconstructed the histopathologies of early ALD, including prominent steatosis, necroinflammatory foci and spotted apoptosis, while microarray analysis provided the first evidence of ER stress involvement in disease etiology. In addition to the activation of the three arms of ER stress sensor cascades (PERK, IRE-1a, ATF6), ER resident sterol regulatory binding protein (SREPB)-1c and 2 were also activated, leading to the up-regulation of fatty acid/ triglyceride synthesis and beta oxidation (SREPB-1a) and cholesterol synthesis (SREPB2); a prelude to the development of fatty liver. Systematic analysis of ER triggers identified elevated homocysteine level as a likely culprit evoking ER stress, in agreement with the literature from animal and human studies. Plasma homocysteine levels were increased 5-10 times in alcohol fed mouse model. Although the underlying regulatory mechanism of hyperhomocysteinemia is unclear at this point, betaine feeding reversed the increase in homocysteine levels, prevented induction of UPR and alcohol-induced fatty liver, and decreased necroinflammation and apoptosis. Elegant experiments using genetically modified mice (TNF receptor-1 knockout) demonstrated that TNF alpha does not induce either ER stress or elevated homocysteine levels and SREPBs have pivotal role in the pathogenesis of fatty liver. SREPB-2 up-regulation also leads to increased cholesterol synthesis and cholesterol accumulation in the inner mitochondrial membrane that alters membrane fluidity, causes mitochondrial transport defects and GSH depletion. In addition, cholesterol rise in the ER membrane induces ER stress and potential feed-forward mechanism if combined with alcohol feeding that (through homocysteine or acetaldehyde) further increases SREBP-2 and cholesterol synthesis leading to a vicious circle and aggravated ER stress. This interesting working model in combination with other alcohol feeding paradigms will provide further clues of the participation of ER stress in alcohol induced liver injury.

Alcohol exposure of the developing embryo induces neuronal loss in selected brain areas leading to structural and pathophysiological alterations that contributes to brain dysfunction and causes Fetal Alcohol Syndrome (FAS). In adults, heavy alcohol consumption has also been associated with neuronal loss in selected brain region. Although mechanistic details of alcohol induced neuronal death are incomplete, oxidative stress has been implicated in the development of FAS. In vitro experiments using and primary and tissue culture cells of neuronal origin demonstrated that although ethanol itself does not induce the UPR, it synergizes with ER stressors to up-regulate the expression of ER resident chaperones and promote apoptosis. CHOP, a proapoptotic transcription factor and a downstream effector of the UPR cascade, plays an important role in alcohol induced cell death. Additional work in in vivo model systems is needed to clarify the role of alcohol in neuronal death in FAS and provide clues of the functional interplay between oxidative and ER stress.

Chronic ethanol consumption causes alcoholic cardiomyopathy with hallmark features of cardiac hypertrophy, compromised myocardial contractility, dampened ejection fraction and stroke volume. Various theories have been put forward to explain the origination of alcoholic cardiomyopathy including reactive oxygen species, ethanol toxicity, protein-aldehyde adducts, hormonal changes, lipoprotein modifications and fatty acid ethyl-ester buildup although the fundamental mechanisms still remain poorly defined. Exciting current investigations lend impetus to the “acetaldehyde toxicity theory” that links aldehyde toxicity to insulin sensitivity and ER stress with subsequent apoptotic cell loss. Chronic alcohol exposure of mice induces glucose intolerance, diminished cardiac glucose uptake, cardiac hypertrophy and contractile dysfunction, concomitant with up-regulated ER stress markers. These pathophysiological and biochemical markers are all exacerbated with increased ADH level and activity, supporting the role of acetaldehyde in the development of insulin resistance and alcoholic cardiomyopathy. Whether ER stress has a direct and causal role in the loss of cardiac insulin sensitivity and whether insulin sensitizers, such as thiazolidinediones (TZD,) or “chemical chaperones” that increase the folding capacity of the ER will be effective drugs in the treatment of alcoholic cardiomyopathy await further investigation.

This initiative is designed to promote innovative research to determine how alcohol exposure affects the protective responses of the cell: the classical Heat Shock Response (HSR) in the cytoplasm and the Unfolded Protein Response (UPR) in the endoplasmic reticulum (ER) leading to tissue injury or protection in both the exposed individuals and the offspring of pregnant women, depending on drinking patterns and volumes. The ultimate goal of this FOA is to decipher the molecular events and interconnecting metabolic and signaling networks engaging the cellular stress machinery in alcohol-induced tissue injury and protection. A better understanding of the molecular underpinnings of alcohol’s effects on HSR and UPR may open new avenues for developing novel diagnostic, prognostic tools, biomarker discovery and therapeutic interventions in the prevention and treatment of alcohol-induced organ damage.

Research Objectives:

NIAAA is interested in understanding the role and potential salutary effects of the classical Heat Shock Response and the Unfolded Protein Response in the pathogenesis of alcohol-induced tissue damage. This FOA aims to encourage and support research that focus on how acute, chronic, or excessive alcohol exposures modulates the classical Heat Shock Response and the Unfolded Protein Response that may contribute to tissue injury and/or protection in human subjects or animal and cellular models. Studies using human samples, animal models, tissue culture cells, or in vitro biochemical systems are all considered to be appropriate in response to this FOA. This announcement also supports the mechanistic studies to explore the alcohol-induced quantitative and qualitative changes in the HSR and UPR pathways associated with tissue injury as potential effective biomarkers for prognosis, diagnosis, and treatment responsiveness of these damages as well as finding biomarkers associated with the salutary effects of moderate alcohol consumption.

Appropriate research topics may include, but are not limited to:

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism of Support

This FOA will use the R01 award mechanism. The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.  

This FOA uses “Just-in-Time” information concepts (see SF424 (R&R) Application Guide). It also uses the modular as well as the non-modular budget formats (see Specifically, a U.S. organization submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs) should use the PHS398 Modular Budget component.

U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component.

2. Funds Available

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds.

Facilities and Administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

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

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

1.B. Eligible Individuals

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI 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.

More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application for projects that require a “team science” approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available at All PDs/PIs must be registered in the NIH electronic Research Administration (eRA) Commons prior to the submission of the application (see for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering the multiple PD/PI option, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application.  Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

Number of Applications. Applicants may submit more than one application, provided that each application is scientifically distinct.

Resubmissions. Applicants may submit a resubmission application, but such application must include an Introduction addressing the previous peer review critique (Summary Statement). Beginning with applications intended for the January 25, 2009 official submission due date, all original new applications (i.e., never submitted) and renewal applications are permitted only a single amendment (A1).  See new NIH policy on resubmission (amended) applications (NOT-OD-09-003, NOT-OD-09-016). Original new and competing renewal applications that were submitted prior to January 25, 2009 are permitted two amendments (A1 and A2).  For these “grandfathered” applications, NIH expects that any A2 will be submitted no later than January 7, 2011, and NIH will not accept A2 applications after that date.

Renewals.  Applicants may submit a renewal application. 

Section IV. Application and Submission Information

To download a SF424 (R&R) Application Package and SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for this FOA, use the “Apply for Grant Electronically” button in this FOA or link to and follow the directions provided on that Web site.


Appropriate registrations with and eRA Commons must be completed on or before the due date in order to successfully submit an applicationSeveral of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered with both and the Commons. All registrations must be complete by the submission deadline for the application to be considered “on-time” (see 3.C.1 for more information about on-time submission).

A one-time registration is required for institutions/organizations at both:

PDs/PIs should work with their institutions/organizations to make sure they are registered in the NIH eRA Commons.

Several additional separate actions are required before an applicant can submit an electronic application, as follows:  

1) Organizational/Institutional Registration in Registered  

2) Organizational/Institutional Registration in the eRA Commons

3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.

Both the PD(s)/PI(s) and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the application image.

Note: The registration process is not sequential.  Applicants should begin the registration processes for both and eRA Commons as soon as their organization has obtained a DUNS number.  Only one DUNS number is required and the same DUNS number must be referenced when completing registration, eRA Commons registration and the SF424 (R&R) forms.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and the SF424 (R&R) Application Guide for this FOA through

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the "Attachment" files may be useable for more than one FOA.

For further assistance, contact GrantsInfo -- Telephone 301-435-0714, Email:

Telecommunications for the hearing impaired: TTY:  (301) 451-5936

2. Content and Form of Application Submission

Prepare all applications using the SF424 (R&R) application forms for this FOA through and in accordance with the SF424 (R&R) Application Guide (  

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. Some fields within the SF424 (R&R) application components, although not marked as mandatory, are required by NIH (e.g., the “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component must contain the PD/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see “Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.”

The SF424 (R&R) application has several components. Some components are required, others are optional. The forms package associated with this FOA in includes all applicable components, required and optional. A completed application in response to this FOA includes the data in the following components:

Required Components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
PHS398 Modular Budget or Research & Related Budget, as appropriate (See Section IV.6. regarding appropriate required budget component.)  

Optional Components:
PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form

Foreign Organizations (Non-domestic [non-U.S.] Entities)

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at:

Applications from Foreign organizations must:

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States (U.S.) or that augment existing U.S. resources.


Applications with Multiple PDs/PIs.

When multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the "Contact” PI, who will be responsible for all communication between the PDs/PIs and the NIH, for assembling the application materials outlined below, and for coordinating progress reports for the project. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PDs/PIs, but has no other special roles or responsibilities within the project team beyond those mentioned above.

Information for the Contact PD/PI should be entered on the SF424 (R&R) Cover component. All other PDs/PIs should be listed in the Research & Related Senior/Key Person component and assigned the project role of “PD/PI.” Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission. The Commons ID of each PD/PI must be included in the “Credential” field of the Research & Related Senior/Key Person component. Failure to include this data field will cause the application to be rejected.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, the Research Plan section and the Multiple PD/PI Leadership Plan must be included. A rationale for choosing a multiple PD/PI approach should be described.  The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators. 

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan.  In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award (NoA).

Applications Involving a Single Institution

When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.

Applications Involving Multiple Institutions 

When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a subcontract to be administered by the prime institution. When submitting a detailed budget, the prime institution should submit its budget using the Research & Related Budget component. All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form. 

When submitting a modular budget, the prime institution completes the PHS398 Modular Budget component only. Information concerning the consortium/subcontract budget is provided in the budget justification. Separate budgets for each consortium/subcontract grantee are not required when using the Modular budget format. See Section 5.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.

3. Submission Dates and Times

See Section IV.3.A. for details.

3.A. Submission, Review, and Anticipated Start Dates
Opening Date: May 5, 2010 (Earliest date an application may be submitted to
Letters of Intent Receipt Date(s): Not Applicable
NOTE: On-time submission requires that applications be successfully submitted to no later than 5:00 p.m. local time (of the applicant institution/organization). 
Application Due Date(s):  Standard dates apply, please see  
AIDS Application Due Date(s): Standard dates apply, please see
Peer Review Date(s): Standard dates apply, please see 
Council Review Date(s): Standard dates apply, please see
Earliest Anticipated Start Date(s): Standard dates apply, please see

3.A.1. Letter of Intent

A letter of intent is not required for the funding opportunity.

3.B. Submitting an Application Electronically to the NIH

To submit an application in response to this FOA, applicants should access this FOA via and follow Steps 1-4. Note:  Applications must only be submitted electronically.  PAPER APPLICATIONS WILL NOT BE ACCEPTED.  All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.

3.C. Application Processing

3.C.1 Submitting On-Time

Applications may be submitted on or after the opening date and must be successfully received by no later than 5:00 p.m. local time (of the applicant institution/organization) on the application due date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the due date(s) and time, the application may be delayed in the review process or not reviewed. All applications must meet the following criteria to be considered “on-time”:

Please visit for detailed information on what to do if or eRA system issues threaten your ability to submit on time.

Submission to is not the last step – applicants must follow their application through to the eRA Commons to check for errors and warnings and view their assembled application!

3.C.2 Two Day Window to Correct eRA Identified Errors/Warnings

IMPORTANT NOTE! NIH has eliminated the error correction window for due dates of January 25, 2011 and beyond. As of January 25, all corrections must be complete by the due date for an application to be considered on-time. See NOT-OD-10-123.

Once an application package has been successfully submitted through, NIH provides applicants a two day error correction window to correct any eRA identified errors or warnings before a final assembled application is created in the eRA Commons.  The standard error correction window is two (2) business days, beginning the day after the submission deadline and excluding weekends and standard federal holidays.  All errors must be corrected to successfully complete the submission process.  Warnings will not prevent the application from completing the submission process.

Please note that the following caveats apply:

3.C.3 Viewing an Application in the eRA Commons

Once any eRA identified errors have been addressed and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two weekdays (Monday – Friday, excluding Federal holidays) to view the assembled application before it automatically moves forward to NIH for further processing.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Incomplete applications will not be reviewed.

There will be an acknowledgement of receipt of applications from and the Commons. The submitting AOR/SO receives the acknowledgments. The AOR/SO and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific Review Group is also in the Commons. 

Note: Since email can be unreliable, it is the responsibility of the applicant to check periodically on their application status in the Commons.

The NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. However, the NIH will accept a resubmission application, but such application must include an Introduction addressing the critique from the previous review.

4. Intergovernmental Review

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. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or renewal award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or renewal award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement

6. Other Submission Requirements

PD/PI Credential (e.g., Agency Login)

The NIH requires the PD(s)/PI(s) to fill in his/her Commons User ID in the “PROFILE – Project Director/Principal Investigator” section, “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component.

Organizational DUNS

The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with For additional information, see “Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.”

PHS398 Research Plan Component Sections

All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating "Just-in-Time" information concepts, and with the following additional requirements:

Budget Component

U.S. applicants submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs) must use the PHS398 Modular Budget component.

U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component.

Specific Instructions for Applications Requesting $500,000 (direct costs) or More per Year

Applicants requesting $500,000 or more in direct costs for any year (excluding consortium F&A costs)  must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as plans are being developed for the study;

2) Obtain agreement from the IC staff that the IC will accept the application for consideration for award; and,

3) Include a cover letter with the application that identifies the staff member and IC who agreed to accept assignment of the application.

This policy applies to all new, renewal, revision, or resubmission applications. See NOT-OD-02-004.

Appendix Materials 

Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See

Do not use the Appendix to circumvent the page limitations. An application that does not comply with the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value and further the advancement of the research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in the Resource Sharing section of the application (see

(a) Data Sharing Plan: Investigators seeking $500,000 or more in direct costs in any year are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact (see Data-Sharing Policy or

(b) Sharing Model Organisms: Regardless of the amount requested, all applications in which the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible (see Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.)

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible.  A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (e.g., blood pressure or weight) or the presence or absence of a disease or condition.  For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (NOT-OD-07-088) and

Foreign Applications (Non-domestic [non-U.S.] Entities)

Indicate how the proposed project has specific relevance to the mission and objectives of the NIH/IC and has the potential for significantly advancing the health sciences in the United States 

Section V. Application Review Information

1. Criteria 

Only the review criteria described below will be considered in the review process.
2. Review and Selection Process

Review Process

Applications submitted for this funding opportunity will be assigned on the basis of established PHS referral guidelines to the ICs for funding consideration.

Applications that are complete will be evaluated for scientific and technical merit by (an) appropriate scientific review group(s) in accordance with NIH peer review procedures ( using the review criteria stated below.  

As part of the scientific peer review, all applications will:

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability.  As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system. 

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 five scored review criteria, and additional review criteria (as applicable for the project proposed). 

Scored Review Criteria

Reviewers will consider each of the five review criteria below in the determination of scientific and technical 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/PIs, collaborators, and other researchers well suited to the project?  If Early Stage Investigators or New Investigators, do they have appropriate experience and training?  If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)?  If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation.  Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions?  Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense?  Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach.  Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project?  Are potential problems, alternative strategies, and benchmarks for success presented?   If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment.  Will the scientific environment in which the work will be done contribute to the probability of success?  Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed?  Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Additional Review Criteria 

As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, 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.

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.

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, see

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.

Resubmission Applications.  When reviewing a Resubmission application (formerly called an amended application), 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.

Renewal Applications.  When reviewing a Renewal application (formerly called a competing continuation application), the committee will consider the progress made in the last funding period.

Revision Applications.  When reviewing a Revision application (formerly called a competing supplement application), 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 address 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.  As applicable for the FOA or submitted application, 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 Agents 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 Support.  Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Selection Process

Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

Not Applicable

Section VI. Award Administration Information

1. Award Notices

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 NIH eRA Commons

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

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. See Section IV.5., “Funding Restrictions.”       

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.

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 Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research (program), peer review, and financial or grants management issues:

1. Scientific/Research Contact(s):

Andras Orosz, Ph.D.
Division of Metabolism and Health Effects
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health, DHHS
5635 Fishers Lane, Room 2037
Bethesda, MD 20892-9304
Telephone: 301-443-2193
Fax: 301-594-0673

2. Peer Review Contact(s):

Not Applicable

3. Financial/Grants Management Contact(s):

Judy Fox
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health, DHHS
5635 Fishers Lane MSC 9304 Room 3023
Bethesda, MD 20892-9304
[For express mail use: Rockville, MD 20852-1705]
Telephone: 301-443-4704
FAX:  301-443-3891

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals ( as mandated by the Health Research Extension Act of 1985 (, and the USDA Animal Welfare Regulations ( as applicable.

Human Subjects Protection:
Federal regulations (45 CFR 46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (“NIH Policy for Data and Safety Monitoring,” NIH Guide for Grants and Contracts,

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible ( Investigators should seek guidance from their institutions, on issues related to institutional policies and local institutional review board (IRB) rules, as well as local, State and Federal laws and regulations, including the Privacy Rule.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh-Dole Act (see the NIH Grants Policy Statement. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are: (1) first produced in a project that is supported in whole or in part with Federal funds; and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research” (; a complete copy of the updated Guidelines is available at The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the SF424 (R&R) application; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at

Human Embryonic Stem Cells (hESC):
Criteria for Federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding ( It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy, investigators funded by the NIH must submit or have submitted for them to the National Library of Medicine’s PubMed Central (see, an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made publicly available no later than 12 months after the official date of publication. The NIH Public Access Policy is available at ( For more information, see the Public Access webpage at

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (HHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the HHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website ( provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, Internet addresses (URLs) or PubMed Central (PMC) submission identification numbers must be used for publicly accessible on-line journal articles. Publicly accessible on-line journal articles or PMC articles/manuscripts accepted for publication that are directly relevant to the project may be included only as URLs or PMC submission identification numbers accompanying the full reference in either the Bibliography & References Cited section, the Progress Report Publication List section, or the Biographical Sketch section of the NIH grant application. A URL or PMC submission identification number citation may be repeated in each of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at and is not subject to the intergovernmental review requirements of Executive Order 12372. 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. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see:

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