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: Molecular Mechanisms of Development and Reversal of Alcohol-Induced Liver Fibrosis (R01)

Announcement Type

Update: The following update relating to this announcement has been issued:

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 weeks prior to the grant submission date. See Section IV.

Program Announcement (PA) Number: PA-07-360

Catalog of Federal Domestic Assistance Number(s)

Key Dates
Release/Posted Date: April 19, 2007
Opening Date: May 5, 2007 (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 Submission/Receipt Date(s): Standard dates apply, please see
AIDS Application Submission/Receipt 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: March 6, 2010

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
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
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


The National Institute on Alcohol Abuse and Alcoholism invites grant applications that will employ an integrated approach to investigate the underlying molecular mechanisms of the development as well as reversal of alcohol-induced liver fibrosis. Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components, especially collagen, due to increased matrix production and/or decreased matrix degradation. Activation of hepatic stellate cells (HSCs) is the primary event that triggers the process of fibrogenesis. Understanding the underlying molecular mechanisms by which chronic alcohol consumption leads to the development of liver fibrosis, and the mechanisms by which liver fibrosis is reversed, is important for the development of strategies for prevention and treatment of this condition.

A. Development of Liver Fibrosis: Published studies have identified the following factors as contributors to the development of alcohol-induced liver fibrosis.

A1. Acetaldehyde:

Acetaldehyde, an immediate metabolite of ethanol, is primarily produced in hepatocytes and can diffuse out to activate HSCs in a paracrine manner. Acetaldehyde has been shown to increase collagen production by cultured rat HSCs in vitro via:1) increasing the transcription of a1(I) collagen gene; 2) decreasing the synthesis of matrix metalloproteinases-1, an enzyme known to degrade type I collagen; and 3) increasing the expression of other extracellular matrix components, including type III collagen and fibronectin. Acetaldehyde also up-regulates transforming growth factor beta1 (TGF-1) expression, suggesting that some fibrogenic actions of acetaldehyde could be indirectly mediated by TGF- 1. Acetaldehyde increased cell membrane-associated PKC activity of HSCs, whereas PKC inhibitors blocked acetaldehyde-mediated a1(I) collagen gene up regulation, suggesting a role of this kinase in transducing the intracellular signal. However, subsequent steps involved in the signal transduction pathways are not clear, and the molecular mechanisms whereby acetaldehyde up-regulates gene transcription for collagen and other matrix proteins are not well understood.

A2. Oxidative stress:

Chronic alcohol ingestion causes oxidative stress in the liver by increasing generation of superoxide anions, hydrogen peroxide, hydroxyl radicals and lipid peroxidation products. It also decreases glutathione levels in the liver. These ROS have been shown to stimulate HSC proliferation and collagen synthesis. Lipid peroxidation products such as malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) have been implicated in hepatic fibrosis due to chronic ethanol administration. Furthermore, MDA and 4-HNE have been shown to induce gene expression of procollagen a1(I) and increase collagen production by several folds in cultured HSCs. Studies are needed to clarify the role, if any, of lipid peroxidation products in activating quiescent HSC, and identify the molecular and signal transduction pathways involved in this process.

A3. Role of Kupffer cells:

Kupffer cells have been implicated as mediators of alcoholic liver injury through the release of free radicals as well as generation of inflammatory and fibrogenic mediators in response to alcohol and lipopolysaccharide (LPS). Tumor necrosis factor-alpha (TNF-a) produced by activated Kupffer cells may contribute to HSC activation by inducing apoptosis of hepatocytes. In addition, Kupffer cell-derived TGF-1has been implicated in the activation of stellate cells through a paracrine mechanism. Furthermore, using co-cultures of Kupffer cells and HSCs, it was demonstrated that the stimulatory effect of Kupffer cells on HSC collagen I production was mediated through xanthine oxidase, NADPH oxidase, and CYP2E1, which are known sources of ROS. These results suggest a role of oxidative stress in Kupffer cell-mediated HSC activation. Further studies are necessary to understand the relative contribution of Kupffer cell mediators and how this information can be used to prevent fibrosis.

A4. Lipopolysaccharide (LPS):

Chronic ethanol exposure is associated with increased transfer of LPS (endotoxin) from the intestine to portal vein. Elevated levels of endotoxin in plasma can activate Kupffer cells leading to release of pro-inflammatory and pro-fibrogenic cytokines and both of these factors can contribute to fibrosis. Recently, researchers have discovered that activated human HSCs express LPS-recognizing receptors such as CD14 and TLR4. Furthermore, LPS was shown to induce activation of NF-kB and JNK and expression of chemokines and adhesion molecules in activated human HSCs. In cultured rat HSCs, LPS induced expression of TNF-a, iNOS, and IL-6, which was initiated by MAPK p38 and mediated by NF-kB. These results suggest that in addition to playing an indirect role via Kupffer cell activation, LPS may contribute to hepatic fibrosis directly by regulating gene expression of inflammatory mediators in HSCs. How do these inflammatory mediators activate HSCs and increase collagen production is not clear.

A5. Role of hepatocyte apoptosis:

Hepatocyte apoptosis is significantly increased in patients with alcoholic hepatitis, and correlates with disease severity and hepatic fibrosis. Increased apoptosis of hepatocytes results in increased fibrosis in experimental models. Hepatocyte apoptosis produces chemokines and inflammation, which in turn may activate HSCs. Furthermore, apoptosis of hepatocytes results in generation of apoptotic bodies which can release lipid signals for uptake by Kupffer cells and HSCs. Phagocytosis of the apoptotic bodies by HSCs and Kupffer cells enhances their expression of pro-fibrogenic genes, such as TGF-1, that may initiate HSC activation. These studies suggest that alcohol-induced apoptosis of hepatocytes may be a mechanism of liver fibrosis. Further studies are required to clarify the mechanisms by which alcohol ingestion induces the formation of apoptotic bodies and how these bodies activate HSCs.

A6. Transforming growth factor-beta1 (TGF-b1):

TGF-b1 is a potent profibrogenic cytokine involved in hepatic fibrosis. In the liver, it is expressed in Kupffer cells, sinusoidal endothelial cells and HSCs. It activates HSCs resulting in their conversion to myofibroblasts which produce excess of ECM proteins including collagens. TGF-b1 can indirectly enhance collagen production via increasing the expression of platelet-derived growth factor (PDGF), which is a potent mitogen for HSC proliferation, and by up-regulating the expression of connective tissue growth factor (CTGF), a fibrogenic cytokine. In addition, TGF-b1 can enhance its own production in HSCs in an autocrine manner. Thus, once TGF-b1 is secreted, it can perpetuate both HSC proliferation and increased matrix production that can result in fibrosis. Recently researchers have discovered the inhibitor of differentiation 1 (Id1) gene that appears to be a critical mediator in the TGF-b1-induced transdifferentiation of rat HSCs. The possible involvement of TGF-b1 in alcohol-induced liver fibrosis is based on the following information. Patients with advanced alcoholic liver disease exhibit increased hepatic expression of TGF-b1 mRNA as well as increased serum levels of TGF-b1. In addition, Kupffer cells isolated from chronically ethanol exposed rats secreted TGF-b1 which induced Collagen production in HSCs. Furthermore, acetaldehyde has been shown to enhance the production of TGF-b1 in cultured HSCs. How to use the available information on TGF-1 for the treatment of liver fibrosis needs further research.

A7. Platlet-derived growth factor (PDGF):

PDGF is the most potent mitogen for HSCs and is therefore likely to be an important mediator of the increased proliferation of HSCs during hepatic fibrogenesis in chronic liver diseases. Upregulation of the PDGF receptorb during the transition of quiescent stellate cell to activated stellate cells is an early event following liver injury. PDGF produced from activated HSCs, activated Kupffer cells, and infiltrating macrophages can stimulate HSC proliferation through PDGF receptorb during liver fibrogenesis. TGF-b1, a fibrogenic cytokine, has been shown to potentiate PDGF-stimulated cell proliferation via inducing expression of PDGF receptorb. The role of PDGF in mediating the fibrogenic effect of chronic ethanol in liver needs investigation.

A8. Connective tissue growth factor (CTGF):

CTGF is a profibrogenic molecule which is over-expressed in fibrotic liver. CTGF expression in cultured HSCs is enhanced following their activation or stimulation by TGF-b1 which itself is a fibrogenic cytokine. Exogenous CTGF is capable of promoting adhesion and proliferation of cultured HSCs as well as collagen production by these cells. In addition, CTGF contributes to the survival of primary HSCs through activation of NF-kappaB pathway. Furthermore, CTGF is produced at high levels in hepatocytes during CYP2E1-mdiated ethanol metabolism. The CTGF produced in hepatocytes may activate HSCs in a paracrine manner. Taken together, these findings suggest a role of CTGF in alcohol-induced hepatic fibrosis; however, further research is needed to establish this connection.

A9. Adenosine:

Adenosine, a potent endogenous regulator of inflammation and tissue repair, is released in vitro by HepG2 cells in response to ethanol or methotrexate treatment. Activation of adenosine A2A receptor promotes stellate cell collagen production. Adenosine release was increased in the liver in response to carbon tetrachloride (CCl4) and thioacetamide exposure and this was associated with the development of liver fibrosis. However,

A2 A receptor deficient mice were protected from development of hepatic fibrosis following exposure to CCl4 or thioacetamide. Whether adenosine plays a significant role in mediating alcoholic liver fibrosis remains to be determined.

A10. Leptin:

Leptin plays an important role in the development of hepatic fibrosis. It is present in activated stellate cells but not in quiescent HSCs. Leptin has been shown to increase a1 (I) collagen mRNA and type I collagen production in human stellate cell line, LX-1, and up-regulate a2(I) collagen gene expression in cultured rat HSCs. This effect of leptin can be mediated through up-regulation of TGF-1, enhancement of the TGF1 type II receptor, or increased production of tissue inhibitor of metalloproteinase-1 (TIMP-1) in activated HSCs. The mechanism of leptin-induced alcoholic hepatic fibrosis is not clear.

A11. Role of innate immunity :

The liver immune system has predominant innate immunity (nonspecific immunity) comprised of Kupffer cells, natural killer (NK) cells and NKT cells, and interferon alpha (IFN-a) and interferon gamma (IFN-?) cytokines. Increasing evidence suggests that these innate immune cells and cytokines play important roles in regulating the development and progression of liver fibrosis: a) macrophages have been shown to inhibit liver fibrosis through killing HSCs and enhancing matrix degradation during recovery; b) innate cytokines IFN-a and IFN-? inhibit liver fibrosis by blocking TGF-1 signaling and HSC activation; c) IFN-a in combination with ribavirin has been shown to attenuate liver fibrosis in patients infected with hepatitis C virus (HCV); and d) NK cells have been shown to kill activated HSCs and attenuate the severity of liver fibrosis. These results suggest that innate immunity (NK/IFNs) plays an important role in suppression of liver fibrosis. Activation of the innate immune system (NK/IFNs) during HCV infection may help to control the progression of hepatic fibrosis.

Alcohol-mediated suppression of the innate immunity has been reported in both animal experiments and clinical studies. Chronic alcohol consumption has been shown to decrease NK cell activity and numbers. Decreased NK activity has also been reported in human alcoholics. Acute ethanol exposure markedly suppresses IFN-b and IFN-g activation of STAT1 signaling pathways in primary hepatocytes. STAT2 and protein kinase R, which are the key downstream signaling components for IFN-a, are significantly downregulated in human alcoholic liver disease. Chronic alcohol consumption interferes with the efficacy of IFN-a treatment in HCV patients. Since these innate immune cells and cytokines play an important role in suppressing liver fibrosis as discussed above, alcohol suppression of innate immunity may be a mechanism whereby alcohol accelerates liver fibrosis in HCV patients. Further research is required to investigate the role of innate immune system in alcoholic liver fibrosis.

A12. HCV and liver fibrosis:

Alcohol consumption is known to accelerate the process of liver fibrosis in patients infected with HCV, but the mechanisms of this interaction are not clear. Alcohol consumption has been shown to increase apoptosis of hepatocytes and oxidative stress in patients with chronic hepatitis C virus infection. Furthermore, HCV core protein and chronic alcohol consumption additively increased lipid peroxidation and synergistically increased hepatic TNF-a and TGF-1 expression in HCV core protein-expressing transgenic mice. All these fibrogenic factors apoptosis, oxidative stress, lipid peroxidation, TNF-a, and TGF-1 - may be involved in promoting the effect of alcohol on hepatic fibrosis in HCV infected patients. Further research is required to establish the connection between alcohol, HCV, and liver fibrosis and identify targets for intervention.

B. Reversion of Liver Fibrosis

Reversion of fibrosis may be accomplished by inducing apoptosis or necrosis of activated HSCs, or by transformation of activated HSCs to quiescent phenotype.

B1. Apoptosis of activated HSCs:

Spontaneous resolution of experimental fibrosis is associated with the clearance of collagen-producing a-SMA positive myofibroblasts (activated HSCs and transdifferentiated portal fibroblasts), which has been attributed to the induction of apoptosis of these cells. Apoptosis of myofibroblasts is associated with decreased expression of TIMP mRNA but increased collagenase activity in the liver. This concept of spontaneous reversion of fibrosis mediated by HSC apoptosis has been used to design chemical-induced apoptosis of activated HSCs. For example, gliotoxin induces apoptosis of activated HSC which resulted in the resolution of liver fibrosis induced by CCl4 in experimental animals . In addition, sulfasalazine has been shown to induce apoptosis of activated rat and human stellate cells in vitro, and promote accelerated recovery from CCl4 -induced fibrosis in rats. This effect was mediated through the inhibition of the inhibitor of kappaB kinases, blocking the NF-kB pathway. TIMP-1 protects activated HSCs from apoptosis and blocking TIMP-1 with specific monoclonal antibody reverses CCl4-induced hepatic fibrosis. Hepatocyte growth factor (HGF) stimulates hepatocyte regeneration but apoptosis of activated HSCs and reversal of fibrosis. Further research is required to identify agents that will selectively cause apoptosis of activated HSCs without adversely affecting hepatocytes.

B2. Necrosis of activated HSCs:

Activated HSCs can be selectively killed by the endogenous cannabinoid anandamide via inducing necrosis. Anandamide blocks HSC proliferation at concentrations of 1 to 10 micromol/L. At higher concentrations (25-100 micromol/L), anandamide dose-dependently induced cell death in culture-activated and in vivo-activated HSCs. The cell death was caspase-independent and showed typical features of necrosis, such as rapid adenosine triphosphate depletion and propidium iodide uptake. Anandamide induces ROS formation and increased intracellular Ca(2+) levels. Pretreatment with the antioxidant glutathione or Ca(2+)-chelation attenuated anandamide-induced cell death. In primary hepatocytes, anandamide failed to induce cell death even after prolonged treatment. Thus, anandamide efficiently induces necrosis in activated HSCs, an effect that depends on membrane cholesterol and a subsequent increase in intracellular Ca(2+) and ROS. The anti-proliferative effects and the selective killing of HSCs, but not hepatocytes, indicate that anandamide may be used as a potential anti-fibrogenic tool. Studies are required to test the efficacy and safety of anandamide and other related agents in animal models of liver fibrosis.

B3. Reverse trans-differentiation of activated HSCs to quiescent phenotype:

One theoretical approach to reverse fibrosis is the reverse trans-differentiation of activated HSCs to quiescent phenotype. Quiescent HSCs are full of Vitamin A and triglycerides which are depleted in the activated HSCs. The adipogenic/lipogenic transcriptional regulation conferred by PPAR?, LXRa, and SREBP-1c is required for the maintenance of the fat-storing quiescence phenotype of HSCs. Expression of these adipogenic transcription factors is lost in activated HSCs. On the other hand, treatment of the activated HSCs with an adipocyte differentiation cocktail or ectopic expression of PPAR? or SREBP-1c causes their reversal to the quiescent phenotype. Of the known adipogenic transcription factors, PPAR? has been investigated extensively. The expression of PPAR? is reduced in activated HSCs which can be restored with PPAR? ligands. Furthermore, by using adenoviral vector to ectopically express PPAR? in culture-activated HSCs, researchers have demonstrated that expression of PPAR? can restore the morphological and biochemical characteristics of quiescent HSCs, including accumulation of vitamin A. These findings suggest a possibility that PPAR? and other adipogenic factors may serve as important therapeutic targets for liver fibrosis. Indeed, researchers have demonstrated the therapeutic efficacy of two thiazolidinedione (TZD) derivatives, the PPAR? ligands pioglitazone and rosiglitazone in two toxic and one cholestatic models of liver fibrosis. However, in a recent human study, pioglitazone was found to be ineffective in reducing liver fibrosis in subjects with nonalcoholic steatohepatitis. Further studies are required to test the efficacy of PPAR? and other adipogenic factors in the treatment of liver fibrosis.

Areas of Research:

Examples of research that might be supported under this PA include, but are not limited to, the following:

Characterization of key genes initiating HSC activation in liver fibrosis

Mechanisms by which quiescent HSCs lose lipid droplets and adipogenic/lipogenic factors upon activation

Investigation of molecular mechanisms whereby adipogenic/lipogenic regulation promotes HSC quiescence but makes hepatocytes steatotic

Understanding the role of acetaldehyde in activation, migration, and proliferation, of HSCs

Elucidating the signaling pathways that mediate the effect of oxidative stress on the initiation and perpetuation of liver fibrosis

Understanding the role of cytokines - TGF-1, PDGF, CTGF, leptin, and adenosine - in alcohol-induced liver fibrosis

Understanding the intracellular signaling of acetaldehyde, oxidative stress, cytokines, and ECM in initiating HSC activation in an integrative manner using system biology approach

Development of co-culture models of hepatocytes, Kupffer cells, sinusoidal endothelial cells and HSCs for investigating the effects of various fibrogenic mediators

Molecular mechanisms of upregulation of collagen and TIMP production and downregulation of matrix metalloproteinases (MMPs) in alcoholic liver fibrosis

Roles of myofibroblasts of bone marrow and portal tract origin and epithelial mesenchymal transition in alcoholic liver fibrosis

Elucidation of mechanisms whereby hepatocyte apoptosis triggers activation of HSCs and identification of the apoptotic signals for hepatocytes, Kupffer cells, and HSCs

Mechanisms of interaction of innate immune system and alcohol on alcoholic liver fibrosis

Mechanisms of additive and synergistic effects of alcohol and HCV on the development of liver fibrosis

Characterization of key genes initiating apoptosis of activated HSCs during the resolution of fibrosis

Identification of agents that will selectively kill activated HSCs via inducing apoptosis or necrosis

Understanding the role of hepatocyte growth factor/scatter factor in the resolution of hepatic fibrosis

Understanding of the biology of matrix resorption

Elucidation of the role of epigenetic factors in the development and reversal of liver fibrosis

Evaluating the role of cannabinoid receptor agonists and antagonists in the suppression of liver fibrosis

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

Section II. Award Information

1. Mechanism of Support

This Funding Opportunity Announcement (FOA) will use the NIH Research Project Grant (R01) award mechanism.

The applicant will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses Just-in-Time information concepts. It also uses the modular as well as the non-modular budget formats (see

Specifically, if you are a U.S. organization and are submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs), use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide (see specifically Section 3.4, Modular Budget Component, of the Application Guide).

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 found in the application package for this FOA. See NOT-OD-06-096, August 23, 2006.

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 Institutes and Centers (ICs) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

NIH grants policies as described in the NOT-OD-05-004, November 2, 2004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit an application(s) if your institution/organization has any of the following characteristics:

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, or multiple PDs/PIs, may be designated on the application for projects that require a team science approach that clearly does 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 eRA Commons prior to the submission of the application (see for instructions).

The decision of whether to apply for a single PD/PI or multiple PD/PI grant is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for multiple PD/PI grants will require additional information, as outlined in the instructions below. When considering multiple PDs/PIs, 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 PD/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

Applications can be renewed by competing for additional project periods.

Applicants may submit more than one application, provided each application is scientifically distinct.

Section IV. Application and Submission Information

Appropriate registrations with and eRA Commons must be completed on or before the due date in order to successfully submit an application. Several 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).

To download a SF424 (R&R) Application Package and SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for this FOA, link to and follow the directions provided on that Web site.

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 eRA Commons.

Several additional separate actions are required before an applicant institution/organization 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/PI(s) and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the application image.

Note that if a PD/PI is also an NIH peer-reviewer with an Individual DUNS and CCR registration, that particular DUNS number and CCR registration are for the individual reviewer only. These are different than any DUNS number and CCR registration used by an applicant organization. Individual DUNS and CCR registration should be used only for the purposes of personal reimbursement and should not be used on any grant applications submitted to the Federal Government.

Several 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 in both and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.

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 301-710-0267, 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 and in accordance with the SF424 (R&R) Application Guide for this FOA through

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. There are fields within the SF424 (R&R) application components that, 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/PIs 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., Special Instructions, regarding appropriate required budget component.)
Research & Related Budget (required for foreign applications)

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

Foreign Organizations (Non-domestic (non-U.S.) Entity)

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 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 in Item 13 of 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.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership of the project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled 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, including 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.

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 note required when using the Modular budget format. See Section 3.4 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, 2007 (Earliest date an application may be submitted to
Letters of Intent Receipt Date(s): Not Applicable
Application Submission/Receipt Date(s): Standard dates apply, please see
AIDS Application Submission/Receipt 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.

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.

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 receives the acknowledgments. The AOR 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. This does not preclude the submission of an application already reviewed with substantial changes, but such application must include an Introduction addressing the previous critique. Note such an application is considered a "resubmission" for the SF424 (R&R).

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 competing renewal (formerly competing continuation) award if such costs: are necessary to conduct the project, and 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 competing 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 the NIH Grants Policy Statement.

6. Other Submission Requirements

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

The NIH requires the PD/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

Item 3 of the PHS398 Research Plan is limited to 12 pages.

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:

Special Instructions for Modular Grant applications

R01 applications from U.S. institutions/organizations requesting up to $250,000 per year in direct costs (excluding consortium F&A costs) must be submitted in a modular budget format. Additional information on modular budgets is available at submitting a modular budget, the applicant organization will include only the PHS398 Modular Budget component.See Section 3.4 of the SF424 (R&R) Application Guide for further instructions regarding the use of the PHS398 Modular Budget component.

Foreign organizations may not submit modular budgets. See NOT-OD-06-096.

Special 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 you are developing plans for the study;

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

3) Include the PHS398 Cover Letter component with the application to identify the staff member and IC who agreed to accept assignment of the application.

This policy applies to all new applications, competing renewal (formerly competing continuation) applications, resubmission (formerly revised/amended) applications, and revision (formerly competing supplemental) applications. See NOT-OD-02-004, October 16, 2001.

Appendix Materials

NIH has published new limitations on grant application appendix materials to encourage applications to be as concise as possible while containing the information needed for expert scientific review. See

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

Foreign Applications (Non-domestic (non-U.S.) Entity)

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal Web site, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the impact/priority score.

Sharing Research Resources

NIH policy expects that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590). See Section VI.3., Reporting.

Section V. Application Review Information

1. Criteria (Update: Enhanced review criteria have been issued for the evaluation of research applications received for potential FY2010 funding and thereafter - see NOT-OD-09-025).

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

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

Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures ( will evaluate applications for scientific and technical merit.

As part of the initial merit review, all applications will:

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:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application.

Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high impact/priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

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

Core 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?

2.A. 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.

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.

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.

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 score.

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.

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).

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.

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) (

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 Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

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, peer review, and financial or grants management issues:

1. Scientific/Research Contact(s):

Vishnudutt Purohit, Ph.D.
Program Director
Division of Metabolism and Health Effects
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 2035, MSC 9304
Bethesda, MD 20892-9304
Telephone: (301) 443-2689
Fax: (301) 594-0673

2. Peer Review Contact(s):

Not Applicable

3. Financial/Grants Management Contact(s):

Judy Fox
Chief, Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 3023, MSC 9304
Bethesda, MD 20892-9304
Telephone: (301) 443-4704
Fax: (301) 443-3891

Section VIII. Other Information

Required Federal Citations

Vertebrate Animals:
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 IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the impact/priority score.

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.

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.

Inclusion of Women, Minorities, and Children:
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:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system ( at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process, please visit the NIH Public Access Policy Web site at and view the Policy or other Resources and Tools, including the Authors' Manual.

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) must be used for publicly accessible on-line journal articles.Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

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 or Health Systems Agency review. 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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