Part I Overview Information


Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Institute on Alcohol Abuse and Alcoholism (NIAAA), (http://www.niaaa.nih.gov)

Title: Epigenetic Mechanisms in the Neurobiology of Alcohol Tolerance and Dependence (R01)

Announcement Type
New

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

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).

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.

Request for Applications (RFA) Number: RFA-AA-07-011

Catalog of Federal Domestic Assistance Number(s)
93.273

Key Dates
Release/Posted Date: January 5, 2007
Opening Date: March 25, 2007 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): March 25, 2007
NOTE: On time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization).
Application Receipt Date(s): April 25, 2007
Peer Review Date(s): July/August 2007
Council Review Date(s): August 2007
Earliest Anticipated Start Date(s): September 15, 2007
Additional Information To Be Available Date (Activation Date): N/A
Expiration Date: April 26, 2007

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

Background

Alcoholism is a major under-recognized health problem in the U.S., affecting about 14 % of men and 5% of women and costing society more than $185 billion annually. Genetic factors contribute to alcoholism risk but not all phenotypic variations related to alcohol use can be explained by genetics; in fact, alcoholism is a complex disease resulting from both genetic and environmental factors. Alcohol dependence is characterized as compulsive and excessive alcohol use resulting from neuroadaptative process such as tolerance, sensitization, withdrawal, and relapse. This initiative will focus on only two aspects of neuroadaptation, primarily tolerance and withdrawal.

Neuroadaptation to alcohol exposure could result in changes in gene expression as a consequence of epigenesis, a mechanism that results in heritable and stable alterations in the genome that does not involve changes in the DNA sequence itself. Epigenetic mechanisms such as DNA methylation, histone modifications (acetylation, methylation, phosphorylation, sumoylation, and ubiquitylation/ADP-ribosylation), and regulatory short interfering RNAs are known to affect gene transcription (Jablonka and Lamb 2002; Jiang et al., 2004; Shilatifard 2006). Some of them (e.g., methylation changes and chromatin remodeling) are associated with numerous diseases including alcoholism.

Epigenetic mechanisms involved in alcohol dependence

Some genes (and their regulatory regions) associated with alcohol dependence have been shown to be affected by abnormal DNA methylation. For example, changes in DNA methylation in the promoter region of the alpha-synuclein gene are shown to influence gene expression in alcohol dependent patients undergoing withdrawal (Bonsch et al., 2005). Furthermore, epigenetic DNA hypermethylation of the homocysteine-induced endoplasmic reticulum protein (HERP) gene promoter was shown to down-regulate its mRNA expression in alcohol dependent patients (Bleich et al., 2006). In animal studies, chronic alcohol exposure results in demethylation of the gene for the NMDA receptor subunit NR2B, a receptor involved in reward-related learning and memory (Ravindran and Ticku 2005). In another example, the upstream regions of alcohol dehydrogenase genes, ADH1B and ADH1C, are methylated in human hepatoma cells (Dannenberg et al., 2006). Expression of these genes is enhanced by demethylation.

Genomic imprinting, a consequence of DNA methylation, is another mechanism that influences gene expression. Recently, paternal alcohol exposure was shown to cause abnormal development, growth, and behavior in rats by reducing DNA methylation in the sperm. Imprinting errors are often associated with physical illnesses, neurological and mental disorders, and other complex diseases. The GABA-A receptor gene cluster on chromosome 15, which was previously shown to be associated with alcohol dependence in humans, is located in an imprinted area on the paternal chromosome (Song et al., 2003). Whether genetic imprinting contributes to the development of alcohol dependence remains unknown and requires further study. Histone acetylation also influences the expression of some alcohol-relevant genes. For example, histone deacetylation correlates with increased expression of the alcohol metabolizing enzyme genes ADH1B and ADH1C (Dannenberg et al., 2006). Histone acetylation is also important for short-term to long-term memory consolidation as well as drug-induced neural and behavioral plasticity (Korzus et al., 2004).

Epigenetic mechanisms involved in alcohol tolerance and withdrawal

Alcohol tolerance: Alcohol tolerance can be divided into two major types: functional tolerance and metabolic tolerance. Functional tolerance is characterized by a decrease in pharmacologic or physiologic responsiveness upon alcohol exposure and is hypothesized to be mediated by neuroadaptative changes in the CNS. Three potentially interrelated classes of functional tolerance include acute, rapid and chronic tolerance. Acute tolerance is the term used to describe tolerance that develops within a single exposure to ethanol where the extent of impairment is greater during the ascending portion of the blood alcohol curve than at the same blood alcohol concentration (BAC) during the descending portion. Rapid functional tolerance is observed 8-24 hours after the initial ethanol exposure when the response to a second, identical dose of ethanol is attenuated. This form of functional tolerance persists for a short duration usually no longer than 48 hours following the first ethanol exposure; however, this persisted much longer (10 days) in an animal model of alcoholism. Finally, chronic functional tolerance occurs when increased doses of ethanol are required to produced a given level of intoxication following chronic or repeated ethanol exposure.

Selective breeding experiments and QTL analysis suggest a genetic basis for tolerance development. As candidate genes for tolerance development to ethanol-induced motor impairment were identified, expression differences in these candidate genes in response to ethanol were examined. This led to the identification of a signal transduction cascade involving the glutamate receptor delta2 protein, the Ephrin B3 ligand, the NMDA receptor, the zinc finger protein 179 and peroxiredoxin. These changes suggested that ethanol exposure leads to phosphorylation of the NMDA receptor and its translocation, resulting in resistance to the inhibitory effects of ethanol. Genetic variation in other biochemical and signal transduction pathways associated with alcohol tolerance have been identified (e.g., PKC epsilon, GABA receptor, adenosine A1 receptor, dopamine D1 receptor, neuronal nitric oxide synthetase), but the role of epigenetic mechanisms on their expression, if any, remains unknown (Hoffman and Tabakoff 2005).

Metabolic tolerance: Metabolic tolerance is the term used to describe changes in efficiency or capacity to metabolize ethanol resulting in a decrease in the BAC following a given dose of alcohol. In both humans and rodent models, ethanol is metabolized principally by liver cytosolic alcohol dehydrogenases (ADH). Another metabolic pathway for the metabolism of ethanol involves the ethanol-inducible microsomal cytochrome P450, CYP2E1, which is found in many tissues and organs including the CNS. CYP2E1 has been shown to be increased more than ten fold after chronic alcohol consumption. An additional potential metabolic route for the metabolism of ethanol involves peroxisomal catalase, which is also found in many tissues including the CNS. Studies on double mutant mice Cyp2e1 (-/-)/Csb/Csb showed that sleep time is increased 160% in male and 76% in female animals after ethanol administration, indicating that CYP2E1 and catalase in the brain may play a role in ethanol sensitivity and potentially tolerance. With the demonstration of the induction of CYP2E1 in human CNS as well as rat hippocampus and cerebellum, and the involvement of CYP2E1 in dopamine metabolism, the interplay of functional and metabolic tolerance mechanisms is an additional possibility. Epigenetic alterations may affect alcohol metabolic pathway in a manner to affect metabolic as well as functional tolerance (Park et al., 2005; Upadhya et al., 2000; Vasiliou et al., 2006).

Alcohol withdrawal: Alcohol dependence is characterized by excessive consumption, loss of control over intake, and the presence of a withdrawal syndrome, including both motivational and physical symptoms including autonomic activity such as hyperpyrexia, tachycardia, etc. Alcohol withdrawal has been characterized as a latent state of hyperexcitability and symptoms include increased anxiety, tremulousness, and convulsions. In rats, withdrawal symptoms are maximal after 3-4 days of high doses of alcohol and the anxiety-like symptoms are known to increase with repeated withdrawal.

Chronic ethanol exposure results in the adaptation of numerous neurotransmitter, neuropeptide and hormonal systems in order to maintain homeostatic functioning. Long-term exposure engenders an imbalance in these systems and is manifested as a behaviorally definable withdrawal syndrome once ethanol administration ceases. Acute withdrawal effects reflect neural excitability resulting from GABA-A receptor hypofunction, voltage-operated calcium channel hyperfunction, and elevated glutamatergic neurotransmission. Acute withdrawal signs subside after a few days. Repeated cycles of alcohol exposure and withdrawal engender more enduring changes in these and other systems which can last for long periods of time following alcohol cessation. Protracted withdrawal is characterized by emotional disturbances such as anxiety, and altered circadian functions resulting in sleep impairment. In addition, enduring changes in neural substrates of motivation may contribute to the continuation of alcohol relapse. In mice, expression of alcohol-induced seizures is modified by variation in the Mpdz gene possibly through interaction with GABA-B receptors, which, in turn, regulate GABA and glutamate release (Shirley et al., 2004). To determine the significance of epigenetic mechanisms on the development and expression of alcohol withdrawal, the epigenetic status of relevant neural genes and systems at distinct time points during alcohol chronic exposure and after cessation of alcohol (withdrawal phase) is of interest.

In addition, examining the impact of various environmental factors on the epigenetic status of genes involved in alcohol tolerance and withdrawal is warranted. Animal paradigms modeling environmental risk factors for alcohol dependence (e.g., maternal deprivation, social stress, neglect, exposure to trauma) can reveal additional mechanisms in the development of alcohol dependence. For example, maternal separation and handling, a rat model of early life stress, causes profound neurochemical and behavioral changes in pups that persist into adulthood. These treatments affect alcohol intake in adult male rats and may be related to changes in receptor systems (e.g., opiate, serotonin, dopamine, GABA-A) involved in alcohol drinking and other aspects of alcohol dependence. Pup licking and grooming, behaviors that are reduced by maternal separation, stimulate changes in DNA methylation patterns, histone acetylation, and subsequent glucocorticoid gene expression (Weaver et al., 2004).

Several human genes have been shown to contribute to the risk of alcohol dependence including NPY, ADH4, ADH7, ALDH2, GABRA2, CHRM2, SERT, and OPRM1. However, it is not known whether the expression of these genes is modulated through epigenetic events that alter physiological and behavioral function, ultimately leading to alcohol dependence. It would be of interest to examine in animal models whether these human risk genes are modified through epigenetic events.

Objective and Scope

The goal of this initiative is to (1) determine whether epigenetic mechanisms are involved in neuroadaptative processes (CNS and metabolic tolerance, withdrawal) that lead to alcohol dependence in animals; and (2) using animal models to determine if epigenetic mechanisms play a role in the expression of risk genes for human alcoholism. Ultimately, these findings are expected to inform potential therapeutic targets and to predict individual responses to medications for alcohol dependence. Examples of research areas appropriate to this announcement include, but are not limited to:

This RFA encourages the collaboration between experienced alcohol researchers and experts in epigenetics and bioinformatics.

Key References

Bonsch D, Lenz B, Kornhuber J, and Bleich’s (2005). DNA hypermethylation of the alpha synuclein promoter in patients with alcoholism. Neuroreport 16, 167-170.

Bleich S, Lenz B, Ziegenbein M, Beutler S, Frieling H, Kornhuber J, and Bonsch D (2006). Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence. Alcohol Clin Exp Res 30, 587-591.

Dannenberg LO, Chen HJ, Tian H, Edenberg HJ 2006. Differential regulation of the alcohol dehydrogenase 1B (ADH1B) and ADH1C genes by DNA methylation and histone deacetylation. Alcohol Clin Exp Res. 30:928-37.

Hoffman,P. and Tabakoff,B. 2005. Gene expression in animals with different acute responses to ethanol. Addict. Biol. 10, 63-69.

Jablonka E, Lamb MJ 2002. The changing concept of epigenetics. Ann N Y Acad Sci 981:82-96.

Jiang YH, Bressler J, Beaudet AL 2004. Epigenetics and human disease. Annu Rev Genomics Hum Genet 5:479-510.

Korzus E, Rosenfeld MG, Mayford M 2004. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42:961-72.

Park PH, Lim RW, and Shukla SD 2005. Involvement of histone acetyltransferase (HAT) in ethanol-induced acetylation of histone H3 in hepatocytes: potential mechanism for gene expression. Am J Physiol Gastrointest Liver Physiol 289:1124-36.

Ravindran CRM and Ticku MK 2005. Methylation of NMDA receptor NR2B gene as a function of age in the mouse brain. Neuroscience Letters 380, 223 228.

Shilatifard A (2006). Chromatin Modifications by Methylation and Ubiquitination: Implications in the Regulation of Gene Expression. Annu. Rev. Biochem. 75, 243 269.

Shirley RL, Walter NA, Reilly MT, Fehr C, Buck KJ (2004). Mpdz is a quantitative trait gene for drug withdrawal seizures. Nat Neurosci. 7:699-700.

Song J, Koller DL, Foroud T, Carr K, Zhao J, Rice J, Nurnberger JI Jr, Begleiter H, Porjesz B, Smith TL, Schuckit MA, Edenberg HJ 2003. Association of GABA(A) receptors and alcohol dependence and the effects of genetic imprinting. Am J Med Genet B Neuropsychiatr Genet 117:39-45.

Upadhya SC, Tirumalai PS, Boyd MR, Mori T, Ravindranath V 2000. Cytocrhome P4502E (CYP2E) in brain: constitutive expression, induction by ethanol and localization by fluorescence in Situ hybridization. Archives of Biochemistry and Biophysics 373(1):23-34.

Vasiliou V, Ziegler TL, Bludeau P, Petersen DR, Gonzalez FJ, and Deitrich RA 2006. CYP2E1 and catalase influence ethanol sensitivity in the central nervous system. Pharmacogenetics and Genomics 16:51-58.

Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ 2004. Epigenetic programming by maternal behavior. Nat Neurosci 7:847-54.

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 http://grants.nih.gov/grants/funding/modular/modular.htm). 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 5.4, Modular Budget Component, of the Application Guide).

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.

Competing renewal (formerly competing continuation ) applications will not be accepted. At this time, it is not known if this FOA will be reissued.

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.

The NIAAA intends to commit approximately $1.5 Million dollars in fiscal year 2007 to fund 4-6 applications. Applications are limited to $250,000 direct costs per year under this initiative.

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.

F&A costs requested by consortium participants are not included in the direct cost limitation. See 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 http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm 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. The NIH review criteria for approach, investigators, and environment have been modified to accommodate applications involving either a single PD/PI or multiple PDs/PIs. 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 http://grants.nih.gov/grants/multi_pi.

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

The proposed studies should employ state-of-the-art tools and technologies and will be considered non responsive if they propose only descriptive studies.

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

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, link to http://www.grants.gov/applicants/apply_for_grants.jsp 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 Grants.gov/Get 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 Grants.gov 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 Grants.gov/Apply.

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: GrantsInfo@nih.gov.

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 Grants.gov/Apply.

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/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 Grants.gov/APPLY 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: http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

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.

SPECIAL INSTRUCTIONS

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 15 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 (Section 14 of the Research Plan Component in the SF424 (R&R)), 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 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: March 25, 2007 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): March 25, 2007
Application Receipt Date(s): April 25, 2007
Peer Review Date(s): July/August 2007
Council Review Date(s): August 2007
Earliest Anticipated Start Date(s): September 15, 2007
Additional Information To Be Available Date (Activation Date): N/A
Expiration Date: April 26, 2007

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Dr. Abraham P. Bautista
Chief, Extramural Project Review Branch
Office of Extramural Activities
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
5635 Fishers Ln Room 3039
Rockville, MD 20852
Phone: 301.443.9737
Fax: 301 443 6077
Email: bautista@mail.nih.gov

3.B. Submitting an Application Electronically to the NIH

To submit an application in response to this FOA, applicants should access this FOA via http://www.grants.gov/applicants/apply_for_grants.jsp and follow steps 1-4. Note: Applications must only be submitted electronically. PAPER APPLICATIONS WILL NOT BE ACCEPTED.

In order to expedite the review, applicants are requested to notify the NIAAA Referral Office by email bautista@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

3.C. Application Processing

Applications may be submitted on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization) on the application submission/receipt date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the receipt date(s) and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully submitted through Grants.gov, any 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 business days to view the application image.

Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NIAAA. Incomplete and non-responsive applications will not be reviewed.
There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. The submitting AOR receives the Grants.gov 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 funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

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.

Applications are limited to $250,000 direct cost per year under this initiative. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

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 Grants.gov. For additional information, see Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

PHS398 Research Plan Component Sections

Items 2-5 of the PHS398 Research Plan component are limited to 25 pages. While each section of the Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. 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.

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 http://grants.nih.gov/grants/funding/modular/modular.htm. When submitting a modular budget, the applicant organization will include only the PHS398 Modular Budget component. See Section 5.4 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.

Appendix Materials

Stop SignIMPORTANT NOTE: 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.

Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See http://grants.nih.gov/grants/funding/424/index.htm).

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

Note: While each section of the PHS398 Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to monitor better formatting requirements such as page limits. 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.

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

Plan for Sharing Research Data

Not applicable

Sharing Research Resources

Not applicable

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). (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.

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIAAA in accordance with the review criteria stated below.

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 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.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? For applications designating multiple PDs/PIs, is the leadership approach, including the designated roles and responsibilities, governance, and organizational structure, consistent with and justified by the aims of the project and the expertise of each of the PDs/PIs?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the PD/PI(s) and other key personnel appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the PD/PI(s) and investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Do(es) the scientific environment(s) in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

2.A. Additional Review Criteria

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. See the Human Subjects Sections of the PHS398 Research Plan component of the SF424 (R&R)..

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. See the Human Subjects Sections of the PHS398 Research Plan component of the SF424 (R&R)

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the adequacy of the plans for their care and use will be assessed. See the Other Research Plan Sections of the PHS398 Research Plan component of the SF424 (R&R).

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget and Period of Support: The reasonableness of the proposed budget and the appropriateness of the requested period of support in relation to the proposed research may be assessed by the reviewers. The priority score should not be affected by the evaluation of the budget.

Applications from Foreign Organizations: Whether the project presents 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 will be assessed.

2.C. Sharing Research Data

Not applicable.

2.D. Sharing Research Resources

Not applicable.

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):

Direct questions regarding neuroscience to:

Lisa A. Neuhold, Ph.D.
Division of Neuroscience & Behavior
National Institute on Alcoholism and Alcohol Abuse
5635 Fishers Lane, Room 2065, MSC 9304
Bethesda, MD 20892-9304
Phone: 301-594-6228
Fax: 301-443-1650
E-mail: lneuhold@mail.nih.gov

Direct questions regarding metabolism to:

Max Guo, Ph.D.
Division of Metabolism and Health Effects
National Institute on Alcoholism and Alcohol Abuse
5635 Fishers Lane, Room 2021, MSC 9304
Bethesda, MD 20892-9304
Phone: 301-443-0639
Fax: 301-594-0673
E-mail: qmguo@mail.nih.gov

2. Peer Review Contact(s):

Dr. Abraham P. Bautista
Chief, Extramural Project Review Branch
Office of Extramural Activities
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
5635 Fishers Ln Room 3039
Rockville, MD 20852
Phone: 301.443.9737
Fax: 301 443 6077
Email: bautista@mail.nih.gov

3. Financial/Grants Management Contact(s):

Ms. Judy Fox
Chief, Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 3023, MSC 9304
Bethesda, MD 20892-9304
Phone: (301) 443-4704
FAX: (301) 443-3891
E-mail: jfox@mail.nih.gov

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 (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) 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 (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

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, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

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 sharing is not possible (http://grants.nih.gov/grants/policy/data_sharing).

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 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 http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. 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 http://grants.nih.gov/grants/policy/model_organism/index.htm). 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 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 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. 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 (http://grants.nih.gov/grants/funding/children/children.htm).

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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov/). 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. Applications that do not provide this information will be returned without review.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov/) 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 http://publicaccess.nih.gov// 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 (http://www.hhs.gov/ocr/) 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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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 PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ 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: http://www.lrp.nih.gov/.


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