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: Alcohol Metabolism and Epigenetic Effects on Tissue Injury [R01]

Announcement Type
New

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

Request For Applications (RFA) Number: RFA-AA-06-004

Catalog of Federal Domestic Assistance Number(s)
93.273

Key Dates
Release Date:  December 2, 2005
Letters of Intent Receipt Date(s): February 28, 2006 
Application Receipt Dates(s): March 28, 2006
Peer Review Date(s): May/June, 2006
Council Review Date(s): September, 2006
Earliest Anticipated Start Date: September, 2006
Additional Information To Be Available Date (Url Activation Date): N/A
Expiration Date:  March 29, 2006

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

This Request for Applications (RFA) solicits new studies on 1) the identification and characterization of epigenetic mechanisms influencing alcohol-induced diseases and 2) the mechanisms by which alcohol-induced changes in redox state and oxidative stress alter gene expression to cause tissue injury.  Studies submitted under this RFA are expected to determine whether alcohol exposure alters the epigenetics of the cells and tissues of exposed individuals and that of their offspring.  Research projects are encouraged to determine if alcohol exposure changes the epigenetic status during pre- and post-natal development, promotes errors in the maintenance of imprinting which results in physiological and/or behavioral changes, and changes the imprinting patterns with concomitant altered gene expression.  Of special interest is the identification of imprinted genes whose methylation and allelic expression are altered by maternal alcohol exposure during pregnancy and lactation.    A second major focus of this RFA is to understand how fluctuations in the cellular redox state due to alcohol metabolism influence histone acetylation and the transcription or silencing of genes in adult and fetal tissues such as the liver, pancreas, brain, lung and the cardiovascular and immune systems.  Studies of animal models are integral to this effort and encouraged along with studies involving human subjects.

This funding opportunity will utilize the Research Project grant mechanism (R01), but will run in parallel with an RFA of identical scientific scope (RFA-AA-06-005) that will utilize the Exploratory/Developmental (R21) grant mechanism.  It is anticipated that approximately $2,000,000 will be available for both.

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(s) 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. Address to Request Application Information
   2. Content and Form of Application Submission
   3. Submission Dates and Times
     A. Receipt, Review and Anticipated Start Dates
       1. Letter of Intent
     B. Sending an Application 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 Contact(s)
   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

Epigenetics

Acute, chronic or excessive alcohol ingestion often leads to a variety of medical disorders affecting millions of adults and children in the US and costing over 185 billion dollars annually.  Excessive alcohol consumption can result in numerous medical disorders including liver disease, pancreatitis, cardiovascular disease, fetal abnormalities, brain damage, and other organ damage.  Alcoholism and alcohol related diseases are the result of the complex interaction of multiple genetic and environmental factors. The dynamic multi-level interactions between genetic and environmental components are responsible for the heterogeneity and complexity of alcohol-induced diseases.  More recently, it has become apparent that in addition to genetic and environmental factors, epigenetic mechanisms are also involved in the etiology of a large number of diseases such as schizophrenia, cancer, and alcohol dependence.   New evidence shows that there is an association between the GABA (A) receptors and alcohol dependence that is modulated by an epigenetic event called genetic imprinting.  There are numerous types of epigenetic modifications on both DNA and nucleosomes, including methylation and acetylation, which could affect gene regulation and expression.  Alcohol exposure at crucial developmental stages could result in alterations of the epigenetic marks, thus altering the expression of key genes resulting in physiological and/or behavioral changes not only in the exposed individuals but also in their offspring.  

Epigenetics deals with regulatory mechanisms of gene activity and inheritance that are independent of changes in the nucleotide sequence of DNA, but epigenetic mechanisms themselves are controlled by genes whose products encode the enzymes needed for DNA methylation, histone modifications, RNA regulatory apparatus, and also for numerous regulatory proteins which produce dynamical chromosomal structures.   So far, a small number of genes which control mechanisms of epigenetic regulation have been identified.  Epigenetic events represent an important mechanism by which gene function is selectively activated or inactivated.

Genomic or genetic imprinting is one of the most studied epigenetic events.  Imprinting is the phenomenon whereby one of the two alleles is preferentially expressed, dependent on its parent of origin.  Current estimates suggest that greater than one percent of all human genes are imprinted.  Imprints are encoded by gene methylation patterns that differ between the maternally and paternally-derived alleles.  The transmission of gene expression state from parental to daughter cells often occurs through DNA methylation.  It involves the introduction of epigenetic marks by methylation of specific cytosine positions in DNA (addition of methyl group from S-adenosylmethionine into the carbon-5 position in the cytosine ring, 5mC).  Usually cytosines of CpG dinucleotides are methylated by a family of cytosine (DNA-5)-methyltransferases.  The level of DNA methylation sharply decreases during early embryogenesis of mammals but later recovers due to so-called de novo methylation.  Fluctuations in the degree of methylation of CpG islands are key to regulating promoters by the binding of transcription factors and methyl-DNA binding proteins.  A variety of regulatory proteins including DNA methyl transferases (DNMT) methyl CpG binding proteins, histone modifying enzymes (acetylases and deacetylases), chromatin remodeling factors, and other chromosomal structural components are involved in the overall epigenetic process.  Since epigenetic events are susceptible to change, they represent excellent targets to explain how environmental factors, including alcohol exposure, may modify disease susceptibility.

Stress, including that resulting from dietary methionine/choline, folate, zinc, and other micronutrient insufficiencies, as well as excessive alcohol intake, can lead to global DNA hypomethylation.  Since methylation of DNA is closely associated with gene silencing, hypomethylation could result in the activation of genes which normally are inactivated.  There is sufficient evidence to indicate that a variety of nutritional components, including polyphenols and estrogenic compounds, modify DNA methylation patterns which could lead to changes in gene expression and, therefore, may predispose to cancer.

Epigenetic events occurring in utero can lead to persistent changes in gene expression and can be modified by environmental factors and diet.  Epidemiological data suggest that a pregnant mother’s diet can affect her health in such a way that not only her children but her grandchildren inherit the same health problems.  In support of this epigenetic transgenerational action, diet provided to female mice of two strains during pregnancy modified the offspring’s hair coat color and DNA methylation patterns.   Dietary methyl supplementation of the mothers with extra folic acid, vitamin B12, choline, and betaine altered the phenotype of their offspring via increased CpG methylation at the coat color locus.   These findings suggest that early nutrition affects adult metabolism in humans and in other mammals, potentially via persistent alterations in DNA methylation patterns.  Since alcohol interferes with the folate and methionine cycles, this could result in DNA hypomethylation and increased risk of cancer and tissue damage.

Alcohol-induced changes in cellular redox state

Gene silencing or activation in somatic cells influence gene expression in a tissue-specific manner.  Alterations in normal gene silencing or activation result in inappropriate gene transcription, leading to tissue dysfunction and disease. Recently, it has been shown that there is a close relationship between fluctuations in the NAD+/NADH ratio and gene transcription.  Key NAD+-dependent enzymes, including c-terminal binding protein (CtBP), silent information regulator, (Sir2), and the heterodimeric Clock/NPAS2 transcriptional regulator, whose activity are altered by changes in the  NAD+/NADH ratio, are implicated in gene silencing.  The major pathway of oxidative metabolism of ethanol in the liver involves the production of acetaldehyde by cytosolic alcohol dehydrogenase (ADH).  This oxidation is accompanied by the reduction of NAD+ to NADH thus, altering the cellular redox state by decreasing the NAD+/NADH ratio. The cytochrome P450 isoenzymes, including CYP2E1 (which is induced by chronic alcohol consumption), 1A2 and 3A4, which are present predominantly in the endoplasmic reticulum, also contribute to ethanol oxidation.  Thus, by decreasing the NAD+/NADH ratio, alcohol metabolism may result in gene activation, which may play a role in tissue injury due to changes in the pattern of gene expression.

Both acute and chronic alcohol consumption can increase the production of ROS.   Ethanol oxidation vastly increases the availability of oxidizable NADH to the electron transport chain in the mitochondria.  NAD+ influences many important cellular reactions and the relative quantities of NAD+ to NADH fluctuate in response to changes in metabolism.  This imbalance may result in altered physiology. 

Objective and Scope

This initiative is designed to promote innovative and exploratory research to determine if and how alcohol exposure changes the epigenetic patterns in both the exposed individuals and their offspring and to determine if alcohol-induced oxidative stress changes the pattern of gene expression and causes tissue injury.  Although our understanding of epigenetic machineries is still far from complete, some of the epigenetic markers of silencing or activation of gene expression include: DNA methylation, lysine methylation in histones, histone acetylations, histone phosphorylation, RNA interference, chromosomal silencing or gene activation via binding protein complexes, and transposable elements.  Since ethanol has been shown to alter DNA methylation in liver, esophagus, colon, uterus and testes, it is important to identify the genomic regions that are likely targets for alcohol-induced CpG methylation changes.  The objective of this initiative is to address the following issues: 1) how alcohol metabolism regulates DNA methylation and other epigenetic events and how these epigenetic events modify gene expression: 2) and how alcohol-induced changes in redox state alter gene expression and cause injury.

Another important aim of this initiative is to encourage collaborations between epigenetic/DNA methylation experts and molecular and epidemiological alcohol researchers in order to establish linkages between epigenetics, methylation patterns, nutrition and alcohol exposure.  The focus of the studies should be on how alcohol metabolism influences DNA methylation and other epigenetic events and how this correlates with phenotypic change.

A variety of state-of-the art technologies to assess DNA methylation and other epigenetic events may be utilized.  Techniques are available to measure the content and distribution of CpG methylation at the genome level (http://www3.cancer.gov/prevention/methylation/summary.html).  The use of genetically modified animals, including transgenic or gene knockouts, is appropriate.  Molecular resources such as gene databases and bioinformatics may also be used to expedite the identification of gene-specific methylation targets (for example see http://www.methdb.de/).

The following topics are areas of investigation for the R01 grant applications in response to this RFA.  These examples are not meant to be all-inclusive.  Innovative ideas and concepts are highly encouraged.

This RFA encourages the collaboration between alcohol researchers and epigenetic experts.

References:

MD Anway et al, “Epigenetic transgenerational actions of endocrine disruptors and male fertility,” Science 2005, 308: 14666-69.

G Kaati et al, “Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period,” Eur J Hum Genet 2002, 10: 682-8.

J Song et al, “Association of GABA (A) receptors and alcohol dependence and the effects of genetic imprinting,” Am J Med Genet B Neuropsychiatr  Genet 2003, 117 (1):39-45.

NA Tchurikov, “Molecular Mechanisms of Epigenetics,” Biochemistry (Moscow) 2005, 70:406-23.

RA Waterland, RA Jirtle  “Transposable elements: targets for early nutritional effects on epigenetic gene regulation,” Mol Cell Biol 2003, 23: 5293-300.

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

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the Research Project grant (R01) award mechanism.  As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

This funding opportunity uses just-in-time 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 submitting an application with direct costs in each year of $250,000 or less, use the modular budget format described in the PHS 398 application instructions. Otherwise follow the instructions for non-modular research grant applications.

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.  The IC might elect to fund more applications if the applications are meritorious and additional funds become available.  Although the financial plans of the IC provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by participants are not included in the direct cost limitation; see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

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

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution 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 programs.

2. Cost Sharing or Matching

Cost sharing is not required under this program, as described in:

The most current Grants Policy Statement can be found at: http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#matching_or_cost_sharing.

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. 

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Date: February 28, 2006
Application Receipt Date(s):  March 28, 2006
Peer Review: May/June, 2006
Council Review Date: September, 2006
Earliest Anticipated Start Date: September, 2006

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 at the beginning of this document.

The letter of intent should be sent to:

Tina Vanderveen, Ph.D.
Office of Extramural Activities
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane Room 3039
Bethesda, MD 20892
Telephone: (301) 443-2531
FAX:301-443-6077
Email: tvanderv@mail.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Tina Vanderveen, Ph.D.
Office of Extramural Activities
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane Room 3039
Bethesda, MD 20892
Telephone: (301) 443-2531
FAX: 301-443-6077
Email: tvanderv@mail.nih.gov

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. 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.

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.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

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. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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 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 continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.

To facilitate the interaction among NIAAA staff and investigators, and to better coordinate this program, it is anticipated that an annual meeting will be held within the commuting area of Bethesda, Maryland. The Principal Investigator is expected to attend these meetings and travel funds should be included in the budget.  Investigators funded by the accompanied RFA-AA-06-005 will also be invited to participate in these meetings.   By accepting an award, the applicant organization and key personnel agree to abide by this condition.

6. Other Submission Requirements

The principal investigator for this RFA does not have to be an active alcohol researcher, although it is expected that an alcohol researcher be included as part of the research team.

Specific Instructions for Modular Grant Applications.

Applications requesting up to $250,000 per year in direct cost must be submitted in a modular budget format.  The modular budget format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail.  Applicants request direct costs in $25,000 modules.  Section C of the research grant application instructions for the PHS 398 at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular budgets.  Applicants must use the currently approved version of the PHS 398.  Additional information on modular budgets is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

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 website, 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.

Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a plan for sharing research data in their application. The funding organization will be responsible for monitoring the data sharing policy (http://grants.nih.gov/grants/policy/data_sharing).

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

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources 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, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria

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

The following will be considered in making funding decisions:

2. Review and Selection Process

Applications that are complete and responsive to the RFA 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:

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?

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 investigators 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 investigative team bring complementary and integrated expertise to the project? In instances where the principal investigator is not an established alcohol research investigator (see 6. Other Submission Requirements), is the plan to establish a collaborative process to support the alcohol research appropriate and is the documentation of the plan adequate?

Environment: Does the scientific environment 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:

Collaborative Research Team:  Does the research team consist of both alcohol and non alcohol researchers in an interactive collaborative agreement (unless an exception is adequately justified)?

Quality of the research proposed:  R01 applications submitted in response to this RFA may be milestone-driven.

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 Research Plan, Section E on Human Subjects in the PHS Form 398).

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 Research Plan, Section E on Human Subjects in the PHS Form 398).

2.B. Additional Review Considerations

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

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The funding organization will be responsible for monitoring the data sharing policy. http://grants.nih.gov/grants/policy/data_sharing.

2.D. Sharing Research Resources

NIH policy requires 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 http://grants.nih.gov/archive/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). 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.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. 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.

3. Anticipated Announcement and Award Dates

The earliest anticipated award date is December 1, 2007. (This should be September 2006, see NOT-AA-06-001)

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

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 (designated in item 14 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the 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 Also 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 notice of grant award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

3. Reporting

The Annual Report is due two months prior to the grant anniversary date. For the awards of this program, there is no specific page limit or format requirement on the progress report at this time; the parameters of the project report will be determined at the 6 month meeting so that certain common elements can be incorporated and so that the information presented across sites will be comparable. The progress reports will include at least the following information: an overview of the major achievements made in the previous year including status on meeting the milestones, and accomplishing the research objectives, outreach development goals, training activities and data collection objectives of the project.

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) 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 Contacts:

José M. Velázquez, Ph.D.
Division of Metabolism and Health Effects
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane Room 2023
Bethesda, MD 20892
Telephone: (301) 402-9408
FAX: 301-443-8614
Email: jvelazqu@mail.nih.gov

2. Peer Review Contacts:

Extramural Project Review Branch
Office of Extramural Activities
Attn: RFA-AA-06-004
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane Room 3039
Bethesda, MD 20892
Telephone: (301) 443-2531
FAX: 301-443-3891
Email: tvanerv@mail.nih.gov

3. Financial or Grants Management Contacts:

Ms. Judy Fox
Chief, Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane
Bethesda, MD 20892
Telephone: (301) 443-4704
FAX: 301-443-3891
Email: 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 (45CFR46) 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 this 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.

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 http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, 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 new PHS Form 398; 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://publicaccess.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 (http://publicaccess.nih.gov/publicaccess_manual.htm).

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.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) 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 DHHS 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. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to 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 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 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 NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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