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/)
National Cancer Institute (NCI), (http://www.nci.nih.gov)
Office of Dietary Supplements (ODS), (http://www.ods.od.nih.gov)

Title: Mechanisms of Alcohol-Associated Cancers (R01)   

Announcement Type
New

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

Looking ahead: As part of the Department of Health and Human Services' implementation of e-Government, during FY 2006 the NIH will gradually transition each research grant mechanism to electronic submission through Grants.gov and the use of the SF 424 Research and Related (R&R) forms. Therefore, once the transition is made for a specific grant mechanism, investigators and institutions will be required to submit applications electronically using Grants.gov.. For more information and an initial timeline, see http://era.nih.gov/ElectronicReceipt/. NIH will announce each grant mechanism change in the NIH Guide to Grants and Contracts (http://grants.nih.gov/grants/guide/index.html). Specific funding opportunity announcements will also clearly indicate if Grants.gov submission and the use of the SF424 (R&R) is required. Investigators should consult the NIH Forms and Applications Web site (http://grants.nih.gov/grants/forms.htm) for the most current information when preparing a grant application.

Program Announcement (PA) Number: PA-06-269

Catalog of Federal Domestic Assistance Number(s)
93.273, 93.393

Key Dates
Release Date: March 24, 2006
Letters of Intent Receipt Date(s): Not applicable
Application Submission Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm
Peer Review Date(s): Standard dates apply, please see   http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward 
Council Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward  
Earliest Anticipated Start Date: Standard dates apply, please see    http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward  
Additional Information To Be Available Date (Url Activation Date): Not applicable
Expiration Date for R01 Non-AIDS Applications: November 2, 2006
Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 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(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. Submission, 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

Background

Chronic alcohol consumption is associated with an increased risk for cancers of various organs. The risk of developing cancer varies from low to moderate to high, depending upon the type of the organ affected as well as the amount of alcohol consumed. In a meta-analysis report of 235 epidemiological studies (117,471 cases), statistically significant relative risks (RR) for the development of cancers of various organs from the consumption of 100 g of alcohol per day were reported as under: oral cavity and pharynx, 6.01; esophagus, 4.23; larynx, 3.95; breast, 2.71; liver, 1.86; ovary, 1.53; colon and rectum, 1.38; and stomach, 1.32. Significant increased risks were also found for most cancer sites with 50 g as well as 25 g of alcohol consumption per day. The later dose of alcohol (25 g or about two drinks) is considered equivalent to moderate alcohol consumption for men. Taken together, the fact that about one-third of Americans drink moderately or heavily, the combined risk of developing cancer from alcohol consumption could be a significant health problem in this country. Indeed, it is estimated that alcohol consumption is responsible for 5% of all cancers in the US. Understanding the underlying molecular and biochemical mechanisms by which chronic alcohol consumption promotes carcinogenesis is important for developing appropriate strategies for the prevention and treatment of alcohol-associated cancers.

Research Scope

The purpose of this PA is to encourage research grant applications that will employ an integrative approach using state-of-the-art technologies to gain insight into the molecular and biochemical mechanisms by which chronic alcohol consumption leads to the development of cancers of various organs such as oral cavity, pharynx, larynx, esophagus, stomach, large intestine, liver, and breast. This includes investigating roles of various factors such as acetaldehyde, CYP2E1, VEGF, impaired immune function, and impaired metabolism of SAMe, folate, iron, and vitamin A by alcohol. This announcement addresses an area considered to be a high priority for liver disease research as delineated in the recently published Trans-NIH Action Plan for Liver Disease Research (http://liverplan.niddk.nih.gov), specifically in the areas of fatty liver disease and liver cancer. 

 a. Acetaldehyde:

Acetaldehyde, a suspected human carcinogen, appears to be a major causal agent responsible for alcohol-associated cancers of upper aero-digestive tract (UADT) and large intestine. It can be formed in the digestive tract from the metabolism of ethanol by alcohol dehydrogenase (ADH) of mucosa and salivary glands, as well as due to increased acetaldehyde production by aerobic bacteria and yeast in the oral cavity and large intestine. Individuals who are heterozygous for inactive ALDH2 encoded by ALDH2*1/2*2 allele are at increased risk for cancers of UADT and large intestine because of the accumulation of acetaldehyde following alcohol consumption. Since most of the acetaldehyde is formed in the liver, it may also contribute to the pathogenesis of hepatocellular carcinoma (HCC). Acetaldehyde may promote the development of HCC by upregulating Gi-proteins and ERK MAPK signaling. In addition, acetaldehyde may play a role in the development of alcohol-associated cancers of other organs such as pancreas and breast. Acetaldehyde has been shown to have direct mutagenic and carcinogenic effects in in vitro and in vivo animal studies. It has been reported to cause point mutations in lymphocytes, induce sister chromatid exchanges, impair DNA repair, induce metaplasia of tracheal epithelium, and cause nasopharyngeal and laryngeal carcinoma. Acetaldehyde may cause replication errors and/or mutations in oncogenes or tumor suppressor genes by forming adducts with DNA. Acetaldehyde can react with DNA to form adducts such as N2-ethyl-2’-deoxyguanosine (N2-ethyl-dG) and 1,N2-Propano-2’-deoxyguanosine (1,N2-PdG). These adducts may be responsible for the genotoxic, mutagenic, and carcinogenic effects of acetaldehyde.

b. Cytochrome P4502E1 (CYP2E1):

Chronic ethanol is known to induce CYP2E1 in various organs including liver, pancreas, GI tract, and breast. The CYP2E1 induction may contribute to carcinogenesis by metabolizing ethanol to acetaldehyde and by converting various procarcinogens to carcinogens in various organs. In addition, CYP2E1 can release reactive oxygen species (ROS) such as superoxide anion that can be converted to hydrogen peroxide, which in turn can serve as a precursor for the formation of highly reactive hydroxyl and hydroxyethyl radicals. These radicals can cause oxidative DNA damage which has been implicated in the genesis of cancer. Metabolism of ethanol by other members of CYP family enzymes such as CYP1A2 and CYP3A4 may also contribute to the development of cancers of various organs via generation of ROS. 

c. Vascular endothelial growth factor (VEGF):

Growth and expansion of tumor mass are dependent upon the sustained angiogenesis which is characterized by formation of new blood vessels. VEGF is an important angiogenic factor, which is significantly up-regulated in a majority of human tumors.

Ethanol has been shown to: 1) stimulate angiogenesis in rat gastric mucosa that was mediated through significant increases in VEGF mRNA and protein expression; 2) increase VEGF mRNA in rat skeletal muscle; 3) induce angiogenesis in human umbilical vein endothelial cells, which was mediated through VEGF up-regulation; and 4) induce VEGF expression and angiogenesis in both models of cell culture and chick chorioallantoic membrane. These findings suggest that VEGF may be a mechanism whereby ethanol promotes vascular carcinogenesis.

d. Impaired immune function:

Natural Killer cells (NK) are immune surveillance cells which inhibit development and growth of certain tumors. Alcohol administration has been shown to inhibit NK cell activity and number in mice and rats. NK cell activity and number were also found to be decreased in alcoholic cirrhotic patients. Furthermore, NK cell numbers were found to be decreased in actively drinking individuals without alcoholic liver disease. These reports suggest that alcohol may promote tumor development by impairing the functions of NK cells.

e. Impaired S-adenosylmethionine (SAMe) metabolism:

SAMe is the principal biological methyl donor, the precursor for polyamines and a precursor of glutathione. SAMe is synthesized from methionine in a reaction catalyzed by methionine adenosyl transferase (MAT). A possible connection between SAMe levels and cancer is based on the following information. In MAT1A knockout mice, SAMe deficiency is associated with hepatic hyperplasia, steatohepatitis, and HCC. In rats, chronic ethanol administration results in decreased SAMe levels, hypomethylation of c-myc, increased c-myc expression, and increased DNA strand breaks, suggesting an association between reduced SAMe levels and malignant degeneration. In patients affected with alcoholic hepatitis and cirrhosis, both MAT activity and SAMe levels are reduced, suggesting that these patients may be susceptible to the development of HCC. Exogenous SAMe inhibits the growth of hepatoma cells in culture and prevents development of HCC in rats treated with hepatocarcinogens. Taken together these studies suggest that chronic ethanol consumption can result in SAMe deficiency that may render liver and other organs susceptible to malignant transformation via inducing global hypomethylation of DNA, which is an early feature of neoplastic transformation of epithelial cells. In addition, SAME may have potential for the treatment of HCC.

f. Impaired folate metabolism:

Folate deficiency has been linked to an increased risk of cancers for several organs such as colorectum, lung, breast, and cervix. In addition, chronic ethanol intake is known to impede the normal bioavailability and metabolism of folate. Thus alcohol intake and folate deficiency may act synergistically in promoting carcinogenesis. Excessive alcohol intake may impair the bioavailability of folate by diminishing its intestinal absorption, increasing its urinary excretion, and inducing cleavage of its molecule. Alcohol can impair folate metabolism in many ways. Both acute and chronic ethanol ingestion are known to inhibit the activity of methionine synthase, which catalyzes the transfer of a methyl group from folate to homocysteine leading to methionine reformation. The decreased methionine synthase activity can result in decreased production of SAMe and increased accumulation of homocysteine and S-adenosylhomocysteine. A decreased ratio of SAMe to s-adenosylhomocysteine can inhibit activities of many methyl transferases leading to global hypomethylation of DNA, which is an early feature of neoplastic transformation of epithelial cells. Thus alcohol-induced inhibition of methionine synthase activity may promote neoplastic growth via decreasing SAMe levels. 

g. Impaired Betaine Metabolism:

Betaine (trimethylglycine) is an important human nutrient obtained from a variety of foods, and it is available as a dietary supplement. As a methyl donor, betaine provides methyl group to homocysteine to form methionine in a reaction that is catalyzed by betaine homocysteine methyl transferase (BHMT). This maintains an adequate supply of methionine for the synthesis of SAMe. In body, betaine is synthesized from choline in a reaction that is catalyzed by choline oxidase. Chronic ethanol exposure has been shown to deplete hepatic levels of betaine, which is associated with depletion of hepatic SAMe and elevation of hepatic levels of homocysteine and S-adenosylhomocysteine (SAH). Depletion of SAMe may promote neoplastic growth by inducing global DNA hypomethylation. Dietary betaine supplementation has been shown to increase hepatic levels of SAMe and decrease hepatic levels of SAH in rats exposed to chronic alcohol. SAH is a potent inhibitor of several methyltransferases including DNA methyltransferases which catalyze the transfer of methyl groups from SAMe to DNA. Thus betaine is potentially capable of improving DNA methylation by increasing SAMe levels and by rescuing DNA methyltransferases from the inhibitory effect of SAH.

h. Impaired iron metabolism:

Chronic alcohol intake is associated with increased accumulation of iron in the liver cells, including hepatocytes and Kupffer cells. Hepatic iron overload also develops in many individuals who consume alcohol on a chronic basis. Both alcohol and iron are known pro-oxidants. Alcohol’s metabolism through CYP2E1 can lead to the generation of superoxide and hydrogen peroxide. On the other hand, hydrogen peroxide can react with ferrous iron (Fe+2), through Fenton reaction, and generate hydroxyl radicals which are highly reactive. Hydroxyl radicals can react with lipid molecules, initiating chain reactions leading to lipid peroxidation and generation of products such as acrolein, crotonaldehyde, malondialdehyde, and 4-hydoxynonenal (4-HNE). The 4-HNE is known to cause mutations of p53 gene which may initiate the development of HCC. Thus it is possible that sustained oxidative stress associated with chronic alcohol consumption and hepatic iron overload could play an important role in the initiation and promotion of carcinogenesis. Indeed a synergistic effect of alcohol intake and iron accumulation on HCC has been reported in patients with hemochromatosis. An excess of iron accumulated in hepatic macrophage (Kupffer cells) in response to chronic alcohol intake can activate, via oxidative stress, NF-kappaB which can increase the transcription of pro-inflammatory cytokine TNF-á. Thus in alcoholics, alcohol and iron together may initiate chronic inflammation which is a known risk factor for cancer. 

i. Impaired vitamin A metabolism:

Alcohol may promote cancers of various organs by impairing metabolism of vitamin A. Vitamin A (retinol) is oxidized by retinol dehydrogenase to retinal, which is further oxidized to retinoic acid by retinal dehydrogenase. In addition, ADH and ALDH also participate in the metabolism of retinol to retinal and retinoic acid. Retinoic acid is the most active form of vitamin A, and a ligand for both retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Retinoic acid is known to control cell proliferation, cell growth, cell differentiation, and cell apoptosis. Perturbation (impaired homeostasis) of these activities may render cells susceptible to carcinogenesis. Alcoholics generally have reduced levels of vitamin A (retinol and retinyl esters), which is likely to reduce the levels of retinoic acid. Chronic ethanol ingestion may impair retinoid metabolism in three ways: 1) by inhibiting retinol metabolism to retinoic acid via competing for ADH and ALDH; 2) by accelerating catabolism of vitamin A by inducing CYP2E1; and 3) by increasing mobilization of vitamin A from the liver to other tissues. Alcohol-induced impairment of retinoic acid homeostasis may interfere with Vitamin A action and signaling in following ways. For example, alcohol may interfere with retinoic acid signaling, including down-regulating retinoid target gene expression and inhibiting RARs binding activity to retinoic acid responsive element (RARE). In addition, alcohol may interfere with retinoic acid cross talk with MAPK signaling pathway, which is involved in cellular proliferation, apoptosis, oxidative stress, and carcinogenesis. Thus chronic alcohol ingestion may promote cancer via perturbing homeostasis of retinoic acid metabolism and by impairing its action and signaling. 

j. Other mechanisms: 

For breast cancer in particular, alcohol consumption is associated with increased risk in both premenopausal and postmenopausal women. Breast tissue may metabolize alcohol to acetaldehyde, catalyzed by ADH and CYP2E1. Acetaldehyde can be further metabolized to acetate via ALDH or xanthine oxidoreductase (XOR) in the breast tissue. Metabolism of alcohol by CYP2E1 and of acetaldehyde by XOR can result in ROS generation. Both acetaldehyde and ROS have been implicated in the initiation and progression of cancer. Alcohol has been shown to down-regulate the expression of the tumor suppressor gene BRCA1 and increase the transcriptional activity of estrogen receptor-alpha. Thus alcohol may contribute to breast cancer by inactivation of BRCA1 and increasing estrogen responsiveness. In experimental animals, alcohol has been shown to initiate as well as promote dimethylbenzathracene-initiated mammary tumors. Alcohol appears to render rodent mammary gland susceptible to carcinogen-induced damage by altering mammary gland structural development and stimulating cell proliferation in the terminal end buds of the mammary gland. Alcohol consumption is associated with increased breast mammographic density, which is a risk factor for developing breast cancer. 

Areas of Research

Listed below are examples of areas of interest. Research relevant to this PA is not limited to these examples.

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 National Institutes of Health (NIH) research project grant (R01) award mechanism(s).

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. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium 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

This program does not require cost-sharing. 

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

Not applicable.

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.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Proposed research should provide a unique research opportunity not available in the U.S.

3. Submission Dates and Times

See Section IV.3.A for details.

3.A. Submission, Review and Anticipated Start Dates

Letter of Intent Receipt Date: Not applicable
Application Submission Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm
Peer Review Date(s): Standard dates apply, please see   http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward 
Council Review Date(s): Standard dates apply, please see  http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward  
Earliest Anticipated Start Date(s): Standard dates apply, please see   http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward  

3.A.1. Letter of Intent

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

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant application forms found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and five 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).

3.C. Application Processing
 
Applications must be submitted on or before the application receipt/submission dates described above (Section IV.3.A.) and at http://grants.nih.gov/grants/dates.htm.

Upon receipt applications will be evaluated for completeness by CSR. Incomplete 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 merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique.
 
Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/

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.

6. Other Submission Requirements

Specific Instructions for Modular Grant applications.

Applications requesting up to $250,000 per year in direct costs 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.  

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

Applicants requesting $500,000 or more in direct costs for any year must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study;
2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and,
3) Include a cover letter with the application that identifies the staff member and IC who agreed to accept assignment of the application.

This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.

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.

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

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

2. Review and Selection Process

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

Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit.

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

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?

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 (if applicable)? 

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:

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).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

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: 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 will 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 presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

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

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 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 (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 12 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 NoA. 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

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:

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

National Cancer Institute (NCI)
Sharon Ross, Ph.D., MPH
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, Room 3157, MSC 7328
Bethesda, MD 20892-7328
Phone: 301-594-7547
Fax: 301-480-3925
Email: rosssha@mail.nih.gov

Office of Dietary Supplements (ODS)
Christine A. Swanson, Ph.D.
Office of Dietary Supplements
National Institutes of Health
Room 3B01 MSC 7517
6100 Executive Blvd.
Bethesda MD 20892-7517
Phone: (301) 435-2920
Fax: (301) 480-1845
Email: Swansonc@od.nih.gov 

2. Peer Review Contacts:

Not applicable.

3. Financial or Grants Management Contacts:

National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Judy Fox
Chief, Grants Management Branch
Chief Grants Management Officer
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 3023, MSC 9304
Bethesda, MD 20892-9304
FOR EXPRESS MAIL: Rockville, MD 20852-1705
Phone: (301)443-4704
FAX: (301)443-3891
Email: jfox@mail.nih.gov

National Cancer Institute (NCI)
Barbara Liesenfeld
Office of Grants Administration
Executive Plaza South, Suite 243
6120 Executive Boulevard
Bethesda, MD  20892 (regular mail)
Rockville, MD  10852 (express mail)
Phone:  301-496-3265
Fax:  301-496-8601
Email: liesenfb@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.

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 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://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 (http://publicaccess.nih.gov/publicaccess_Manual.htm).

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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