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 Cancer Institute (NCI), (http://www.nci.nih.gov/)
National Institute on Alcohol Abuse and Alcoholism (NIAAA), (http://www.niaaa.nih.gov/)

Title: Molecular Approaches to Diet and Pancreatic Cancer Prevention

Announcement Type
New

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

Program Announcement (PA) Number: PA-05-040

Catalog of Federal Domestic Assistance Numbers
93.393, 93.396, 93.273

Key Dates
Release Date January 24, 2005
Letter of Intent Receipt Dates: Not applicable
Application Receipt Dates: Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.
Peer Review Dates: Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.
Council Review Dates: Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.
Earliest Anticipated Start Dates: Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.
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

The purpose of this initiative is to invite innovative preclinical and clinical R01 applications to determine how dietary energy intake and bioactive food components, including alcohol, influence pancreatic cancer development and prevention. This PA seeks to encourage collaboration between nutritional scientists and cancer biologists, oncologists and gastroenterologists to jointly examine key mechanisms in the pancreatic cancer process (e.g., carcinogen metabolism, cell division, differentiation, apoptosis) in order to begin to establish mechanistic links between quantity and form of energy consumed and/or bioactive food component intakes with pancreatic tumor incidence and behavior. The linkage between diet and pancreatic cancer comes from its long-recognized interrelationships with diabetes and obesity, and thus with caloric intake and expenditure. This PA seeks to expand research that will clarify the importance of diet-related energetics and bioactive food components in pancreatic cancer prevention.

This PA will use the NIH investigator-initiated research project grants (R01) award mechanism. Investigators interested in submitting Small Grants Program grant applications (R03) on this topic are directed to use the Small Grant Program opportunity listed at http://grants.nih.gov/grants/guide/pa-files/PAR-04-147.html.  Please see the link at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-041.html for the NIH policy on submitting revised applications.  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 total amount awarded and the number of awards will depend upon the numbers, qualities, durations, and costs of the applications received. Application materials and instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format.  You may submit (an) application(s) if your institution has any of the following characteristics:

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.  There is no limitation on the number of different applications an institution or individual may submit. Telecommunications for the hearing impaired is available at: TTY 301-451-5936.

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 and 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
    A. Cooperative Agreement Terms and Conditions of Award
      1. Principal Investigator Rights and Responsibilities
      2. NIH Responsibilities
      3. Collaborative Responsibilities
      4. Arbitration Process
  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

Approximately 30,000 Americans are diagnosed yearly with pancreatic cancer. This is a particularly devastating cancer since the case-fatality proportion approaches 90 percent within 12 months following diagnosis. Today, pancreatic cancer ranks as the fourth leading cause of cancer mortality in the U.S.

It is widely acknowledged that genetic, epigenetic, and environmental factors influence the onset of pancreatic cancer. Germline mutations are thought to account for only a very small proportion of the cases. Nevertheless, there are more than a dozen inherited germline mutations that increase the risk of pancreatic cancer. Hereditary pancreatitis frequently surfaces as conferring the greatest risk, whereas BRCA2 mutations are the most common inherited disorder. A gene whose penetrance is modified by the presence of environmental factors, including smoking and dietary habits, may explain the difference in risk between the densely aggregated and less densely aggregated families. Smoking is a well-documented environmental risk factor for the development of pancreatic adenocarcinoma. The linkage between diet and pancreatic cancer comes from its long-recognized interrelationships with diabetes and obesity, and thus caloric intake and expenditure. Evidence already exists that h eavy alcohol consumption, infrequent intake of vegetables, high BMI, and high caloric intake are associated with an increased risk of pancreatic cancer in humans.

In addition, to germline defects, there are several common polymorphisms in genes that control detoxification of environmental carcinogens (e.g., CYP1A2) that may alter the risk of pancreatic cancer and be influenced by dietary components. A host of dietary factors are recognized to modify several of the detoxification pathways and may also contribute to the onset of pancreatic cancer.

Since early diagnosis is difficult and the mortality rate is high, it is important to identify individuals with high risk for pancreatic cancer. Chronic pancreatitis has been shown to be a risk factor for pancreatic ductal adenocarcinoma. The duration of inflammation seems to be the major factor involved in the transition of benign to malignant condition. Long term heavy alcohol consumption is the major cause of chronic pancreatitis. In the United States and other developed countries, 60 to 90 percent of cases of chronic pancreatitis are linked to alcohol consumption. Therefore, prevention or treatment of alcoholic pancreatitis may reduce the incidence of pancreatic cancer in this country.

This initiative seeks to expand research that will clarify the importance of diet-related energetics and bioactive food components in pancreatic cancer prevention. Specifically, preclinical and clinical studies are sought that utilize innovative molecular biological approaches to determine the importance of energy intake and/or bioactive food constituents as site-specific modifiers of the pancreatic cancer process.

Some of the possible mechanistic pathways leading to pancreatic cancer involve: insulin signaling pathways, the impact of glycated proteins, free radical damage, and aberrant methylation processes. The discovery, identification, and characterization of the roles of dietary components in regulating these and other biological processes in the development of pancreatic cancer deserve further study, and serve as the basis of this PA. Additionally, understanding the underlying molecular, biochemical, and cellular mechanisms by which alcohol ingestion leads to the development of pancreatitis and subsequent pancreatic cancer risk also is a relevant topic in response to this PA.

IGF Axis

The insulin/insulin-like growth factor (IGF) axis may contribute to the observed correlation between obesity and mortality from several cancers. Insulin-like growth factors (IGFs) are endocrine mediators of growth hormone and also act in paracrine and autocrine fashion to regulate cell growth, differentiation, apoptosis, and transformation in many tissues including the exocrine pancreas. The IGF axis is complex and is comprised of growth factors (IGF-1, IGF-2, and insulin), cell surface receptors (IGF-1R and IGF-2R), six binding proteins (IGFBP-1 to IGFBP-6), IGFBP proteases, as well as other IGFBP-interacting molecules that regulate the IGF axis' actions. Imbalance of these processes may support uncontrolled cell proliferation and promote carcinogenesis. Evidence suggests that IGF-1 enhances the growth and survival of human pancreatic cancer cells both through autocrine and paracrine mechanisms. Findings from a nested case-control study conducted in Japan suggest that high serum levels of insulin-like growth factor-1 (IGF-I) and insulin-like growth factor binding protein-1 (IGFBP-3) may be associated with an increased risk of death from pancreatic cancer ( 31 ). However, findings from a nested case-control study in male smokers do not support the hypothesis that serum IGF-1 and IGFBP-3 concentrations are associated with pancreatic cancer risk, suggesting that multiple factors in the insulin-IGF-axis may influence risk.

Glycation

Nonenzymatic glycation of proteins, lipids, and DNA molecules has been implicated in a number of pathologies. DNA Glycation damage is associated with mutagenesis and carcinogenesis. Glycation can be formed through a number of complex pathways, including nonenzymatic glycation by glucose and reaction with metabolic intermediates and reactive dicarbonyl intermediates. Glycation initially results in the formation of Amadori-modified proteins. Advanced glycation end products (AGE) are irreversibly formed from Amadori products leading to the formation of reactive intermediates. Studies suggest the presence of AGE-binding receptors (i.e., RAGE) on a range of various cell types. Advanced glycation end products (AGE) have been found to interact with receptors and alter signal transduction pathways that are involved in the inflammatory response, cell proliferation, tumor growth and metastasis. More information on diet-induced glycation and its impact on pancreatic cancer development is needed.

Free Radicals

High circulating glucose concentrations are associated with oxidative stress. Increased levels of reactive oxygen species can promote insulin resistance. In vitro studies using a variety of cell lines have demonstrated that micromolar concentrations of hydrogen peroxide can inhibit insulin signaling and glucose transport. A few studies of small numbers of diabetic subjects have shown that oral vitamin E or lipoic acid administration could improve insulin-mediated glucose utilization. However, in all these studies, the antioxidants were able to effect only a partial improvement in insulin sensitivity. It is noteworthy that high levels of reducing sugars, such as glucose and fructose, have been found to increase oxidative stress in pancreatic cells. Fructose added to the cell culture medium, for example, increased cellular peroxide levels and lipid peroxidation in hamster islet tumor (HIT) cells and impacted measures of cellular damage/ apoptosis. Fructose also suppressed the expression of glutathione peroxidase (GPx) messenger RNA and inactivated GPx activity in HIT cells.

The effects of vitamins A, C and E on neoplastic growth and lipid peroxidation in pancreatic tissue have also been evaluated in chemically-induced pancreatic adenocarcinoma in the Syrian hamster. In that study, the incidence of pancreatic cancer was decreased by vitamin A and vitamin C as compared to the control group. Another study using the same model did not find protection from vitamin E, vitamin C, beta-carotene, or selenium (alone or in combination) in the development of pancreatic cancer. Mechanistic studies should provide clues as to why these inconsistencies occur.

DNA methylation and other epigenetic events

Several experimental studies suggest that disturbed methylation can influence cellular differentiation in the pancreas and contribute to toxic injury in ways that enhance the pathogenesis of pancreatitis and carcinogenesis. An epidemiological study in smokers indicated that the risk of pancreatic carcinoma was inverse to serum levels of folate, which may suggest alterations in DNA methylation patterns. Another study, however, did not find an association between folate intake and the risk of pancreatic cancer in men or women. Experimental studies of gene expression patterns in pancreatic cancer cell lines have identified many genes overexpressed in pancreatic cancer including 14-3-3 ä, Claudin-4, PSCA, S100A4, S100P, MMP-7, IL-8, CD44 , and mesothelin. Many of these genes are normally methylated and not expressed in normal pancreatic epithelium and undergo gene specific hypomethylation in conjunction with overexpression in pancreatic cancer. More studies are necessary to gain an understanding of their connection to methyl availability and possible site-specific DNA hypomethylation events. Nevertheless, involvement of methylation in normal differentiation is supported by reports of development of hepatocyte-like cells in the pancreas of rats fed a choline-deficient diet. Those studies suggest that disturbed methyl metabolism may contribute to the pathogenesis of several pancreatic diseases.

Cell Signaling Pathways

The effect of the green tea polyphenol epigallocatechin-3-gallate (EGCG) on proliferation and cell invasion of three different human pancreatic carcinoma cells (PANC-1, MIA PaCa-2, and BxPC-3) has been examined. The growth of all three pancreatic carcinoma cells was significantly suppressed by EGCG treatment in a dose-dependent manner. EGCG treatment caused significant suppression of the invasive ability of pancreatic carcinoma cells PANC-1, MIA PaCa-2, and BxPC-3, but did not affect the cell cycle protein cyclin D1.

These investigators concluded that the cell cycle itself is not affected by EGCG and that the antioxidant potential of EGCG is a possible factor in its inhibitory effect; these investigators suggest that modulation of transcription via the antioxidant response elements may be implicated in the response.

The effects of other bioactive food components have recently been investigated in pancreatic cancer cells. For example, the constitutively activated signal transducer and activator of transcription-3 protein (STAT3) was found to be modulated by indole-3-carbinol (13C) and genistein in pancreatic tumor cell lines (Panc-1 and MIA PaCa-2). At concentrations higher than 10 microM of I3C or genistein, STAT3 constitutive activation is inhibited. Induction of apoptosis by 13C was also demonstrated.

Furthermore, metabolic profiling is being used to define pancreatic phenotypes associated with normal and neoplastic cells. This strategy has been used to identify certain changes in metabolic phenotypes induced by tumor growth-inhibiting phytochemicals such as genistein which not only altered glucose uptake and its incorporation into a variety of intermediates, but suppressed the activities of several kinases. Additional studies examining the effect of these and other bioactive food components in modulating molecular targets in newer animal models for pancreatic adenocarcinoma are encouraged.

Alcohol consumption and chronic pancreatitis

Several factors such as acetaldehyde, oxidative stress, and cytokines are known to mediate the effect of alcohol in the development of pancreatitis. In addition to the direct effects of alcohol, various predisposing factors such as genetics, intestinal infection, and dietary factors may make the pancreas more susceptible to alcohol-induced tissue injury.

Oxidative stress has been linked to the pathogenesis of alcoholic pancreatitis, as well as pancreatic cancer. Chronic ethanol administration is known to be associated with oxidative stress in the pancreas. Alpha-hydroxyethyl radicals as well as 4-hydroxynonenal, an index of lipid peroxidation, have been detected in pancreatic secretion after chronic ethanol exposure. Furthermore, chronic ethanol has been shown to induce CYP2E1 in the pancreas, which can result in the generation of reactive oxygen species (ROS). Chronic alcohol consumption may further exacerbate oxidative stress by reducing the levels of reduced glutathione (GSH) in the pancreas.

Dietary fat appears to play an important role in the pathogenesis of alcoholic pancreatitis via modulating oxidative stress. For example, unsaturated fat (corn oil) potentiated alcoholic pancreatits, which was mediated through oxidative stress. On the other hand, saturated fat (medium-chain triglycerides) attenuated the injury via blunting oxidative stress. The amount of dietary fat is also important in eliciting alcoholic pancreatic injury. For example, intragastric infusion of ethanol with 25 to 35 percent of fat calories (corn oil) led to the development of chronic pancreatitis, while 5 percent of fat calories failed to induce this condition.

Acetaldehyde has been shown to be mutagenic and carcinogenic in many in vitro and in vivo studies. It can be produced in the pancreas through oxidative metabolism of alcohol, catalyzed by alcohol dehydrogenase (ADH) as well as CYP2E1. Increased acetaldehyde production in pancreas during heavy alcohol ingestion may increase the risk of pancreatic cancer. The mechanism of action of these factors in pancreatitis and pancreatic cancer development requires additional study.

This PA seeks to promote innovative preclinical and clinical research to determine how diet-induced changes in energetics and bioactive food components impact pancreatic cancer development and prevention. This PA seeks to encourage collaboration between nutritional scientists and cancer biologists, oncologists, and gastroenterologists to jointly examine key mechanisms in the pancreatic cancer process (e.g., carcinogen metabolism, cell division, differentiation, apoptosis) in order to begin to establish mechanistic links between quantity and form of energy consumed and/or bioactive food component intakes and tumor incidence/behavior. Investigators may choose from the full range of clinical and preclinical approaches.

The use of chemically induced, transgenic, and knockout animal models offers additional opportunities for addressing the specific roles of nutrients beyond that possible when cell culture systems are used. The use of transgenic and/or conditional knockout models available through the Mouse Models for Human Cancer Consortium (MMHCC, http://emice.nci.nih.gov/) is encouraged. Studies that examine the influences of suppressed or exaggerated activities of genes regulating nutrient absorption or metabolism may provide clues to variations in response. Additionally, transcriptional factors, cofactors, and other regulators that influence a specific target may be appropriate for manipulation in chemically induced or transgenic models used to define the roles of diet and nutrients in pancreatic cancer. The use of a variety of molecular technologies including genetic manipulation of animal models, Complementary DNA and/or tissue microarrays, serial analysis of gene expression (SAGE), and proteomic tools are encouraged. Investigators are encouraged to utilize NCI's Cancer Genome Anatomy Project database on human and mouse genomics including expressed sequence tags (ESTs), gene expression patterns, single nucleotide polymorphisms (SNPs), cluster assemblies, and cytogenetic information (http://cgap.nci.nih.gov/).

Illustrative examples for the development of R01 applications include, but are not limited to, the following examples:

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

Section II. Award Information

1. Mechanism of Support

This funding opportunity will use the NIH investigator-initiated research project grants (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).

2. Funds Available

No set-aside funds are available for this PA. Applicants may request up to five years of support for R01 awards with costs appropriately tailored to the proposed work. Although no limit is set on R01 requested costs you should follow the instructions in Section IV. 6. Other Submission Requirements if you anticipate that the budget will exceed $500,000 in direct costs in any year. 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 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-05-002.html).

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 as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.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 should 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 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 mailed 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 Dates: not applicable
Application Receipt Dates: http://grants.nih.gov/grants/funding/submissionschedule.htm
Peer Review Dates: http://grants.nih.gov/grants/funding/submissionschedule.htm
Council Review Dates: http://grants.nih.gov/grants/funding/submissionschedule.htm
Earliest Anticipated Start Dates: http://grants.nih.gov/grants/funding/submissionschedule.htm

3.A.1. Letter of Intent
A letter of intent is not required for this funding opportunity.

3.B. Sending an Application to the NIH

Applications must be prepared using the PHS 398 research grant application instructions and forms as described above. 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)

3.C. Application Processing

Applications must be submitted on or before the application receipt 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.

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. 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.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 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 (see also Section VI.3. Reporting)

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/grants/policy/nihgps_2003/NIHGPS_Part6.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.

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/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.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 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.

1. 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?

2. 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?

3. 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?

4. 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)?

5. 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.

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/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.

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 Principal Investigator will also receive a written critique called a Summary Statement.

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/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Grant Award (NGA) will be provided to the applicant organization. The NGA signed by the grants management officer is the authorizing document.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

The NGA will be sent via either via email or via regular mail to the administrative official whose name is listed in Block 12 on the Face Page of the Form PHS 398.

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/grants/policy/nihgps_2003/NIHGPS_Part4.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/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award
Not applicable.

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 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
Rockville, MD 20852 (express/courier service)
Telephone: (301) 594-7547
FAX: 301-480-3925
Email: rosssha@mail.nih.gov

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

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

2. Peer Review Contacts:
Not applicable.

3. Financial or Grants Management Contacts:

National Cancer Institute (NCI)
Ms. Connie Murphy
Grants Management Branch
National Cancer Institute
6120 Executive Boulevard
Executive Plaza South, Room 243
Bethesda, MD 20892
Rockville, MD 20852 (express/courier service)
Phone: (301) 496-8657
FAX: (301) 496-8601
Email: murphco@gab.nci.nih.gov

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Ms. Judy Fox
Chief, Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 3023, MSC 9304
Bethesda, MD 20892-9304
Rockville, MD 20852-1705 (for express/courier service)
Phone: (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); and 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. (See the NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts at 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 (http://grants.nih.gov/grants/policy/data_sharing) or state why this is not possible.

Investigators should seek guidance from their institutions, on issues related to institutional policies, 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 at http://grants.nih.gov/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 that is available at 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 (see 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.

Public 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 public 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 PA 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.healthypeople.gov/.

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. Kirschstein-NRSA Awards are made under the authorization of Section 487 of the Public Health Service Act as amended (42 USC 288) and Title 42 of the Code of Federal Regulations, Part 66. 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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