Expired PA-08-210: Diet-Induced Changes in Inflammation as Determinants of Colon Cancer (R01)

Department of Health
and Human Services (HHS)

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EXPIRED

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://cancer.gov)

Title: Diet-Induced Changes in Inflammation as Determinants of Colon Cancer (R01)

Announcement Type
This Funding Opportunity Announcement (FOA) is a reissue of PA-05-125.

Program Announcement (PA) Number: PA-08-210

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

September 29, 2010 (NOT-OD-11-007) - NIH to Require Use of Updated Electronic Application Forms in 2011. Adobe B1 forms are required for due dates on or after May 8, 2011.
November 25, 2009 - This FOA has been updated to reflect the new requirements from NIH’s Enhancing Peer Review Initiative. The new requirements are effective for submissions intended for due dates January 25, 2010 and beyond. If submitting an application intended for a due date of January 25, 2010 and beyond, follow the guidance below and be sure to use the Adobe-Forms-B version of the application forms and instructions. If applying for a due date before January 25, 2010, follow the guidance in the archived version of this FOA and be sure to use the Adobe-Forms-A version of the application forms and instructions.

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

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

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

A registration process is necessary before submission and applicants are highly encouraged to start the process at least four (4) weeks prior to the grant submission date. See Section IV.

Catalog of Federal Domestic Assistance Number(s)
93.393, 93.396, 93.399

Key Dates
Release/Posted Date: July 18, 2008
Opening Date: September 5, 2008 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): Not Applicable
NOTE: On-time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization).
Application Due Dates:Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm
AIDS Application Due Dates: Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#AIDS.
Peer Review Dates: Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Council Review Dates: Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Earliest Anticipated Start Dates: 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: September 8, 2011

Due Dates for E.O. 12372

Not Applicable.

Additional Overview Content

Executive Summary

Purpose. This funding opportunity announcement (FOA), issued by the National Cancer Institute (NCI), encourages the submission of grant applications that describe research projects focused on the identification and characterization of diet-induced changes in inflammation linked to colon cancer risks. This FOA is designed to stimulate research efforts that will lead to the identification and characterization of: diet-induced changes in anti- and pro-inflammatory mediators that modulate colon cancer risk; b) genetic polymorphisms that modify the responses to specific bioactive food components with regard to colon cancer inhibition; and c) the physiological effectiveness of dietary components in terms of concentration, activity, duration of exposure, degrees of stability, chemical forms, and receptor-binding affinity in inflammatory colonocytes. This FOA will not support applications that propose epidemiological studies based on diet-related risks of colon cancer.
Mechanism of Support. This FOA uses the NIH research project R01 grant mechanism and runs in parallel with an FOA of identical scientific scope, PA-08-211, that solicits applications under the NIH Exploratory/Developmental (R21) Grant mechanism.
Funds Available and Anticipated Number of Awards. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.
Budget and Project Period. The total project period for an application submitted in response to this funding opportunity may not exceed 5 years.Applicants for an R01 award are not limited in dollars but need to reflect the actual needs of the proposed project.
Research Plan Component Length: Item 3 of the PHS398 research plan component of the R01 application may not exceed 12 pages, including tables, graphs, figures, diagrams, and charts. http://grants.nih.gov/grants/funding/funding_program.htm
Eligible Institutions/Organizations. Institutions/organizations listed in Section III, 1.A. are eligible to apply.
Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/ organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
Number of PDs/PIs. More than one PD/PI (i.e., multiple PDs/PIs) may be designated on the application.
Number of Applications. Applicants may submit more than one application, provided each application is scientifically distinct.
Resubmissions. Applicants may submit a resubmission application, but such application must include an Introduction addressing the previous peer review critique (Summary Statement).
Renewals. Applications can be renewed by competing for additional project periods.
Application Materials. See Section IV.1 for application materials.
All applications, including resubmission, revision and renewal, submitted for due dates January 25, 2010 and beyond, must utilize the current forms and instructions.
General Information. For general information on SF424 (R&R) Application and Electronic Submission, see these Web sites:
- SF424 (R&R) Application and Electronic Submission Information at http://grants.nih.gov/grants/funding/424/index.htm; and
- General information on Electronic Submission of Grant Applications at http://era.nih.gov/ElectronicReceipt/.
Hearing Impaired. Telecommunications for the hearing impaired are 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 of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2. Cost Sharing or Matching
3. Other-Special Eligibility Criteria

Section IV. Application and Submission Information
1. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt, Review, and Anticipated Start Dates
1. Letter of Intent
B. Submitting an Application Electronically to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements and Information

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
3. Reporting

Section VII. Agency Contacts
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Purpose

This funding opportunity announcement (FOA), issued by the National Cancer Institute (NCI), is designed to promote research on the mechanistic links connecting diet, inflammation, and colon cancer. Applications submitted in response to this FOA should be focused on the identification and characterization of diet-induced changes in inflammation linked to colon cancer risks. Of particular interest are research efforts that will lead to the identification and characterization of: a) diet-induced changes in anti- and pro-inflammatory mediators that modulate colon cancer risk; b) genetic polymorphisms that modify the responses to specific bioactive food components with regard to colon cancer inhibition; and c) the physiological effectiveness of dietary components in terms of concentration, activity, duration of exposure, degrees of stability, chemical forms, and receptor-binding affinity in inflammatory colonocytes.

Using the NIH Research Project Grant (R01) funding mechanism, this FOA focuses on discrete, specified, circumscribed projects based upon strong preliminary data.

Related Funding Opportunity: Investigators, who are interested in proposing early phase, pilot/exploratory, and/or hypothesis-driven projects, should submit applications in response to the partner FOA of identical scientific scope (PA-08-211), which uses the NIH exploratory/developmental (R21) grant mechanism.

Background

The incidence of colon cancer remains a significant concern to global health. Colon cancer is the third most prevalent form of cancer, and the second leading cause of cancer-related deaths in the United States. The increased risk for developing colon cancer in patients with ulcerative colitis, and the observed benefits of anti-inflammatory drugs in retarding intestinal tumors, provide compelling evidence that inflammation is associated with incidence of colon cancer. Several epidemiological and pre-clinical studies reveal that specific bioactive food components can suppress colonic inflammation as well as reduce the risks of colon cancer. Nonetheless, it remains unclear whether these diet-induced shifts in the inflammatory process can account for their anti-tumorigenic properties. The lack of mechanistic information on the association of diet, inflammation and colon cancer hampers further progress in this area.

Inflammation is a normal physiological response to tissue injury or infection; however, when untreated, inflammation can lead to serious complications, including cancer. The various restraining mechanisms inherent within the inflammatory process may be either compromised by the severity and duration of tissue insult, or a host of genetic and environmental factors. Dietary habits are likely one of key determinants of the balance that influences the overall inflammatory process. In addition, genetic polymorphisms at multiple sites in the genome may determine the pro- and/or anti-inflammatory cytokine response to different bioactive food components.

Inflammatory Cytokines. The inflammatory process is generally initiated by the expression and secretion of pro-inflammatory cytokines such as tumor necrosis factor- a (TNF-a), the interleukins (IL-1, IL-6, IL-12) and g-interferon. An increased production of cytokines and the subsequent elevation in both reactive oxygen and nitrogen species are recognized hallmarks of the inflammatory response. This accumulation of reactive oxygen and nitrogen species is mitigated by negative feedback mechanisms that involve the secretion of specific anti-inflammatory cytokines (e.g., IL-4, IL-10, and TGF-). In addition, activation of the cellular antioxidant defense system also contributes to the anti-inflammatory functions. However, these defense mechanisms may not always be sufficient to prevent development of chronic inflammation, which is known to escalate the risk for cancer.

Signaling Pathways in the Inflammatory Process. Activation of pro-inflammatory cytokine receptors triggers the mitogen-activated protein kinase (MAPK) pathway, which activates two redox-sensitive transcription factors, nuclear factor k B (NF-kB) and the c-Jun part of activating protein-1 (AP-1). These transcription factors activate the expression of a wide variety of genes including cytokines, chemokines, adhesion molecules, and inducible effector enzymes such as inducible nitric oxide synthase (iNOS) and cycloxygenase-2 (COX-2).

The COX-2 enzyme plays a significant role in colon tumorigenesis. There is a marked reduction in numbers of intestinal polyps occurring in the double mutant mice of COX-2 ^-/-and adenomatouspolyposis coli (Apc) mutant Apc ^D⁷¹⁶, compared with COX-2 wild-type animals. An unrestrained activation of NF-kB /COX-2 combined with inactivation of TGF- signaling frequently occurs in colon tumor cells. These findings suggest that the loss of balance between anti- and pro-inflammatory mediators may precipitate neoplastic transformation in the intestinal epithelium.

Dietary Components and the Inflammatory Process. Evidence exists that selected dietary components including conjugated linoleic acid (CLA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), butyrate, (-)-epigallocatechin gallate (EGCG), curcumin, resveratrol, genistein, luteolin, quercetin, and vitamins A and D may influence the inflammatory process at various sites and thus modulate the balance within the process. For example, the concentration of TNF-a and IL-1 was reduced by more than 70 percent in humans consuming fish-oil rich in EPA and DHA. Likewise, a number of dietary components, including resveratrol in red grapes, CLA in dairy products, butyrate generated through the microbial metabolism of dietary fiber in colon, and curcumin in curry spice, have been reported to suppress the TNF-a induced activation of NF-kB and COX-2 expression in vitro and in vivo. The mechanisms by which these bioactive components can influence inflammation may involve processes related to transport, activation, or inactivation. Resveratrol has been shown to inhibit the translocation of NF-kB from the cytoplasm to the nucleus by modulating the activity of IkB kinase (IKK) in various cell types such as myeloid, lymphoid, and epithelial cells. Other food components such as curcumin are recognized to block NF-kB activation. While these findings are intriguing, it remains to be resolved if the effectiveness of these dietary components exists at the site of inflammation in the colon with the concentrations that are physiologically achievable.

Considerably more research is needed to characterize the physiological significance of bioactive food components in inflammatory colonocytes in terms of relative effectiveness, dose-dependence, temporality, consistency, and specificity. Dietary components can undergo various structural modifications such as methylation, glucuronidation, or sulfation; these modified dietary components are further digested into small molecular weight metabolites that directly interact with their target molecules. The function and stability of these metabolites are influenced by the cellular redox status. For example, the ability of EGCG to inhibit cell growth is increased in the presence of superoxide dismutase, an enzyme that reduces reactive oxygen species. These changes are especially important in inflammatory sites where a flux of reactive oxygen species removes potentially injurious substances. Knowledge about these variables will help explain under what circumstances dietary components can influence inflammatory processes and who might benefit most from intervention.

Genetic Polymorphisms, Diet, and Colon Cancer Risk. It is well documented that genetic polymorphisms that modulate the utilization of bioactive food components can alter the risks for colon cancer. For example, several studies have reported that a preventive effect of broccoli on colon cancer was observed only among individuals with the glutathione S-transferase class (GSTM1) null genotype. These results suggested that genetic polymorphisms in GSTM1 genes might contribute to variations (in cancer risk) in response to cruciferous vegetable intake. Likewise, a single nucleotide polymorphism (677 C>T) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, which is critical in folate metabolism, is associated with an increased risk for colon cancer in individuals with marginal folate intake status. Thus, genetic polymorphisms that are associated with utilization of bioactive food components may account for the variation in their ability to modify the inflammatory process.

Polymorphism may also affect the pro-inflammatory molecules. The production of inflammatory cytokines can vary widely among healthy people due to a number of functional polymorphisms. For example, individuals with TNF-a polymorphisms at nucleotides -238 (G>A), -308 (G>A), -857 (C>T), and -859 (C>T) are typically characterized by increased TNF-a production, as well as a greater susceptibility to various cancers. Increased TNF-a can be downregulated, admittedly with considerable variability, by a number of bioactive food components including DHA, EPA, and quercetin. While these findings suggest that genetic polymorphisms in inflammatory mediators can alter the response to dietary components in carcinogenesis, much more information is needed to clarify interrelationships among genetics, diet, and inflammation, as they relate to the prevention of colon cancer.

Detectable Phenotypic Changes Associated with Dietary Components in Inflammatory Colon Cancer Cells. Phenotypic changes accompanying a shift in either anti- or proinflammatory components as a function of eating behaviors need to be systematically evaluated. Preneoplastic aberrant crypt foci (ACF), C-reactive protein (CRP), adenomatous polyposis coli (APC) gene mutation, and -catenin expression may serve as useful early markers for changes in the risk for colon cancer.

ACF may be used as surrogate biomarkers for detecting cancer-preventive effects of anti-inflammatory dietary factors and drugs (including curcumin, selenium, EGCG, sulindac, celecoxib, or indomethacin) against colon cancers in preclinical models. Recently, it has been reported that the content of -catenin or mucin in the ACF is more predictive of colon carcinogenesis than the number and size of the ACF. It remains to be determined whether changes in ACF can serve as a marker for the inflammatory alterations induced by dietary constituents.

CRP is an acute-phase protein synthesized in liver and upregulated by pro-inflammatory cytokines, such as IL-6, IL-8, and TNF-a. Elevated levels of serum CRP were associated with the subsequent development of colon cancer. In a recently randomized controlled trial, circulating levels of CRP were significantly reduced by the consumption of Mediterranean-style diets that are rich in whole grains, fruits, vegetables, nuts, and olive oil. However, the mechanism(s) by which specific components of this type of diet can reduce CRP is unclear. Undeniably, further research is needed to discover effective biomarkers to assess the effects of diet on the inflammation and colon cancer.

Animal Models Help Characterize the Effects of Dietary Components on Inflammation and Colon Cancer. The recent development of transgenic and knockout mice for IL-10, TGF-, iNOS, and SOCS3 genes, and crossing experiments with existing colonic models such as APC^D⁷¹⁶ or multiple intestinal neoplasia (Min), have expanded our understanding of the involvement of inflammation in colon polyp formation. For example, TGF-1 deficiency in mice can lead to colon cancer that is preceded by precancerous lesions having submucosal inflammation and hyperplastic crypts. Similarly, IL-10 knockout mice develop spontaneous intestinal colitis, and often express COX-2 in regions that contain inflammatory cells. In addition, iNOS null mice (iNOS-/-) also manifest an attenuated colitis in response to tissue injury. The appropriate use(s) of these and other animal models should allow us to better understand the physiological targets of diet in various stages of the inflammatory process, as well as how these events may be associated with an increased risk for colon cancer and tumor cell behavior.

Investigators may choose preclinical animal models to define the role of diet in modulating inflammatory processes that can be linked to development of colon cancer. The use of animal models that have been genetically engineered to influence inflammatory phenotypes, particularly in the intestine, may be useful for gaining insights into both targets and potential dietary intervention strategies for colon cancer prevention. A variety of genomic, proteomic, and metabolomic technologies may be used. Since inflammatory processes can also be influenced by post-translational mechanisms (e.g., protein-protein interactions, modifications of protein activities through acetylation, phosphorylation, and methylation, degradation by the ubiquitin-proteasome mediated pathway), the profiling of proteins and/or metabolites in cells or tissues should provide greater insight into the relevance of dietary modifications to inflammatory processes that are linked to colon cancer. The efficient utilization of molecular resources such as gene, protein, and metabolome databases may be used to expedite research. Bioinformatic approaches may also be necessary to identify patterns of gene, protein, and/or metabolite changes that can generate unique fingerprints for the given dietary treatments. Information about bioinformatics at NCI is available at http://ncicb.nci.nih.gov/.

Research Objectives and Scope of this FOA

The overarching goal of this FOA is to encourage innovative research that will both identify and characterize diet-induced changes in inflammation, which are linked with altered risks for colon cancer. This FOA is not intended to support epidemiological studies.

Research topics that are relevant to this FOA include, but are not limited to, the following examples:

Examination of any association(s) between the inhibition of pro-inflammatory mediators (e.g., TNF-a, NF-kB) with the efficacy of resveratrol and curcumin and colon cancer cell growth rates;
Evaluation of whether anti-inflammatory mediators (e.g., TGF-) may account for the effects of dietary butyrate on inhibition of colon tumor growth;
Evaluation of whether polymorphisms in anti- or proinflammatory genes may explain the differential responsiveness among individuals to dietary n-3 fatty acids with regard to colon cancer inhibition;
Examination of whether the modulation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) may explain possible associations of green tea polyphenols and selenium with reductions in colon cancer incidence; and
Examination of whether the production of prostaglandin E2 (PGE2) and/or nitric oxide (NO) might be influenced by dietary conjugated linoleic acid and/or associated with colon cancer risk.

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

Section II. Award Information

1. Mechanism of Support

This FOA will use the NIH Research Project Grant (R01) award mechanism. The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses Just-in-Time information concepts (see SF424 (R&R) Application Guide). It also uses the modular as well as the non-modular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm).

U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related (R&R) Budget component.

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 NCI provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Facilities and Administrative (F&A) 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

The following organizations/institutions are eligible to apply:

Public/State Controlled Institutions of Higher Education;
Private Institutions of Higher Education;
Hispanic-serving Institutions;
Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education);
Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education);
Small Businesses;
For-Profit Organizations (Other than Small Businesses);
State Governments;
U.S. Territories or Possessions;
Regional Organizations;
Non-Domestic (non-U.S.) Entities (Foreign Organizations); and
Eligible Agencies of the Federal Government.

1.B. Eligible Individuals

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is (are) invited to work with his/her (their) organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application for projects that require a team science approach and therefore clearly do not fit the single-PD/PI model.Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH electronic Research Administration (eRA) Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs grant is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering the multiple PD/PI option, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application. Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically.Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement.

3. Other-Special Eligibility Criteria

Applicants may submit resubmission applications, but any such application must include an introduction addressing issues raised in the previous critique (Summary Statement).

Applicants may submit renewal applications.

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

Section IV. Application and Submission Information

Registration:
Appropriate registrations with Grants.gov and eRA Commons must be completed on or before the due date in order to successfully submit an application. Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered with both Grants.gov and the Commons. All registrations must be complete by the submission deadline for the application to be considered ?on-time? (see 3.C.1 for more information about on-time submission).

To download a SF424 (R&R) Application Package and SF424 (R&R) SBIR/STTR Application Guide for completing the SF424 (R&R) forms for this FOA, use the Apply for Grant Electronically button in this FOA or link to http://www.grants.gov/Apply/ and follow the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

Grants.gov (http://www.grants.gov/applicants/get_registered.jsp);and
eRA Commons (https://commons.era.nih.gov/commons/ and related site http://era.nih.gov/ElectronicReceipt/preparing.htm).

PDs/PIs should work with their institutions/organizations to make sure they are registered in the NIH eRA Commons.

Several additional separate actions are required before an applicant small business concern (SBC) can submit an electronic application, as follows:

1) Organizational/Institutional Registration in Grants.gov/Get Registered

Your organization will need to obtain a Data Universal Number System (DUNS) number and register with the Central Contractor Registration (CCR) as part of the Grants.gov registration process.
If your organization does not have a Taxpayer Identification Number (TIN) or Employer Identification Number (EIN), allow for extra time. A valid TIN or EIN is necessary for CCR registration.
The CCR also validates the EIN against Internal Revenue Service records, a step that will take an additional 1 to 2 business days.
Direct questions regarding Grants.gov registration to:
Grants.gov Customer Support
Contact Center Phone: 800-518-4726
Business Hours: M-F 7:00 a.m. - 9:00 p.m. Eastern Time
Email: [email protected]

2) Organizational/Institutional Registration in the eRA Commons

To find out if an organization is already Commons-registered, see the "List of Grantee Organizations Registered in NIH eRA Commons.
Direct questions regarding the Commons registration to:
eRA Commons Help Desk
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Business hours: M-F 7:00 a.m. 8:00 p.m. Eastern Time
Email: [email protected]

3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.

The individual(s) designated as PDs/PIs on the application must be registered also in the NIH eRA Commons.In the case of multiple PDs/PIs, all PDs/PIs must be registered and be assigned the PI role in the eRA Commons prior to the submission of the application.
Each PD/PI must hold a PD/PI account in the Commons. Applicants should not share a Commons account for both an Authorized Organization Representative/Signing Official (AOR/SO) role and a PD/PI role; however, if they have both a PD/PI role and an NIH Internet Assisted Review (IAR) role, both roles should exist under one Commons account.
When multiple PDs/PIs are proposed, all PDs/PIs at the applicant organization must be affiliated with that organization.PDs/PIs located at another institution need not be affiliated with the applicant organization, but must be affiliated with their own organization to be able to access the Commons.
This registration/affiliation must be done by the AOR/SO or his/her designee who is already registered in the Commons.

Both the PDs/PI(s) and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the application image.

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

Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the "Attachment" files may be useable for more than one FOA.

For further assistance, contact GrantsInfo Telephone: 301-710-0267; Email: [email protected].

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

2. Content and Form of Application Submission

Prepare all applications using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. Some fields within the SF424 (R&R) application components, although not marked as mandatory, are required by NIH (e.g., the Credential log-in field of the Research & Related Senior/Key Person Profile component must contain the PD/PIs assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

The SF424 (R&R) application has several components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY includes all applicable components, required and optional. A completed application in response to this FOA includes the data in the following components:

Required Components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
PHS398 Modular Budget or Research & Related Budget, as appropriate (See Section IV.6 Special Instructions, regarding appropriate required budget component.)

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

Foreign Organizations (Non-Domestic [non-U.S.] Entities)

NIH policies concerning grants to Foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

Applications from Foreign organizations must:

Request budgets in U.S. dollars;
Prepare detailed budgets for all applications (that is, complete the Research & Related Budget component of the SF424 (R&R) application forms not the PHS398 Modular Budget component)(see NOT-OD-06-096);
Not include any charge-back of customs and import fees;
Comply with the format specifications, which are based upon a standard U.S. paper size of 8.5 x 11 within each PDF;
If appropriate, request funds for up to 8% administrative costs (excluding equipment) (see NOT-OD-01-028, March 29, 2001);
Comply with Federal/NIH policies on human subjects, animals, and biohazards; and
Comply with Federal/NIH biosafety and biosecurity regulations (see Section VI.2., Administrative and National Policy Requirements).

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States (U.S.) or that augment existing U.S. resources.

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs

When multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the "Contact PI, who will be responsible for all communication between the PDs/PIs and the NIH, for assembling the application materials outlined below, and for coordinating progress reports for the project. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PDs/PIs, but has no other special roles or responsibilities within the project team beyond those mentioned above.

Information for the Contact PD/PI should be entered in Item 13 of the SF424 (R&R) Cover component.All other PDs/PIs should be listed in the Research & Related Senior/Key Person component and assigned the project role of PD/PI.Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission.The Commons ID of each PD/PI must be included in the Credential field of the Research & Related Senior/Key Person component.Failure to include this data field will cause the application to be rejected.

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

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled Multiple PD/PI Leadership Plan, must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts.The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators.

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award (NoA).

Applications Involving a Single Institution

When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.

Applications Involving Multiple Institutions

When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a subcontract to be administered by the prime institution. When submitting a detailed budget, the prime institution should submit its budget using the Research & Related (R&R) Budget component.All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form.See Section 4.8 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form.

When submitting a modular budget, the prime institution completes the PHS398 Modular Budget component only.Information concerning the consortium/subcontract budget is provided in the budget justification. Separate budgets for each consortium/subcontract grantee are not required when using the Modular budget format. See Section 3.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.

3. Submission Dates and Times

See Section IV.3.A. for details.

3.A. Submission, Review, and Anticipated Start Dates
Opening Date: September 5, 2008 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): Not applicable
Application Due Dates: Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm
AIDS Application Due Dates: Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#AIDS
Peer Review Dates: Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Council Review Dates: Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Earliest Anticipated Start Dates: 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. Submitting an Application Electronically to the NIH

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

3.C. Application Processing

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

Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have 2 weekdays (Monday Friday, excluding Federal holidays) to view the application image to determine if any further action is necessary.

If everything is acceptable, no further action is necessary. The application will automatically move forward to the Division of Receipt and Referral in the NIH Center for Scientific Review (CSR) for processing after 2 weekdays, excluding Federal holidays.
Prior to the submission deadline, the AOR/SO can Reject the assembled application and submit a changed/corrected application within the 2-day viewing window. This option should be used if it is determined that some part of the application was lost or did not transfer correctly during the submission process, the AOR/SO will have the option to Reject the application and submit a Changed/Corrected application. In these cases, please contact the eRA Help Desk to ensure that the issues are addressed and corrected. Once rejected, applicants should follow the instructions for correcting errors in Section 2.12, including the requirement for cover letters on late applications. The Reject feature should also be used if you determine that warnings are applicable to your application and need to be addressed now. Remember, warnings do not stop further application processing. If an application submission results in warnings (but no errors), it will automatically move forward after 2 business days if no action is taken. Some warnings may need to be addressed later in the process.
If the 2-day window falls after the submission deadline, the AOR/SO will have the option to Reject the application if, due to an eRA Commons or Grants.gov system issue, the application does not correctly reflect the submitted application package (e.g., some part of the application was lost or didnt transfer correctly during the submission process). The AOR/SO should first contact the eRA Commons Helpdesk to confirm the system error, document the issue, and determine the best course of action. NIH will not penalize the applicant for an eRA Commons or Grants.gov system issue.
If the AOR/SO chooses to Reject the image after the submission deadline for a reason other than an eRA Commons or Grants.gov system failure, a changed/corrected application still can be submitted, but it will be subject to the NIH late policy guidelines and may not be accepted. The reason for this delay should be explained in the cover letter attachment.
Both the AOR/SO and PD/PI will receive e-mail notifications when the application is rejected or the application automatically moves forward in the process after 2 days.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Incomplete applications will not be reviewed.

There will be an acknowledgement of receipt of applications from Grants.gov and the Commons . The submitting AOR/SO receives the Grants.gov acknowledgments. The AOR/SO and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific Review Group is also in the Commons.

Note: Since email can be unreliable, it is the responsibility of the applicant to check periodically on the application status in the Commons.

The NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. However, the NIH will accept a resubmission application, but such application must include an Introduction addressing the critique from the previous review.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable. A grantee may, at his/her 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 renewal award if such costs: 1) are necessary to conduct the project; and 2) 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 renewal award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved timeframe or in any way adversely affect the conduct of the project (see the NIH Grants Policy Statement).

6. Other Submission Requirements and Information

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

The NIH requires the PD(s)/PI(s) to fill in his/her Commons User ID in the PROFILE Project Director/Principal Investigator section, Credential log-in field of the Research & Related Senior/Key Person Profile component.

Organizational DUNS

The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

PHS398 Research Plan Component Sections

All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating "Just-in-Time" information concepts, and with the following additional requirements:

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 (excluding consortium F&A costs) must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as plans are being developed for the study;

2) Obtain agreement from the IC staff that the IC will accept the 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 new, renewal, revision, or resubmission applications. See NOT-OD-02-004, October 16, 2001.

Appendix Materials

Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (see http://grants.nih.gov/grants/funding/424/index.htm). Also see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-018.html.

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

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value and further the advancement of the research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in the Resource Sharing section of the application (see http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.)

(a) Data Sharing Plan: Regardless of the amount requested, investigators are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact (see Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.)

(b) Sharing Model Organisms: Regardless of the amount requested, all applications in which the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible (see Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.)

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (e.g., blood pressure or weight) or the presence or absence of a disease or condition. For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (NOT-OD-07-088) and http://grants.nih.gov/grants/gwas/.

Foreign Applications (i.e., those from Non-Domestic [non-U.S.] Entities)

Indicate how the proposed project has specific relevance to the mission and objectives of the NIH/IC and has the potential for significantly advancing the health sciences in the United States.

Section V. Application Review Information

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

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

2. Review and Selection Process

Applications submitted for this funding opportunity will be assigned on the basis of established PHS referral guidelines to the NIH institutes and centers for funding consideration.

Applications that are complete will be evaluated for scientific and technical merit by (an) appropriate scientific review group(s) in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/) using the review criteria stated below.

As part of the scientific peer review, all applications will:

Undergo a selection process in which only those applications deemed to have the highest scientific and technical merit, generally the top half of applications under review, will be discussed and assigned an impact/priority score;
Receive a written critique; and
Receive a second level of review by the appropriate national advisory council or board.

Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following items will be considered in making funding decisions:

Scientific and technical merit of the proposed project as determined by scientific peer review;
Availability of funds; and
Relevance of the proposed project to program priorities.

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, and weighted 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 meritorious impact/priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Overall Impact. Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following five core review criteria, and additional review criteria (as applicable for the project proposed).

Core Review Criteria. Reviewers will consider each of the five review criteria below in the determination of scientific and technical merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance: Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s): Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation: Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach: Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?
If the project involves clinical research, are the plans for 1) Protections for Human Subjects, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? For applications designating multiple PDs/PIs, is the leadership approach, including the designated roles and responsibilities, governance, and organizational structure, consistent with and justified by the aims of the project and the expertise of each of the PDs/PIs?

Environment: Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

2.A. Additional Review Criteria

As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

Protections for Human Subjects. For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials.

Inclusion of Women, Minorities, and Children. When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

Vertebrate Animals. The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia.

Resubmission Applications. When reviewing a Resubmission application (formerly called an amended application), the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewal Applications. When reviewing a Renewal application (formerly called a competing continuation application), the committee will consider the progress made in the last funding period.

Revision Applications. When reviewing a Revision application (formerly called a competing supplement application), the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

Biohazards. Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Additional Review Considerations

As applicable for the project proposed, reviewers will address each of the following items, but will not give scores for these items and should not consider them in providing an overall impact/priority score.

Budget and Period Support. Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Select Agents Research. Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Applications from Foreign Organizations. Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Resource Sharing Plans. Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan (http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

3. Anticipated Announcement and Award Dates

Not applicable.

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the NIH eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Section IV.5., Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

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 (program); peer review; and financial or grants management issues.

1. Scientific/Research Contact(s):

Young S. Kim, Ph.D.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room 3156, MSC 7328
Bethesda, MD 20892-7328 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-0126
Fax: (301) 480-3925
Email: [email protected]

T. Kevin Howcroft, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, EPN Room 5060, MSC 7388
Bethesda, MD 20892- 7388 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-7815
Fax: (301) 480-2844
Email: [email protected]

2. Peer Review Contact(s):

Not applicable.

3. Financial/Grants Management Contact(s):

Jane Paull
Office of Grants Administration
National Cancer Institute
6120 Executive Boulevard, EPS Room 243, MSC 7150
Bethesda, MD 20892-7150 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-2182
FAX: (301) 496-8601
E-mail: [email protected]

Section VIII. Other Information

Required Federal Citations

Vertebrate Animals:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45 CFR 46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (Phase I); efficacy studies (Phase II); 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 (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (e.g., blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time, the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh-Dole Act (see the NIH Grants Policy Statement). Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

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.

Inclusion of Women, Minorities, and Children:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the SF424 (R&R) application; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for Federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-09-116.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.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy, investigators funded by the NIH must submit or have submitted for them to the National Library of Medicines PubMed Central (see http://www.pubmedcentral.nih.gov/), an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made publicly available no later than 12 months after the official date of publication. The NIH Public Access Policy is available at (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html). For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (HHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information," the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the HHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, Internet addresses (URLs) or PubMed Central (PMC) submission identification numbers must be used for publicly accessible on-line journal articles.Publicly accessible on-line journal articles or PMC articles/manuscripts accepted for publication that are directly relevant to the project may be included only as URLs or PMC submission identification numbers accompanying the full reference in either the Bibliography & References Cited section, the Progress Report Publication List section, or the Biographical Sketch section of the NIH grant application. A URL or PMC submission identification number citation may be repeated in each of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.

Healthy People 2010:
The U.S. Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at 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. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Program:
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 Loan Repayment Program (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 2 years to the research. For further information, please see http://www.lrp.nih.gov/.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices