Part I Overview Information
Update: The following update relating to this announcement has been issued:
Program Announcement (PA) Number: PA-06-289
Catalog of Federal Domestic Assistance Number(s)
Release Date: March 29, 2006
Application Submission Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.
Peer Review Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details
Council Review Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details
Earliest Anticipated Start Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details
Additional Information To Be Available Date (URL Activation Date): Not applicable
Expiration Date for R01 Non-AIDS Applications: November 2, 2006
Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 2007
This Funding Opportunity Announcement (FOA) research project (R01) grant applications from researchers interested in the investigations of two aspects of gastrointestinal carcinogenesis: (i) the roles of the mucosal immune system in initiating and maintaining inflammatory responses that contribute to the development of pre-malignant and malignant gastrointestinal cancers; and/or (ii) the molecular mechanism(s) by which immunoregulatory cells dampen inflammation and decrease tumorigenesis. Applications submitted in response to this FOA should be focused on research that will increase our understanding of how the unique gastrointestinal microenvironment shapes mucosal immune responses in the setting of inflammatory disease-associated carcinogenesis. The ultimate goal of this scientific initiative is to generate a comprehensive understanding of how the innate and adaptive immune responses participate in gastrointestinal carcinogenesis.
Table of Contents
1. Research Objectives
This funding opportunity is focused on the roles of the mucosal immune system in initiating and maintaining inflammatory responses leading to the development of pre-malignant and malignant gastrointestinal cancers. Innovative research efforts prompted by this FOA are expected to: (1) identify how the unique gastrointestinal microenvironment shapes mucosal immune responses leading to a better understanding of inflammatory disease-associated gastrointestinal carcinogenesis; and (2) determine the mechanism(s) by which immunoregulatory cells (from either innate or adaptive immune systems) dampen inflammation and decrease tumorigenesis. Ultimately, the goal is to generate a comprehensive understanding of how the innate and adaptive immune responses participate in gastrointestinal carcinogenesis.
Gastrointestinal cancers are among the most prevalent cancers worldwide, with colorectal cancer representing the third-most common cancer in the United States. The gastrointestinal epithelium serves both as an absorptive surface for the uptake of nutrients and as a barrier between the body and the complex microbiota of the gut lumen. By adulthood, the lower gastrointestinal tract harbors approximately 1014 viable bacteria consisting of an estimated 500-1000 different microbial species. In order to maintain an intact barrier, the intestinal epithelium is constantly renewed on a massive scale; new cells, generated by multipotent stem cells in the crypts, repopulate the villi every few days. The host immune system, including both its innate and adaptive components, is also well represented in the gastrointestinal mucosa and provides immune surveillance against environmental threats that pass through or reside in the gut lumen. A remarkable 50-70 percent of all immune cells in the body reside in the gastrointestinal mucosa and epithelial cell layer underscoring the essential role of immunosurveillance in gastrointestinal homeostasis. Numerous studies have confirmed that the gut microflora is necessary for normal gastrointestinal development, as well as the maturation and function of the mucosal and systemic immune systems.
Association between Chronic Inflammation and Cancer. Dynamic interactions between the gastrointestinal epithelium, the commensal microflora of the gut and the mucosal immune system contribute to ensure intestinal homeostasis and proper immunosurveillance. Subversion of these interactions can lead to the development of chronic inflammatory diseases and cancer. However, the precise mechanisms by which the gut microbiota influences innate and adaptive mucosal immune responses leading to chronic inflammatory disease and gastrointestinal carcinogenesis are still poorly understood. Similarly, the various mechanisms by which the mucosal immune system initiates, responds to, and regulates chronic inflammation and the relevance of these mechanisms to carcinogenesis have not been fully elucidated.
Several lines of evidence that implicate chronic inflammation of the gastrointestinal mucosa as a significant predisposing factor for developing cancer include the following observations: (1) cancer risk is proportional to both the duration and extent of inflammation; (2) inflammation-associated genes cyclooxygenase-2 (COX-2) and nitric oxide synthease-2 (NOS-2) are increased in inflamed mucosa and remain elevated in colorectal cancers; (3) non-steroidal anti-inflammatory drugs (NSAIDs) reduce cancer risk in the setting of inflammatory bowel disease; and (4) infection with Helicobacter pylori, a major human pathogen, initiates chronic inflammation that has convincingly been linked to the development of gastric cancer. Chronically inflamed mucosa and the associated extensive re-epithelialization (that occurs in response to ulcerative damage) are thought to create a microenvironment that promotes the carcinogenic process. The ability of immune cells of both the innate and adaptive immune systems to initiate and regulate inflammatory responses is a critical aspect of this association that has not been fully explored. Understanding how distinct immune cell populations integrate their immunosurveillance activities with the mucosal epithelia to maintain homeostasis and how these processes become deregulated leading to inflammatory disease and carcinogenesis are areas of high interest to the cancer research community.
The Innate Immune System. Recent findings have led some researchers to suggest that the innate immune system plays a critical role in gastrointestinal carcinogenesis. The innate immune system initiates inflammatory responses largely through the secretion of cytokines, chemokines, and other bioactive molecules. Cells of the innate immune system include myeloid lineage cells, such as macrophages, dendritic cells, mast cells, and neutrophils. Innate lymphocyte populations include natural killer, natural killer T (NKT) and gd T cells that are found dispersed throughout the lamina propria and epithelial cell border. A recent study demonstrated that, in response to mucosal injury and subsequent exposure to the gut microbiota, cells of the innate immune system become activated and produce cytokines that support aberrant epithelial cell survival in chronically inflamed tissues. When innate immune cells were genetically modified to be unable to respond to activation stimuli, tumor incidence was decreased by half, thereby establishing a direct link between immune-mediated inflammatory responses and tumorigenesis. Furthermore, NKT cells have been reported to either upregulate or downregulate inflammatory and/or anti-tumor immune responses. Understanding how innate inflammatory immune responses contribute to cancer progression is a critically important area in cancer research.
Inflammation attributable to innate immune responses is modulated by both commensal and pathogenic enteric bacteria. Integral to intestinal homeostasis and host defense in the gut epithelium are pattern recognition receptors, both Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (Nod) molecules. Engagement of TLRs or Nods by their cognate ligands activates pro-inflammatory and pro-angiogenic gene expression leading to a chronic inflammatory microenvironment favorable to cancer progression. Identifying how the gastrointestinal microbiota affects innate immune responses and the relevance of those responses to cancer progression is an important research goal.
The Adaptive Immune System. Protective mucosal immune responses in the gut are generated in secondary lymphoid organs, such as Peyer’s patches, cryptopatches, and mesenteric lymph nodes. Recently, tertiary lymphoid organs (TLOs) have also been identified in various mucosal tissues. TLOs are organized immune structures, similar to lymph nodes, that dynamically arise in chronically inflamed mucosal tissues. These organized lymphoid structures likely optimize host immune responses, but may also provide microenvironments that promote the formation of tumors such as mucosal-associated lymphoid tissue (MALT) lymphoma. Given that chronic inflammation is a major cancer risk factor, understanding the role of TLOs in anti-tumor immune responses and tumorigenesis may be critical to support the development of anti-cancer immunotherapies.
Cells of the adaptive immune system, both T and B lymphocytes, also play a significant role regulating mucosal immune responses in the gut. These cells types have been observed to either promote or inhibit tumor progression. Several reports have provided evidence that elimination of either T or B lymphocytes reduces chronic inflammatory responses and decreases tumor incidences in animal models. A large number of T lymphocytes, mostly CD4+, reside in the lamina propria. Although the effects of CD4+ T lymphocytes on inflammation and cancer are only now being investigated, these cells have been shown in a mouse model to be required for the Helicobacter pylori initiated chronic gastritis and its progression to adenoma. These and other data indicate that chronic inflammatory responses that facilitate cancer emergence and progression may involve cells from both innate and adaptive immune responses.
Whereas adaptive immune cells participate in initiating inflammation, these cells can also play the opposite role in regulating chronic inflammation and tumor progression. For example, CD4+CD25+ T regulatory (Treg) cells have been reported to prevent colitis-associated colon cancer in Rag-deficient mice challenged with the pathogen Helicobacter hepaticus. Moreover, Treg cells also inhibited by 90 percent the development of intestinal tumors in ApcMin/+ mice, a widely used animal model for the study of human colorectal carcinogenesis. These findings clearly demonstrate the potential of Treg cells to attenuate cancer progression. This property is thought to reflect the ability of Treg cells to decrease immune cell activation by the release of the inhibitory cytokines, IL10 and TGF- . Furthermore, Treg cells can dampen inflammatory immune responses initiated by either innate or adaptive immune systems. In addition, mesenteric lymph node B lymphocytes also have been reported to down-regulate CD4+-dependent colitis in mice by expanding a population of immunoregulatory NKT cells. Taken together, these findings indicate there is extensive crosstalk between cells of the innate and adaptive immune systems. Further, investigations to determine whether lymphocytes of the adaptive immune response can be harnessed to regulate innate immune responses to gastrointestinal microbiota and to prevent chronic inflammatory disease and cancer progression may lead to improved immunotherapies and are thus highly warranted.
Objectives and Scope.
This funding opportunity is intended to promote research that will lead to advances in our understanding of the two opposite roles of the mucosal immune system in gastrointestinal carcinogenesis: (1) in initiating and maintaining inflammation associated with the development of pre-malignant and malignant cancers and (2) in immunoregulatory processes that attenuate inflammation and decrease tumorigenesis.
Grant applications submitted in response to this FOA should be focused on understanding how the unique gastrointestinal microenvironment shapes mucosal responses in the setting of cancer-related inflammatory diseases. The ultimate goal of this scientific initiative is to elucidate how the innate and adaptive immune responses participate in gastrointestinal carcinogenesis. It is anticipated that these studies will ultimately inspire improved approaches to enhancing anti-tumor immune responses in humans.
The following topics exemplify research areas of high interest, but other relevant innovative projects are also encouraged.
? Define how interactions between innate immune cell populations and host enteric microbiota shape mucosal immunosurveillance and chronic inflammatory responses that that facilitate gastrointestinal cancer development. Identification of mechanisms through which pattern recognition receptors such as TLRs, NODs, or others contribute to inflammation and cancer development would be considered appropriate.
? Identify immune cell surface or secreted signal transduction molecules associated with distinct inflammatory phenotypes in gastrointestinal mucosal tissues, and define their relationship to tumor progression.
? Identify immune cell interactions, cytokines, and other factors that contribute to tertiary lymphoid organ development and define the role of tertiary lymphoid tissues in anti-tumor immune responses or as microenvironments conducive for lymphoma development.
? Identify immunoregulatory cell populations (including, but not limited to, T and B lymphocytes, NKT cells, dendritic cells and macrophage) that have the ability to dampen gastrointestinal chronic inflammation and decrease tumor incidence. Define the molecular mechanism(s) underlying these effects.
? Examine the role of cancer-modulating factors, such as dietary components, in the regulation of immune and/or inflammatory responses occurring in the gastrointestinal mucosa relevant to tumor formation.
Note: Applications not directly related to carcinogenesis or tumor progression will be considered unresponsive to this FOA and will be returned to applicants without being peer reviewed.
Who should consider this FOA? Since this FOA uses the traditional research project grant R01 mechanism, applicants are expected to have already accumulated significant preliminary data. Potential applicants who would like to propose exploratory research projects that may involve considerable risk but may have a major impact on the field should consider a partner FOA of the same title (PA-06-290) and scientific scope that uses the R21 funding mechanism. Extensive preliminary data are not required for the R21 mechanism.
VIII, Other Information - Required Federal Citations, for policies related
to this announcement.
Section II. Award Information
1. Mechanism(s) of Support
This funding opportunity will use the NIH investigator-initiated research project grants (R01) award mechansim.
As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.
This funding opportunity uses just-in-time concepts. It also uses the modular as well as the non-modular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format described in the PHS 398 application instructions. Otherwise follow the instructions for non-modular research grant applications.
2. Funds Available
No set-aside funds are available for this funding opportunity. Applicants may request up to 5 years of support for R01 awards with costs appropriately tailored to the proposed work. No limit is set on the costs requested by R01 applicants. The request should be tailored to the needs of the project. 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 and the receipt of a sufficient number of meritorious applications.
Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.
Section III. Eligibility Information
1. Eligible Applicants
1.A. Eligible Institutions
You may submit (an) application(s) if your organization has any of the following characteristics:
Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.
2. Cost Sharing or Matching
This program does not require cost sharing. The most current Grants Policy Statement can be found at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing
3. Other-Special Eligibility Criteria
Section IV. Application and Submission Information
1. Address to Request Application Information
The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.
Telecommunications for the hearing impaired: TTY 301-451-5936.
2. Content and Form of Application Submission
Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.
The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.
Several special provisions apply to applications submitted by foreign organizations:
research should provide a unique research opportunity not available in the U.S.
3. Submission Dates and Times
See Section IV.3.A for details.
3.A. Submission, Review and Anticipated Start Dates
Letter of Intent Receipt Date: not applicable
Application Submission Date(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
Peer Review Date(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
Council Review Date(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
Earliest Anticipated Start Date(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
3.A.1. Letter of Intent
A letter of intent is not required for the funding opportunity.
3.B. Sending an Application to the NIH
Applications must be prepared using the research grant application forms found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).
3.C. Application Processing
Applications must be submitted on or before the application receipt/submission dates described above (Section IV.3.A.) and at http://grants.nih.gov/grants/dates.htm. Upon receipt applications will be evaluated for completeness by CSR. Incomplete applications will not be reviewed.
The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique.
Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.
4. Intergovernmental Review
This initiative is not subject to intergovernmental review.
5. Funding Restrictions
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.
Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.
The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/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:
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
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.
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.
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
Only the review criteria described below will be considered in the review process.
2. Review and Selection Process
Applications submitted for this funding opportunity will be assigned to the ICs on the basis of established PHS referral guidelines.
Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit.
As part of the initial merit review, all applications will:
The following will be considered in making funding decisions:
goals of NIH supported research are to advance our understanding of biological
systems, to improve the control of disease, and to enhance health. In their
written critiques, reviewers will be asked to comment on each of the following
criteria in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals. Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application. Note that an application does not need to be
strong in all categories to be judged likely to have major scientific impact
and thus deserve a high priority score. For example, an investigator may
propose to carry out important work that by its nature is not innovative but is
essential to move a field forward.
Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Approach: Are the conceptual or
clinical framework, design, methods, and analyses adequately developed, well
integrated, well reasoned, and appropriate to the aims of the project? Does the
applicant acknowledge potential problem areas and consider alternative tactics?
Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?
Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?
Environment: Does the scientific
environment in which the work will be done contribute to the probability of
success? Do the proposed studies benefit from unique features of the scientific
environment, or subject populations, or employ useful collaborative
arrangements? Is there evidence of institutional support?
2.A. Additional Review Criteria:
In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:
Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).
Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).
Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.
Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.
2.B. Additional Review Considerations
Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.
2.C. Sharing Research Data
Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data 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. Program staff will be asked to assess the adequacy of the data sharing plan.
2.D. Sharing Research
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://ott.od.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible. Program staff will be responsible for the administrative review of the plan for sharing research resources.
The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.
3. Anticipated Announcement and Award Dates
Section VI. Award Administration Information
1. Award Notices
After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.
If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.
Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.
2. Administrative and National Policy Requirements
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/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).
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
Kevin Howcroft, Ph.D.
Cancer Immunology and Hematology Branch
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, EPN Room 5060
Bethesda, MD 20892-7388 (for U.S. Postal Service express or regular delivery)
Rockville, MD 20852 (for express/courier delivery)
For specific inquiries concerning the appropriateness of Helicobacter-related research projects:
Phillip J. Daschner, M.S.
Cancer Etiology Branch
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, EPN Room 5014
Bethesda, MD 20892-7398 (for U.S. Postal Service express or regular delivery)
Rockville, MD 20852 (for express/courier delivery)
For specific inquiries concerning the appropriateness of research projects investigating cancer modulating factors such as diet:
S. Kim, Ph.D.
Nutritional Science Research Group
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, ERN Room 3156
Rockville, MD 20892
Rockville, MD 20852 (Express/Courier Service)
Telephone: (301) 496-0126
Fax: (301) 480-3925
2. Peer Review Contacts:
3. Financial or Grants Management Contacts:
Leslie N. Hickman
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, EPS Room 234. MSC 7148
Bethesda, MD 20892-7150 (for U.S. Postal Service express or regular delivery)
Rockville, MD 20852 (for express/courier delivery)
Telephone: (301) 496-7800
FAX: (301) 846-5720
Required Federal Citations
Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.
Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).
Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).
Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.
Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.
Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.
Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.
Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.
All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).
Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov/). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.
NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov/) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.
NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.
For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).
Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).
Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.
URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.
Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.
Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.
The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov/.
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