and Human Services (HHS)
EXPIRED
Department
of Health and Human Services
Participating
Organizations
National
Institutes of Health (NIH), (http://www.nih.gov)
Components of
Participating Organizations
National
Cancer Institute (NCI), (http://www.nci.nih.gov/)
Title: Immunoregulation of Gastrointestinal Carcinogenesis
(R21)
Announcement Type
New
Update: The following update relating to this announcement has been issued:
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 weeks prior to the grant submission date. See Section IV.
Two steps are required for on time submission:
1) The application must be successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization) on the submission/receipt date (see Key Dates below).
2) Applicants must complete a verification step in the eRA Commons within two business days of notification from NIH. Note: Since email can be unreliable, it is the responsibility of the applicant to periodically check on their application status in the Commons.
Program Announcement (PA) Number: PA-06-290
Catalog of Federal
Domestic Assistance Number(s)
93.393, 93.396
Key Dates
Release/Posted Date: March 29, 2006
Opening
Date: May 2, 2006 (earliest date an
application may be submitted to Grants.gov).
Letters of Intent Receipt Date(s): Not
applicable.
Application Submission Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward.
AIDS Application Submission Dates(s): Not
Applicable
Peer Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward.
Council Review Date(s): Standard dates apply,
please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward.
Earliest Anticipated Start Date(s): Standard
dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward.
Additional Information To Be Available Date
(Activation Date): Not Applicable
Expiration Date: March 2, 2009. (now May 8, 2009 per NOT-OD-07-093)
Due Dates for E.O. 12372
Not Applicable.
Additional
Overview Content
Executive Summary
This Funding Opportunity Announcement (FOA) solicits innovative Exploratory/Developmental (R21) 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.
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. Submission, Review, and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements
Section V. Application Review
Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates
Section VI. Award Administration
Information
1. Award Notices
2. Administrative and National Policy Requirements
3. Reporting
Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/Grants Management Contact(s)
Section VIII. Other Information
- Required Federal Citations
Part II
- Full Text of Announcement
Section I. Funding Opportunity Description
1.
Research Objectives
Purpose
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.
Background
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-b. 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? 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 this FOA, which uses the R21 funding mechanism. Extensive preliminary data are not required for the R21 mechanism. Applicants who have already accumulated significant preliminary results may consider the partner FOA of the same title (PA-06-289) and scientific scope that uses the R01 mechanism to support conventional research project grants.
The R21 mechanism is intended to encourage new exploratory and developmental research projects. For example, such projects could assess the feasibility of a novel area of investigation or a new experimental system that has the potential to enhance health-related research. Another example could include the unique and innovative use of an existing methodology to explore a new scientific area. These studies may involve considerable risk, but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, and/or applications that could have a major impact on a field of biomedical, behavioral, and/or clinical research.
Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. For example, long-term projects, or projects designed to increase knowledge in a well-established area, will not be considered for R21 awards. Applications submitted under this mechanism should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications.
See Section VIII, Other Information - Required Federal Citations for policies related to this announcement.
Section II. Award Information1.
Mechanism of Support
This FOA will use the NIH Exploratory/Developmental Research Grant (R21) award mechanism. As an
applicant, you will be solely responsible for planning, directing, and
executing the proposed project.
This FOA uses just-in-time concepts. It also uses the modular budget formats (see the Modular Applications and Awards section of the NIH Grants Policy Statement. Specifically, if you are submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs), use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide (see specifically Section 5.4, Modular Budget Component, of the Application Guide).
Exploratory/developmental grant support is for new projects only; competing renewal (formerly competing continuation ) applications will not be accepted. Up to two resubmissions (formerly revisions/amendments") of a previously reviewed exploratory/developmental grant application may be submitted. See NOT-OD-03-041, May 7, 2003.
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 and the submission of
a sufficient number of meritorious applications.
The total project period for an application submitted in response to this funding opportunity may not exceed 2 years. Although the size of award may vary with the scope of research proposed, it is expected that applications will stay within the budgetary guidelines for an exploratory/developmental project; direct costs are limited to $275,000 over an R21 2-year period, with no more than $200,000 in direct costs allowed in any single year. Applicants may request direct costs in $25,000 modules, up to the total direct costs limitation of $275,000 for the combined two-year award period. NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this Program Announcement funding opportunity.
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
You may submit an
application(s) if your organization has any of the following characteristics:
1.B. Eligible Individuals
Any
individual with the skills, knowledge, and resources necessary to carry out the
proposed research as the Project Director/Principal Investigator (PD/PI) is
invited to work with his/her 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.
2. Cost Sharing or
Matching
Not applicable. This program does not require
cost sharing as defined in the current NIH
Grants Policy Statement.
3. Other-Special
Eligibility Criteria
Applicants may submit more than one application, provided
each application is scientifically distinct.
To download a SF424
(R&R) Application Package and SF424 (R&R) Application Guide for
completing the SF424 (R&R) forms for this FOA, 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:
PDs/PIs should work with their institutions/organizations to make sure they are registered in the eRA Commons.
Several additional separate actions are required before an applicant institution/organization can submit an electronic application, as follows:
1) Organizational/Institutional Registration in Grants.gov/Get Started
2) Organizational/Institutional Registration in the eRA Commons
3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.
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 4 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 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 (MS Word or PDF).
The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. There are fields within the SF424 (R&R) application components that, 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/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see Tips and Tools for Navigating Electronic Submission on the front page of Electronic Submission of Grant Applications.
The SF424 (R&R) application is comprised of data arranged in separate components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY will include all applicable components, required and optional. A completed application in response to this FOA will include 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
Optional Components:
PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s)
Form
Note: While both budget components are included in the SF424 (R&R) forms package, the NIH R21 uses ONLY the PHS 398 Modular Budget. (Do not use the detailed Research & Related Budget.)
Foreign
Organizations
Several special provisions apply to applications
submitted by foreign organizations:
Proposed research should
provide a unique research opportunity not available in the United States.
3. Submission Dates and
Times
See Section IV.3.A for details.
3.A.
Submission, Review, and Anticipated Start Dates
Opening Date: May 2, 2006 (earliest date an
application may be submitted to Grants.gov).
Application Submission
Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm
Peer Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Council Review Date(s): Standard dates apply, please
see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Earliest Anticipated Start Date(s): Standard dates
apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
3.A.1. Letter of Intent
A letter of intent is not required for the funding opportunity.
3.B. Sending an Application to the NIH
To submit an application in response to this FOA,
applicants should access this FOA via http://www.grants.gov/Apply 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
submission/receipt date(s). (See Section IV.3.A. for
all dates.) If an application is
not submitted by the receipt date(s) and time, the application may be delayed
in the review process or not reviewed.
Upon
receipt, applications will be transferred from Grants.gov to the NIH Electronic
Research Administration process for validation. Both the PD/PI and the SO for
the organization must verify the submission via Commons within 2 business days
of notification of the NIH validation.
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. Information related to the
assignment of an application to a Scientific Review Group is also 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. This does not preclude the submission of an application already reviewed with substantial changes, but such application must include an Introduction addressing the previous critique. Note such an application is considered a "resubmission" for the SF424 (R&R).
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
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 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 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 the NIH
Grants Policy Statement.
6. Other Submission
Requirements
The NIH requires the
PD/PI 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. 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 Tips and Tools
for Navigating Electronic Submission on the front page of Electronic
Submission of Grant Applications.
Renewal (formerly competing continuation or Type 2 ) applications are not permitted.
All application instructions outlined in the SF424 (R&R) application are to be followed, with the following requirements for R21 applications:
Note: While each section of the Research Plan needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.
Plan for Sharing Research Data
Data sharing plan is not required.
Sharing Research Resources
NIH policy requires that grant awardee recipients make
unique research resources readily available for research purposes to qualified
individuals within the scientific community after publication (see the NIH
Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131).
Investigators responding to this funding opportunity should include a sharing
research resources plan addressing how unique research resources will be shared
or explain why sharing is not possible.
The adequacy of the resources sharing plan 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). See Section VI.3.,
Reporting.
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 to the NIH 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:
Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:
The NIH R21 exploratory/developmental grant is a mechanism for supporting novel scientific ideas or new model systems, tools, or technologies that have the potential to significantly advance our knowledge or the status of health-related research. Because the Research Plan is limited to 15 pages, an exploratory/developmental grant application need not have extensive background material or preliminary information as one might normally expect in an R01 application. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will place less emphasis on methodological details and certain indicators traditionally used in evaluating the scientific merit of R01 applications, including supportive preliminary data. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.
The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application.
Note
that an application does not need to be strong in all categories to be judged likely
to have major scientific impact and thus deserve a high priority score. For
example, an investigator may propose to carry out important work that by its
nature is not innovative but is essential to move a field forward.
Significance: Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge or clinical
practice be advanced? What will be the effect of these studies on the concepts,
methods, technologies, treatments, services, or preventative interventions that
drive this field?
Approach: Are the conceptual or clinical framework, design, methods,
and analyses adequately developed, well integrated, well reasoned, and
appropriate to the aims of the project? Does the applicant acknowledge potential
problem areas and consider alternative tactics?
Innovation: Is the project original and innovative? For example: Does
the project challenge existing paradigms or clinical practice; address an
innovative hypothesis or critical barrier to progress in the field? Does the
project develop or employ novel concepts, approaches, methodologies, tools, or
technologies for this area?
Investigators: Are the investigators appropriately trained and well suited
to carry out this work? Is the work proposed appropriate to the experience
level of the PD/PI 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 item 6 of the
Research Plan component of the SF424 (R&R).
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 item 7 of the Research Plan component of the SF424
(R&R).
Care and Use of Vertebrate Animals in
Research: If vertebrate animals are to
be used in the project, the five items described under item 11 of the Research
Plan component of the SF424 (R&R) 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 and Period of Support: The reasonableness of the proposed budget and the
appropriateness of the requested period of support in relation to the proposed
research may be assessed by the reviewers. Is the percent effort listed for the
PD/PI appropriate for the work proposed? Is each budget category realistic and
justified in terms of the aims and methods?
2.C.
Sharing Research Data
Not applicable.
2.D.
Sharing Research Resources
NIH
policy requires that grant awardee recipients make unique research resources
readily available for research purposes to qualified individuals within the
scientific community after publication (see the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131).
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 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), See Section VI.3.,
Reporting.
3. Anticipated
Announcement and Award Dates
Not
Applicable.
Section VI. Award Administration Information
1.
Award Notices
After the peer review of the application is
completed, the PD/PI will be able to access
his or her Summary Statement (written critique) via the 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 Grant
Progress Report (PHS 2590) annually and financial statements as required in
the NIH
Grants Policy Statement.
We
encourage your inquiries concerning this funding opportunity and welcome the
opportunity to answer questions from potential applicants. Inquiries may fall
into three areas: scientific/research, peer review, and financial or grants
management issues:
1. Scientific/Research
Contacts:
For general
inquires or specific inquiries concerning the appropriateness of research
projects investigating mucosal immune responses in gastrointestinal
carcinogenesis:
Kevin Howcroft, Ph.D.
Cancer
Immunology and Hematology Branch
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 express/courier
delivery)
Telephone:
301-496-7815
Fax:
301-480-2844
Email: [email protected]
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, MSC 7398
Bethesda, MD 20892-7398 (for U.S. Postal
Service express or regular mail)
Rockville, MD 20852 (for express/courier
delivery)
Telephone:
301-496-1951
Fax:
301-496-2025
Email: [email protected]
For specific inquiries concerning the appropriateness of research projects investigating cancer modulating factors such as diet:
Young
S. Kim, Ph.D.
Nutritional
Science Research Group
Division
of Cancer Prevention
National
Cancer Institute
6130
Executive Boulevard, ERN Room 3156, MSC 7362
Bethesda, MD 20892 (for U.S.
Postal Service express or regular mail)
Rockville, MD 20852 (for express/courier delivery)
Telephone:
(301) 496-0126
Fax:
(301) 480-3925
Email: [email protected]
2. Peer Review Contacts:
Not Applicable.
3.
Financial or Grants Management Contacts:
Dena Solomon
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 express/courier
delivery)
Telephone:
(301) 496-7208
FAX:
(301) 496-8601
Email: [email protected]
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 institutional
review board (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. 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.
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 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-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.
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 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 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 percent 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
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