and Human Services (HHS)
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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.cancer.gov)
Title: Diet-Induced Changes in
Inflammation as Determinants of Colon Cancer (R21)
Announcement Type
This is a reissue of PA-05-125, which was previously
released June 20, 2005.
Update: The following update relating to this announcement has been issued:
NOTICE: Applications submitted in response to this 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 4 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); and
2) Applicants must complete a verification step in the eRA Commons within 2 business days
of notification from NIH. Note: Since e-mail 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-06-283
Catalog of Federal Domestic Assistance Number(s)
93.393, 93.396
Key Dates
Release/Posted Date: March 28, 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): http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward.
AIDS Application Receipt Date(s): http://grants1.nih.gov/grants/funding/submissionschedule.htm#AIDS.
Peer Review Date(s): http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward.
Council Review Date(s): http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward.
Earliest Anticipated Start Date(s): http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward.
Additional Information To Be Available Date
(URL Activation Date): Not applicable.
Expiration Date: July 2, 2008 (now September 8, 2008 per NOT-OD-07-093)
Due Dates for E.O. 12372
Not Applicable.
Additional Overview
Content
Executive Summary
Inflammation is a natural response of the human body to tissue injury or infection, but can, in some abnormal conditions, be acute or chronic and result in serious complications, including colon cancer. The various checks and balances within the inflammatory process may be compromised by the quantity and duration of the insult, or by a host of genetic and environmental factors including diet. Several epidemiological and pre-clinical studies reveal that specific bioactive food components can suppress colonic inflammation as well as reduce colon cancer risk. Nevertheless, it remains unclear whether these diet-induced shifts in the inflammatory process account for their anti-tumorigenic properties in colon cancer. This FOA is designed to foster innovative research that will identify and characterize diet-induced changes in inflammation and colon cancer risk.
Table of Contents
Part I Overview Information
Part II Full Text of Announcement
Section I. Funding Opportunity
Description
1. Research Objectives
Section II. Award Information
1. Mechanism of Support
2. Funds Available
Section III. Eligibility
Information
1. Eligible Applicants
A. Eligible
Institutions
B. Eligible
Individuals
2. Cost Sharing or Matching
3. Other - Special Eligibility Criteria
Section IV. Application and
Submission Information
1. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Submission Review and Anticipated
Start Dates
1. Letter of Intent
B. Electronic Transmission of 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 and background
Colon cancer
remains a significant global health concern. It is the third most prevalent form
of cancer and the second leading cause of cancer deaths in the United States. The increased risk of developing colon cancer in patients with ulcerative
colitis and the observed benefits of anti-inflammatory drugs in retarding
intestinal tumors provide rather compelling evidence that inflammation is
involved with cancer at this site. Several epidemiological and pre-clinical
studies reveal that specific bioactive food components can suppress colonic
inflammation as well as reduce colon cancer risk. Nevertheless, it remains
unclear whether these diet-induced shifts in the inflammatory process account
for their anti-tumorigenic properties. This lack of mechanistic information
serves as the basis for this funding opportunity.
Diet and the Inflammatory
Process
Inflammation is a normal
response to tissue injury or infection, but can escape control and result in
serious complications, including cancer. The various checks and balances within
the inflammatory process may be compromised by the quantity and duration of the
insult, or a host of genetic and environmental factors. Dietary habits are likely
one of key determinants of the balance that influences the overall inflammatory
process. Genetic polymorphisms at multiple sites may alter this ability of
bioactive food components to influence the overall process by modulating pro-
and/or anti-inflammatory mediators.
The inflammatory process is
initiated by the synthesis and secretion of pro-inflammatory cytokines (e.g.,
tumor necrosis factor- a [TNF-a], interleukin-1 [IL-1], IL-6, IL-12,
and ?-interferon in macrophages) in response to an inflammatory insult.
The increased production of cytokines and the subsequent elevation in reactive
oxygen and nitrogen species are recognized hallmarks of inflammation. This
process is regulated by a negative feedback mechanism and closely followed by
the secretion of anti-inflammatory cytokines (e.g., IL-4, IL-10, and TGF- ) to
reduce the accumulation of reactive species. The cellular antioxidant defense
system is also activated to limit the development of chronic inflammation in
which the risk for cancer is much higher than normal.
The binding of pro-inflammatory cytokines to their receptors triggers the
mitogen-activated protein kinase (MAPK) pathway that ultimately results in the
activation of two redox-sensitive transcription factors, nuclear factor
?? (NF??) and the c-Jun part of activating protein-1
(AP-1). These transcription factors activate the expression of a wide variety
of genes including cytokines, chemokines, adhesion molecules, and inducible
effector enzymes such as inducible nitric oxide synthase (iNOS) and
cycloxygenase-2 (COX-2). The direct genetic evidence that COX-2 enzyme plays a
significant role in colon tumorigenesis arises from the marked reduction in
numbers of intestinal polyps occurring in the double mutant mice of COX-2 -/-
and Apc?716 as compared with COX-2 wild-type
animals. The unchecked activation of NF??/COX-2 and the inactivation
of TGF- signaling frequently occur in colon tumor cells. These findings
suggest that the loss of inflammatory balance between anti- and pro-mediators may
precipitate neoplastic transformation in the intestinal epithelium.
Evidence exists that selected dietary components including conjugated linoleic
acid (CLA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), butyrate,
(-)-epigallocatechin-3-gallate (EGCG), curcumin, resveratrol, genistein,
luteolin, quercetin, and vitamins A and D may influence the inflammatory
process at various sites and thus modulate the balance within the process. For
example, the concentration of TNF-a and IL-1 was reduced by more than 70
percent in humans consuming fish-oil rich in EPA and DHA. Likewise, a number of
dietary components, including resveratrol in red grapes, CLA in dairy products,
butyrate generated through the microbial metabolism of dietary fiber in colon,
and curcumin in curry spice, have been reported to suppress the TNF-a induced activation of NF-?B and COX-2 expression in vitro
and in vivo. The mechanisms by which these bioactive components influence
inflammation are not known with any high degree of clarity, but can involve
transport, activation, or inactivation processes. Resveratrol has been shown to
inhibit the translocation of NF-?B from the cytoplasm to the nucleus by
modulating the I?B kinase (IKK) activity in various cell types including
myeloid, lymphoid, and epithelial cells. Other food components, such as
curcumin, are recognized to block NF-?B activation. While these findings
are intriguing, it remains to be resolved if the effectiveness of these dietary
components exists at the site of inflammation in the colon with the
concentrations that are physiologically achievable.
Considerably more research is needed to characterize the physiological
significance of bioactive food components in inflammatory colonocytes in terms
of relative effectiveness, dose-dependence, temporality, consistency, and
specificity. Dietary components readily undergo various structural
modifications, such as methylation, glucuronidation, or sulfation, and are
further digested into small molecular weight metabolites that directly interact
with their target molecules. The function and stability of these metabolites
are known to be influenced by the cellular redox status. For example, the
ability of EGCG to inhibit cell growth is increased in the presence of
superoxide dismutase, an enzyme that reduces reactive oxygen species. These
changes are especially important in inflammatory sites where a flux of reactive
oxygen species removes potentially injurious substances. Knowledge about these
variables will help explain under what circumstances dietary components can
influence inflammatory processes and who might benefit most from intervention.
Genetic Polymorphisms,
Diet, and Colon Cancer Risk
It is well documented
that genetic polymorphisms that modulate the utilization of bioactive food
components provide important influence on colon cancer risks. For example, a
number of studies report that a preventive effect of broccoli on colon cancer
was observed only among subjects with the GSTM1 null genotype, suggesting that
genetic polymorphisms in GSTM1 genes may contribute to variations in response
to cruciferous vegetable intake. Likewise, a polymorphism (677 C T) in the 5,10-methylenetetrahydrofolate reductase (MTHFR)
gene that is critical in folate metabolism is associated with the increased
colon cancer risk in individuals with a marginal folate status. Thus, it is
possible that genetic polymorphisms associated with bioactive food components
may account for the variation in their ability to modify the inflammatory
process.
The production of inflammatory cytokines can vary widely among
healthy people due to a number of functional polymorphisms. For example,
individuals with TNF-a polymorphisms at nucleotides -238 (G A), -308 (G A), -857 (C T), and -859 (C T) are
associated with increased TNF-a as well as a greater susceptibility to
various cancers. Increased TNF-a can be down-regulated, admittedly with
considerable variability, by a number of bioactive food components including
DHA, EPA, and quercetin. While these findings suggest that genetic
polymorphisms in inflammatory mediators can alter the response to dietary
components in carcinogenesis, much more information is needed to clarify
interrelationships among genetics, diet, and inflammation in colon cancer
prevention.
Detectable Phenotypic
Changes Associated with Dietary Components in Inflammatory Colon Cancer Cells
Phenotypic changes
accompanying a shift in either anti- or pro-inflammatory components as a
function of eating behaviors need to be systematically evaluated. Preneoplastic
aberrant crypt foci (ACF), c-reactive protein (CRP), adenomatous polyposis coli
(APC) gene mutation, and -catenin expression may serve as useful early markers
for changes in colon cancer risk. ACF may be used as surrogate biomarkers for
detecting cancer preventive effects of anti-inflammatory dietary factors and
drugs (including curcumin, selenium, green tea, sulindac, celecoxib, or
indomethacin) against colon cancers in pre-clinical models. Recently, it has
been reported that the content of -catenin or mucin in the ACF is more
predictive of colon carcinogenesis than the number and size of the ACF. It
remains to be determined if ACF can serve as a marker for the inflammatory
alterations induced by dietary constituents.
CRP is an acute-phase
protein synthesized in liver and up-regulated by pro-inflammatory cytokines,
such as IL-6, IL-8, and TNF- a. Elevated levels of serum CRP were
associated with the subsequent development of colon cancer. In a recently
randomized controlled trial, circulating levels of CRP were shown to be
significantly reduced by the consumption of Mediterranean-style diet rich in
whole grains, fruits, vegetables, nuts, and olive oil. However, the mechanism
by which specific components of this type of diet can reduce CRP is unclear.
Undeniably, further research is needed to discover effective biomarkers to
assess dietary effects on the inflammation and colon cancer.
Animal Models Help
Characterize the Effects of Dietary Components on the Inflammation and Colon
Cancer
The recent development
of transgenic and knockout mice in IL-10, TGF- , iNOS, and SOCS3 genes, and
crossing experiments with existing colonic models such as APC?716 or multiple intestinal neoplasia (Min) has expanded our understanding of the
role that the inflammatory process plays in colon polyp formation. For example,
TGF- 1 deficiency in mice can lead to colon cancer that is preceded by
precancerous lesions having submucosal inflammation and hyperplastic crypts.
Similarly, IL-10 knockouts develop spontaneous intestinal colitis and often
express COX-2 in regions containing inflammatory cells. The iNOS null mice (iNOS-/-)
also manifest an attenuated colitis in response to injury. The appropriate
use(s) of these and other animal models should allow us to better understand
the physiological targets of diet in various stages of the inflammatory process
as well as how these events might be involved with colon cancer risk and tumor
behavior.
Objectives and Scope
The goal of this FOA
concept is to foster innovative research that will identify and characterize
diet-induced changes in inflammation linked with colon cancer risks. This FOA
does not encompass epidemiological studies. The purpose of this initiative is
to promote research to: 1) identify and characterize diet-induced changes in
anti- and pro-inflammatory mediators that modulate colon cancer risk; 2) define
genetic polymorphisms that modify the response to specific bioactive food
components with regard to colon cancer inhibition; and 3) unravel the
physiological effectiveness of dietary components in terms of concentration,
activity, duration of exposure, degree of stability, chemical forms, and
binding affinity to receptors in inflammatory colonocytes.
Investigators may choose from the full range of preclinical or clinical
approaches. The focus should be on defining the physiological significance of
diet in modulating inflammatory processes that may be linked to colon cancer
development. The use of animal models that have been genetically engineered to
influence inflammatory phenotypes in the intestine may be particularly useful
for gaining insights into the targets and potential dietary intervention
strategies for colon cancer prevention. A variety of genomic, proteomic, and
metabolomic technologies may be used. Since inflammatory processes can also be
influenced by post-translational mechanisms (e.g., protein-protein
interactions, modifications of protein activities through acetylation,
phosphorylation, and methylation, degradation by the ubiquitin-proteasome
mediated pathway), the profiling of proteins and/or metabolites in cells or
tissues should provide greater insight into the relevance of dietary treatments
to inflammatory processes on colon cancer.
The efficient utilization of molecular resources such as gene, protein, and
metabolome databases may be used to expedite research. Bioinformatic approaches
may also be necessary to identify patterns of gene, protein, and/or metabolite
changes that can generate unique fingerprints for the given dietary treatments.
Information about bioinformatics at NCI is available at http://ncicb.nci.nih.gov/.
Research topics that are relevant to this FOA include, but are not limited to,
the following examples:
See Section VIII, Other Information - Required Federal Citations for policies related to this announcement.
1. 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.
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.
Section
IV. Application and Submission Information
Registration and Instructions for Submission via Grants.gov
To download a SF424 (R&R) Application Package and SF424 (R&R)
SBIR/STTR Application Guide for completing the SF424 (R&R) forms for this
FOA, 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 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, E-mail: GrantsInfo@nih.gov.
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
Research & Related Budget
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
PHS398
Modular Budget
Optional Components:
PHS398 Cover Letter File
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
Date: May 2, 2006
Letter of Intent Receipt Date: Not applicable.
Application Submission Date(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
AIDS Application Submission Date(s): http://grants1.nih.gov/grants/funding/submissionschedule.htm#AIDS
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. Electronic
Transmission of 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
Not applicable.
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 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). See Section VI.3.,
Reporting.
Section V. Application Review Information
1. Criteria
Only the review criteria described below will be
considered in the review process.
2. Review and
Selection Process
Applications submitted for this funding
opportunity will be assigned to the 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.
Applications that are complete will be evaluated
for scientific and technical merit by an appropriate review group convened by the NIH Center for Scientific
Review in accordance with the review
criteria stated below.
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 SF 424 (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 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 plan for
sharing research resources 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
e-mail 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.
2.A. Cooperative
Agreement Terms and Conditions of Award
Not applicable.
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.
Section
VII. Agency Contacts
We encourage your inquiries
concerning this funding opportunity and welcome the opportunity to answer
questions from potential applicants. Inquiries may fall into three areas:
scientific/research, peer review, and financial or grants management issues.
1.
Scientific/Research Contacts:
Young S.
Kim, Ph.D.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room 3156, MSC 7328
Bethesda, MD 20892-7328 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for express/courier delivery)
Telephone: (301) 496-0126
FAX: (301) 480-3925
Email: yk47s@nih.gov
2. Peer
Review Contacts:
Not applicable.
3. Financial or
Grants Management Contacts:
Barbara
Liesenfeld
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)
Phone: 301-496-3265
FAX: 301-846-5720
Email: liesenfb@mail.nih.gov
Section VIII. Other Information
Required Federal
Citations
Use of Animals in Research:
Recipients of PHS support for activities involving
live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory
Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf)
as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm),
and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm)
as applicable.
Human Subjects Protection:
Federal regulations (45CFR46) require that
applications and proposals involving human subjects must be evaluated with
reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and others,
and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).
Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types
of clinical trials, including physiologic toxicity and dose-finding studies
(Phase I); efficacy studies (Phase II); and efficacy, effectiveness, and comparative
trials (Phase III). Monitoring should be commensurate with risk. The
establishment of data and safety monitoring boards (DSMBs) is required for
multi-site clinical trials involving interventions that entail potential risks
to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for
Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
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 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 at http://grants.nih.gov/grants/policy/nihgps_2003/index.htm).
All investigators submitting an NIH application or contract proposal, beginning
with the October 1, 2004, receipt date, are expected to include in the
application/proposal a description of a specific plan for sharing and
distributing unique model organism research resources generated using NIH
funding or state why such sharing is restricted or not possible. This will
permit other researchers to benefit from the resources developed with public
funding. The inclusion of a model organism sharing plan is not subject to a
cost threshold in any year and is expected to be included in all applications
where the development of model organisms is anticipated.
Inclusion of Women And Minorities in Clinical
Research:
It is the policy of the NIH that women and members of
minority groups and their sub-populations must be included in all NIH-supported
clinical research projects unless a clear and compelling justification is
provided indicating that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research. This policy results from the
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All
investigators proposing clinical research should read the "NIH Guidelines
for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH
definition of clinical research; updated racial and ethnic categories in
compliance with the new OMB standards; clarification of language governing
NIH-defined Phase III clinical trials consistent with the SF424 (R&R); 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
Web site (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 FOA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.
Authority and Regulations:
This program is described
in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive
Order 12372 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 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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