MECHANISMS OF ENVIRONMENTAL OXIDATIVE STRESS AND DIETARY MODULATION
Release Date: February 7, 2001
RFA: RFA-ES-01-004
National Institute of Environmental Health Sciences
(http://www.niehs.nih.gov)
National Institute of Diabetes and Digestive and Kidney Diseases
(http://www.niddk.nih.gov)
Letter of Intent Receipt Date: March 1, 2001
Application Receipt Date: April 16, 2001
PURPOSE
The purpose of this Request For Applications (RFA) is to stimulate and support
investigator-initiated research that will provide data to enhance our
understanding of the role of dietary modulators and nutritional factors in the
molecular control of reactive oxygen species in initiation and progression of
environmentally induced disease processes. Recent evidence has shown the
importance of nutrition in delaying the aging process and in protecting
against many degenerative and chronic diseases. Our growth in knowledge of
reactive oxygen species, oxidative damage, and the role that nutritional
antioxidants play in protection from this damage suggests that factors in our
diet can be effective in preventing or retarding the disease process. In
response to these findings, the National Institute of Environmental Health
Sciences (NIEHS) and the National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK) seek to stimulate research efforts aimed at enhancing
our understanding of the role of nutrition and diet in modifying, positively
or negatively, environmentally induced oxidative damage in the progression of
disease. Results of such investigations should clarify the cellular and
molecular mechanisms by which nutritional agents alter oxidative balance and
thereby prevent disease.
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 Request for Application (RFA),
Mechanisms of Oxidative Stress and Dietary Modulation, 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/
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of state and local governments, and eligible agencies of
the federal government. Foreign institutions are not eligible for RO3 grants.
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.
MECHANISM OF SUPPORT
This RFA will use the National Institutes of Health (NIH) small grants program
(RO3) award mechanism. Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant. The
total project period for an application submitted in response to this RFA may
not exceed two years. This RFA is a one-time solicitation. The anticipated
award date is September 2001.
FUNDS AVAILABLE
The National Institute of Environmental Health Sciences (NIEHS) intends to
commit up to $1.5 million in FY 2001 to fund approximately 20 new grants in
response to this RFA. The National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK) intends to commit $150,000 to fund approximately two
applications relevant to diseases within the mission of NIDDK. NIDDK has a
particular interest in the role of antioxidants in the prevention of diabetic
complications. An applicant may request a project period of up to two years
and a budget for direct costs of up to $50,000 per year. Because the nature
and scope of the research proposed may vary, it is anticipated that the size
of each award will also vary. Although the financial plans of the NIEHS and
NIDDK provide support for this program, awards pursuant to this RFA are
contingent upon the availability of funds and the receipt of a sufficient
number of meritorious applications.
RESEARCH OBJECTIVES
Background
The mission of the NIEHS is to reduce the burden of environmentally associated
diseases by defining how environmental exposures affect our health, how
individuals differ in their susceptibility to these exposures, and how these
susceptibilities change with age. Environmental health comprises those
aspects of human health, including quality of life, that are determined by
physical (ex: radiation), chemical (ex: pesticides), biological (ex: diet),
social and psychosocial factors (ex: socioeconomic status). It also refers to
the theory and practice of assessing, correcting, controlling and preventing
those factors in the environment that can potentially affect adversely the
health of present and future generations. Therefore, a major focus of NIEHS
is in the area of preventive research and medicine. The most effective way to
prevent disease is to understand the cause of an illness and then change the
condition that permits it to occur. Studies have shown that proper diet and
nutrition play a major role in an individual’s susceptibility to environmental
agents. For example, it has been shown that folic acid deficiency may be a
risk factor for the development of cancer. Folate deficiency leads to
chromosome breaks due to deficient methylation of cUMP to dTMP and subsequent
incorporation of uracil into DNA. Increasing folate in the diet inhibits DNA
uracil levels and chromosome breaks, thereby preventing disease. Additional
research has suggested that oxidative stress may contribute to diseases
associated with environmental exposures such as Parkinson’s disease. These
examples serve to highlight the importance of understanding the mechanisms by
which nutritional factors influence environmentally induced oxidative damage.
Reactive Oxygen Species (ROS) are produced during normal cellular function and
are generated as by-products of cellular metabolism, primarily in the
mitochondria. ROS include hydroxyl radicals (OH), superoxide anion (O2-),
hydrogen peroxide (H2O2) and nitric oxide (NO).
Under normal conditions, cells have well-developed antioxidant systems that
minimize the perturbations caused by ROS. However, when ROS generation is
increased to an extent that overcomes the cellular antioxidants, then
oxidative stress results. Therefore, oxidative stress may be viewed as a
continuous battle between inducers (pro-oxidants) and protective factors
(antioxidants). Because ROS are partially reduced products of oxygen, they
have a high chemical reactivity with other bio-macromolecules that may lead to
lipid peroxidation, and oxidation of DNA, RNA and proteins. Due to this
reactivity, oxidative stress is thought to play an important contributory role
in the pathogenesis of numerous degenerative and chronic diseases.
Antioxidants are substances that either directly or indirectly protect cells
against the adverse effects of xenobiotics, toxicants, drugs, and carcinogens.
Antioxidants can be divided into three categories:
1. Dietary (nutritional) antioxidants are low molecular weight compounds
ingested in the diet such as vitamin C, vitamin E, the carotenoids,
flavonoids, other plant phenolics and wine phenolics.
2. Intrinsic molecules such as glutathione, albumin, bilirubin and uric acid.
3. Enzymes that specifically metabolize ROS precursors, such as catalase,
superoxide dismutase (SOD), glutathione peroxidase, and peroxiredoxins.
Many epidemiological studies have shown a link between diet and/or nutrition
and the development of disease. Studies have shown that a low consumption of
fruits and vegetables have been associated with a high risk of cancer,
cardiovascular disease, type 2 diabetes and other chronic diseases. Although
epidemiological studies have shown this link, the understanding of the
mechanism for the efficacy of fruits and vegetables is unclear. Fruits and
vegetables are a rich source of a variety of micronutrients, including
vitamins, trace minerals such as selenium, dietary fiber and many other
classes of biologically active compounds. Several of these micronutrients
have been shown to prevent the disease process by serving as antioxidants in
stopping the free radical chain of events.
To inhibit free radical generation, dietary antioxidants can minimize
oxidative damage by:
1. Inhibiting initiation by blocking cellular free radical generators.
2. Scavenging peroxyl radicals to prevent their propagation by converting
them to hydroperoxides, which are then disposed of by glutathione peroxidase.
3. Repairing long-lived biological radicals before they are converted into
stable products.
4. Inhibiting cellular expression of a mutagenic lesion.
5. Inducing apoptosis of damage cells.
6. Inducing and assisting enzymatic antioxidants and detoxifying agents.
There is scientific evidence that antioxidants and other micronutrients in the
diet may play a major role in preventing or retarding oxidative stress in
disease. Since endogenous antioxidant defenses are not 100 percent efficient,
dietary antioxidants may be important in diminishing the cumulative effects of
oxidative damage over the long human life-span. This influence may account
for some of the beneficial effects of fruits, grains, and vegetables. Studies
have also shown that animals on low caloric diets tend to have lower oxidative
damage to DNA, proteins and lipids and they also have higher levels of
protective catalase activity. In addition, some diseases, such as diabetes,
have been associated with decreased levels of endogenous antioxidants, such
observations could potentially increase the importance of nutrients as a
source of antioxidants in affected individuals. Combined, these studies
indicate that proper nutrition and caloric restriction may improve cells
ability to remove reactive substances and damage to macromolecules, thereby
protecting against many environmentally induced diseases.
Epidemiological studies have also shown that inter-individual variations due
to genetic polymorphisms (ex: single nucleotide polymorphisms (SNP S)) can
contribute to an individual’s susceptibility to ROS damage in various tissues.
Therefore, it is important to understand the role of SNP’s and nutrition in
human health and disease. An example of such studies is the manganese
superoxide dismutase polymorphism linked to increased breast cancer risk in
premenopausal women. This study observed that breast cancer risk was greatest
among women who consumed lower amounts of dietary antioxidants and was minimal
among women who were high consumers of dietary antioxidants. This observation
suggests that a diet rich in sources of antioxidants may minimize the effects
of the manganese superoxide dismutase polymorphism.
Despite these recent advances in nutritional research to understand the role
of nutrition in the prevention of disease, there is an inadequate knowledge
base regarding the underlying molecular mechanisms by which micronutrients
exert their effects in altering the disease process. The NIEHS and NIDDK are
interested in studying nutritional components of disease risks and
understanding the molecular basis of nutrition. Therefore, this RFA
specifically aims to support studies that will better define the molecular
mechanisms by which dietary factors inhibit environmentally induced oxidative
damage.
Research Objectives:
The objectives of this RFA are to encourage and support mechanistically based
research designed to characterize the linkage between diet, nutrition and
environmentally induced oxidative stress (damage) and disease. Emphasis
should be placed on developing the preliminary data that could lead to larger
scale research project grants.
Examples of relevant areas of investigation that examine the influence of
dietary pro-oxidants and antioxidants on oxidative damage may include, but are
not limited to:
o Susceptibility of different cellular systems to environmentally induced in
vitro and in vivo oxidation as a measure of the endogenous antioxidant defense
system.
o The capability of dietary antioxidants to inhibit or scavenge radical
production in cells and tissues under various exposures to environmental
agents, pro-oxidants and antioxidants.
o The mechanism of action of proteins and transcription factors involved in
ROS regulatory pathways as inducers of oxidative stress.
o Molecular mechanisms by which dietary antioxidants, xenobiotics,
environmental toxicants, and carcinogens interact to alter gene expression and
structure/activity relationships of detoxifying enzymes.
o The identification of cytosolic factors that serve as oxidative sensors
within cells and their mechanism of action, and their control by diet or
nutritional supplements.
o Molecular mechanisms that control ROS homeostasis (ex: NF kappa B, Ap-1,
hypoxia inducible factor-1) and their regulation by diet or nutritional
supplements.
o The role of ROS, antioxidant enzymes and cellular redox changes in
transcriptional regulation, cell cycle control and signaling events in
apoptosis.
o The role of single nucleotide polymorphisms in understanding mechanisms
and risk factors in diet and prevention of environmentally induced disease.
o Mechanisms by which caloric restriction decreases production of ROS.
o Mechanisms of oxidant induced alterations in lipid peroxidation, protein
alkylation and DNA modification (ex: hypermethylation and hypomethylation).
Projects may utilize a variety of scientific approaches, including in vitro
studies, animal models or epidemiology. All projects must examine the
interaction of dietary pro-oxidants and antioxidants and environmentally
induced oxidative damage which may lead to disease. Projects lacking an
examination of nutritional factors, which may include nutritional supplements,
will be considered non-responsive and returned to the applicant without
review.
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
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 biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification are 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 research involving human subjects should read the
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research," published in the NIH Guide for Grants and Contracts on
August 2, 2000
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html),
a complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The
revisions relate to NIH defined Phase III clinical trials and require: a) all
applications or proposals and/or protocols to 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) all
investigators to report accrual, and to conduct and report analyses, as
appropriate, by sex/gender and/or racial/ethnic group differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.
All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.
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. Reviewers are cautioned that their anonymity may
be compromised when they directly access an Internet site.
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent by March 1,2001
that includes a descriptive title of the proposed research, the name, address,
and telephone number of the Principal Investigator, the identities of other
key personnel and participating institutions, and the number and title of the
RFA in response to which the application may be submitted. Although a letter
of intent is not required, is not binding, and does not enter into the review
of a subsequent application, the information that it contains allows NIEHS
staff to estimate the potential review workload and plan the review.
The letter of intent is to be e-mailed or mailed to:
Ethel B. Jackson, D.D.S.
Chief, Scientific Review Branch
Office of Program Operations
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
111 T.W. Alexander Drive
P.O. Box 12233
Research Triangle Park, N.C. 27709
Phone (919) 541-7846
Fax (919) 541-2503
email: jackson4@niehs.nih.gov
APPLICATION PROCEDURES
The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants. These forms are available at most institutional
offices of sponsored research and from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:
GrantsInfo@nih.gov.
THE FOLLOWING ARE SUPPLEMENTAL INSTRUCTIONS:
o Only one small grant application may be submitted by a Principal
Investigator.
o The applicant must be explicit in describing the proposed interface between
nutrition and oxidative damage.
o Since this award is to support pilot studies, preliminary data are not
required except to indicate the expertise of the principal investigator to
carry out the proposed studies.
o The research plan (aims, background and significance, preliminary data and
experimental design and methods) is limited to 10 pages. Tables and figures
are included in the 10-page limitation. Applications that exceed page
limitation or PHS requirements for type, size, and margins (see PHS 398
directions) will be returned to the investigator.
o Do not submit an appendix. However, if a color or glossy figure is
essential for full consideration of your application, this material only can
be included as an appendix.
o The RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the application. Type the RFA
number on the label. Failure to use this label could result in delayed
processing of the application such that it may not reach the review committee
in time for review. In addition, the RFA title and number must be typed on
line 2 of the face page of the application form and the YES box must be
marked.
The sample RFA label available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to
allow for this change. Please note this is in pdf format.
Submit a signed, typewritten original of the application, including the
Checklist, and three signed photocopies, in one package to:
CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application must be
sent to:
Ethel B. Jackson, D.D.S.
Chief, Scientific Review Branch
Division of Extramural Research and Training
Office of Program Operations
National Institute of Environmental Health Sciences
111 T.W. Alexander Drive
P.O. Box 12233
Research Triangle Park, N.C. 27709
Phone (919) 541-7846
Fax (919) 541-2503
email: jackson4@niehs.nih.gov
Applications must be post marked by the application receipt date listed in the
heading of this RFA. If an application is received after that date, it will
be returned to the applicant without review.
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application. The
CSR will not accept any application that is essentially the same as one
already reviewed. This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications must include
an introduction addressing the previous critique.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIEHS and NIDDK. Incomplete and/or non-responsive
applications will be returned to the applicant without further consideration.
Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the NIEHS in accordance with the review criteria stated below. As part of the
initial merit review, all applications will receive a written critique and
undergo a process in which only those applications deemed to have the highest
scientific merit, generally the top half of the applications under review,
will be discussed and assigned a priority score.
Review Criteria
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In
the written comments reviewers will be asked to discuss the following aspects
of the application 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 the application
does not need to be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score. For example, an
investigator may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.
1. Significance: Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be advanced?
What will be the effect of these studies on the concepts or methods that drive
this field?
2. Approach: Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics?
3. Innovation: Does the project employ novel concepts, approaches or method?
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?
4. Investigator: Is the investigator appropriately trained and well suited
to carry out this work? Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?
5. Environment: Does the scientific environment in which the work will be
done contribute to the probability of success? Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements? Is there evidence of institutional
support?
In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:
o The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will also be
evaluated.
o The reasonableness of the proposed budget and duration in relation to the
proposed research.
o The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.
SCHEDULE
Letter of Intent Receipt Date: March 1, 2001
Application Receipt Date: April 16, 2001
Peer Review Date: June, 2001
Earliest Anticipated Start Date: September, 2001
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review).
o Availability of funds.
o Programmatic priorities.
INQUIRIES
Inquiries concerning this RFA are encouraged. The opportunity to clarify any
issues or answer questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Joan P. Packenham, Ph.D.
Scientific Program Administrator
Chemical Exposures and Molecular Biology Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-21
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
Telephone: (919)541-4528
Fax: (919)306-4606
Email: Packenhm@niehs.nih.gov
Barbara Linder, M.D., Ph.D.
Program Director
Clinical Endocrinology and Diabetes Complications
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Rm. 699
Bethesda, MD 20892-5640
Telephone: (301) 594-0021
Fax: (301) 480-3505
Email: linderb@extra.niddk.nih.gov
Direct inquiries regarding review issues to:
Ethel B. Jackson, D.D.S.
Director, Scientific Review Branch
National Institute of Environmental Health Sciences
Scientific Review Branch
Division of Extramural Research and Training
P.O. Box 12233, MD EC-30
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
Phone (919) 541-7846
Fax (919) 541-2503
email: Jackson4@niehs.nih.gov
Direct inquiries regarding fiscal matters to:
Carolyn Winters
Grants Management Specialist
Grants Management Branch
Office of Program Operations
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-30
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
Telephone: (919)541-7823
FAX: (919)541-2860
Email: winters@niehs.nih.gov
Charlette Kenley
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes, Endocrinology and Metabolic Diseases
6707 Democracy Blvd., Rm. 640
Bethesda, MD 20892-5456
Telephone: (301) 594-8847
Fax: (301) 480-3504
Email: Kenleyc@extra.niddk.nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.113 and 93.115,and 93.847. Awards are made under authorization of Sections
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)
and administered under NIH grants policies and Federal Regulations 42 CFR 52
and 45 CFR Parts 74 and 92. This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.
The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-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.
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