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 301/435-0714, 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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