Full Text ES-97-002
NIH GUIDE, Volume 26, Number 11, April 4, 1997
RFA:  ES-97-002
P.T. 34

  Environmental Effects 

National Institute of Environmental Health Sciences
National Heart, Lung, and Blood Institute
Letter of Intent Receipt Date:  May 9, 1997
Application Receipt Date:  June 12, 1997
The National Institute of Environmental Health Sciences (NIEHS)
supports research to identify the role of environmental agents in
perturbations of normal physiologic processes leading to human
dysfunction and disease of all types.  The National Heart, Lung, and
Blood Institute (NHLBI) supports research to investigate the
pathologic mechanisms in acute and chronic pulmonary diseases, and
cardiovascular diseases.  It has been shown that reactive oxygen
species (ROS) are formed, and play a role, in the toxic
manifestations of many xenobiotics.  There are also preliminary data
to show that oxidative damage may initiate or exacerbate specific
diseases or dysfunctions including cardiovascular and pulmonary
disease.  However, in most cases no relationships have been developed
to demonstrate that environmental agents act via oxidative damage, or
if diseases and dysfunctions are the result of oxidative damage
stimulated by such agents.  Therefore, the goals of this Request for
Applications (RFA) are to encourage research to develop biomarkers of
oxidative damage and to focus on the oxidative stress mechanism as a
result of exposure to injurious agents and the etiology, initiation
or exacerbation of human disease including direct or indirect roles
for ROS in pulmonary and cardiovascular disease.  It is anticipated
that research projects generated as a result of this RFA will
stimulate scientists to explore oxidative damage as a critical
pathway in pulmonary and cardiovascular disease as well as  diseases
induced by environmental agents in order to develop hypothesis-based
research needed to establish cause and effect relationships.
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
"Linking Environmental Agents, Oxidative Damage and Disease" is
related to the priority area of environmental health, unintentional
injuries, heart disease and stroke, and chronic disabling diseases.
Potential applicants may obtain a copy of "Healthy People 2000":
(Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone: (202)
Applications may be submitted by domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local governments and
eligible agencies of the Federal government.  Applications from
minority individuals and women are encouraged.  Submission of an
application precludes concurrent submission of a regular research
grant application (R01 or R29) containing the same research proposal.
In addition, small grant research support may not be used to
supplement research projects currently supported by Federal or
non-Federal funds or to provide interim support for projects under
review by the Public Health Service.
This RFA will use the National Institutes of Health (NIH) Small
Grants Program (R03) awards.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that
of the applicant. The requested costs and project period will be
$50,000 (direct cost) for a maximum of one year.  Small grants are
not renewable.
The total estimated funds available for support of this Small Grants
Program is $1,200,000, which will support 16-18 awards.  This level
of support is dependent on the receipt of a sufficient number of
applications of high scientific merit.  Although this program is
provided for within the financial plans of the NIEHS and the NHLBI,
awards pursuant to this RFA are contingent upon the availability of
funds for this purpose.
Reactive oxygen species (ROS) include the superoxide anion (O2),
hydrogen peroxide (H2O2), the hydroxyl radical (OH), lipid peroxides,
nitric oxide (NO), singlet oxygen (O21), ozone (O3), and hypochlorous
acid (HOCl).  They are partially reduced products of oxygen; some are
free radicals.  They are known to cause oxidation of membrane
phospholipids; lipid peroxidation; protein damage, including cleavage
of amino acid bonds; DNA strand breaks, or base modifications leading
to point mutations; inhibition of RNA and protein synthesis; protein
cross-linking; impaired maintenance of membrane ion gradients; and
depletion of cellular levels of ATP, leading to cellular dysfunction
and eventually to disease.
Reactive oxygen species are continuously produced in living cells
naturally as a result of leakage of electrons on the electron
transport chain in mitochondria.  In addition, they can be produced
in cells by various enzymatic mechanisms (xanthine oxidase,
cytochrome P450, etc.), auto-oxidation of small molecules
(catecholamines, etc), or in response to xenobiotics, exogenous
environmental exposures, ischemia, or inflammatory stimuli.
Cells have well-developed antioxidant systems to protect themselves
from ROS.  These include low molecular-weight antioxidants like
ascorbic acid; alpha-tocopherol and glutathione; and antioxidant
enzymes such as catalase, glutathione peroxidases and superoxide
dismutases (SODs).  In addition, cells have the ability to repair
damage caused by ROS (DNA repair enzymes, proteases, lipases, etc.).
Many environmental and industrial agents such as tobacco smoke,
stored food products, dietary trace element additives, some metals,
pesticides, ozone, NO2, and TCDD will provoke an oxidative stress
response, overwhelm antioxidant defense systems and result in
oxidative damage to tissues.  Transition metals including iron,
copper, chromium, and vanadium undergo redox cycling that can result
in generation of ROS. Cadmium, mercury and nickel deplete glutathione
resulting in increased levels of ROS leading to lipid peroxidation,
DNA damage, protein cross linking and altered calcium homeostasis.
The toxicities produced by these metals usually involve tissue damage
in the kidneys, liver or central nervous system.  Bacterial products,
such as endotoxin (lipopolysaccharide), and trauma can also induce
production of reactive oxygen species and result in tissue damage and
organ injury.
In 1996 NIEHS held a workshop entitled, "Measurement of Oxidative
Stress in Humans" to stimulate interaction between basic scientists
and epidemiologists.  The recommendations from this workshop
emphasized the importance of the development, standardization and
validation of biomarkers of oxidative stress in humans and the
collaboration between basic scientists and epidemiologists in this
process.  In 1996, the NHLBI convened a Special Emphasis Panel of
investigators in the areas of acute lung injury, interstitial
pulmonary disease, and lung development to stimulate discussion and
solicit recommendations for areas of research to be emphasized in the
future.  They recommended that generation of ROS, mechanisms of
tissue injury, and mechanisms by which ROS generation is regulated in
the lung should be considered areas of high interest to the NHLBI.
This RFA has been developed, in part, to foster implementation of
these recommendations.
Research Goals
The goals and scope of this RFA are to encourage and support
mechanistically-based research designed to establish the linkage
among three events: exposure to an environmental agent tested at
environmentally relevant concentrations, resultant oxidative damage
and the initiation or exacerbation of diseases.  Laboratory research
is encouraged that will increase our understanding of the oxidative
stress pathways of damage in relation to environmentally-induced
disease. Emphasis should be placed on developing the preliminary data
that will lead to the development of cause and effect relationships
among environmental agents, oxidative damage and the etiology of
disease.  The development of new biomarkers of oxidative damage in
human populations is also encouraged.  This includes research which
will assess intra individual variability, sensitivity and specificity
of these biomarkers. Collaborations between laboratory  scientists
and epidemiologists in the development and validation of biomarkers
of oxidative stress in humans is strongly encouraged.
Diseases of specific interest for this program include (but are not
limited to): reproductive; immune; lung; cardiovascular; neural; as
well as gastrointestinal disorders; osteoporosis and other bone
diseases; renal diseases; and abnormalities in growth and
development. Experiments using animal models or human tissue and/or
cell lines would be appropriate. Biomarkers of ROS damage can be
developed in animal models or human specimens but must be validated
in exposed human populations.  Environmentally-relevant
concentrations using dose-response data are encouraged.  The effect
of age and the timing of exposure relative to the toxicity or effect
should also be included as part of the experimental design.
The purpose of this RFA is to expand data on non-cancer health
endpoints.  Therefore, research on the role of ROS on the initiation
or progression of cancers of any type will be considered
In addition, areas of science in which there are sufficient
preliminary data that would support the submission of a regular
research project grant application do not qualify under this RFA.
Investigators are encouraged to consider alternative methods and
approaches in their research applications that do not require the use
of whole animals, that use alternative species such as non-mammals or
invertebrates, that reduce the number of animals required, and that
incorporate refinements to procedures that will result in the
elimination or further minimization of pain and distress to animals.
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
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
All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 58 14508-14513) and in the NIH
Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994.
Prospective applicants are asked to submit, by May 9, 1997, a letter
of intent 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
subsequent application, the information that it contains allows NIEHS
staff to estimate the potential work load and to avoid conflict of
interest in the review.
The letter of intent is to be sent to:
Ethel B. Jackson, D.D.S.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, 111 T.W. Alexander Drive, Building 17, Room 1716
Research Triangle Park, NC  27709-2233
Telephone:  (19) 541-7846
FAX:  (919) 541-2503
Email:  jackson4@niehs.nih.gov
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  Applications kits are available at
most institutional offices of sponsored research and may be obtained
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:
ASKNIH@odrockm1.od.nih.gov; and from the program administrator listed
under inquiries.
o  Only one small grant application may be submitted by a principal
o  A detailed budget should be completed as instructed on Page II of
the U.S. Department of Health and Human Services Public Health
Service Grant Application (PHS 398, rev. 5/95).  The budget may not
exceed $50,000 direct costs.  Equipment will be limited to $5,000.
Indirect costs will be awarded at the grantee's current negotiated
indirect cost rate at the time of the award.
o  The applicant must be explicit in describing either the proposed
interface between an environmentally relevant agent, oxidative stress
and the induction or exacerbation of a specific disease or
dysfunction or the development of biomarkers of oxidative damage in
humans that could be used to develop the relationship between ROS and
diseases/dysfunctions.  Background information must suggest, or at
least not preclude, a possible interaction between these three
parameters or discuss the potential relationship of ROS to the
pathogenic mechanisms in pulmonary or cardiovascular diseases.
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.
The RFA label available in the PHS 398 application kit, (rev. 5/95),
must be affixed to the bottom of the face page of the application.
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 the review.  In addition, the RFA title and number must be typed
on line two of the face page of the application form and the YES box
must be marked.
Submit a signed, typewritten original of the application, including
the checklist, and three signed, clear, and single sided photocopies
in one package to:
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.
Division of Extramural Research and Training
National Institute of Environmental health Sciences
P.O. Box 12233, 111 T.W. Alexander Drive,
Building 17, Room 1716
Research Triangle Park, NC  27709-2233
If these two additional copies are not forwarded to Dr. Jackson, it
will adversely affect the review of the grant application:
Applications must be received by June 12, 1997.  If an application is
received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) 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 DRG 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.
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 NIH peer review
procedures.  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 applications under review, will be
discussed and assigned a priority score.
Review Criteria
o  Scientific, technical, or medical significance and originality of
proposed research as it relates to contributions to knowledge of
health outcomes as a result of exposure to environmental agents;
o  feasibility of the proposed research;
o  appropriateness of the proposed budget and adequacy of the
experimental approach and methodology proposed to carry out the
o  "high risk" with likelihood of "high gain;"
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
o  linkage of an environmental agent, oxidative stress/damage and
initiation or exacerbation of a specific non cancer
o plausibility of the biological mechanism suggested linking the
environmental exposure, oxidative damage and the etiology of disease;
o examination of the role for reactive oxygen species in the
pathogenesis of pulmonary or cardiovascular disease; and
o availability of resources necessary to perform the research.
The anticipated date of award is September 1997 pending availability
of funds.  The following will be considered in making funding
o  quality of the proposed project as determined by peer review;
o  availability of funds; and
o  program balance among research areas of the announcement.
Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcomed.
Direct inquiries regarding programmatic issues to:
Jerrold J. Heindel, Ph.D.
Organs and Systems Toxicology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233, MD 3-02
111 T. W. Alexander Drive, Building 3, Room 316
Research Triangle Park, NC  27709-2233
Telephone:  (919) 541-0781
FAX:  (919) 541-2843
Email:  heindelj@niehs.nih.gov
Gwen W. Collman, Ph.D.
Chemical Exposures and Molecular Biology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233, MD 3-04
111 T.W. Alexander Drive, Building 3, Room 306
Research Triangle Park, NC  27709-2233
Telephone:  (919) 541-4500
FAX:  (919) 541-2843
Email:  collman@niehs.nih.gov
Robert A. Musson, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10018, MSC 7952
Bethesda, MD  20892
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
Email:  rmusson@nih.gov
Momtaz Wassef, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung and Blood Institute
6701 Rockledge Drive, Room 10188, MSC 7956
Bethesda, MD  20892
Telephone:  (301) 435-0550
FAX:  (301) 480-2858
Email:  wassefm@gwgate.nhlbi.nih.gov
Direct inquiries regarding fiscal matters to:
Mr. David L. Mineo
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD 2-01
111 T.W. Alexander Drive, Building 2, Room 203B
Research Triangle Park, NC  27709-2233
Telephone:  (919) 541-7628
FAX:  (919) 541-2860
Email:  mineo@niehs.nih.gov
Inquiries to other institutes with similar R03 Programs:
The National Institute on Deafness and other Communication Disorders
(NIDCD) is interested in research that is directed towards oxidative
damage to the systems of hearing, balance, smell and taste. The NIDCD
has an R03 Program that can be found on the NIH Home Page as
PAR-97-012 under grants and contracts.
This program is described in the Catalog of Federal Domestic
Assistance No. 93.113 and 93.115.  Awards are made under
authorization of the Public Health Service Act, Title IV, Part A
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and
285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  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 and contract 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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