Full Text ES-92-03

MOLECULAR INTERVENTIONS FOR ENVIRONMENTALLY INDUCED DISEASE PREVENTION

NIH GUIDE, Volume 21, Number 24, June 26, 1992

RFA:  ES-92-03

P.T. 34

Keywords: 
  Environmental Health 
  Toxicology 
  Biological Markers 


National Institute of Environmental Health Sciences

Application Receipt Date:  November 24, 1992

PURPOSE

This RFA is the first of an anticipated series of solicitations in a
broad research strategy to develop interventions at the molecular level
for diseases with an environmental etiology.  The current announcement
focuses on the development and use of biomarkers to assess the
effectiveness of intervention strategies.

The elimination of toxic agents from the environment has dominated the
field of prevention.  Although the causes of certain human diseases are
known, explicit preventive strategies still cannot be offered for
avoidance of numerous risk factors associated with many types of
disease sequelae.  This is because there are unavoidable risk factors
and inherent biostatistical and epidemiological limitations involved in
the identification and interpretation of complex disease processes and
potential low-risk hazards.  Recently, control strategies involving a
more mechanistic approach derived from chemical and biological research
have received more emphasis.  The objective of the strategies is
eventual intervention through preventive/protection or other active
means of modulating the risk factors.

The National Institute of Environmental Health Sciences (NIEHS) has
posed as one of its major goals of the 1990s the development of an
effectual knowledge base that would equip clinicians to effectively
treat people who are affected adversely by exposure to environmental
agents.  Accordingly, the NIEHS announces the availability of funds to
support research efforts aimed at the development and clinical trial
use of methods to prevent, modulate, or treat environmentally induced
toxic effects.  Such studies should provide new insight into the
molecular bases for intervention to prevent or ameliorate
environmentally induced diseases as well as associated alterations of
biological processes related to toxicant exposures.  The focus of this
particular RFA is development and use of appropriate biomarkers to
study effectiveness of potential intervention methods.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Health People 2000," a
PHS-led national activity for setting priority areas.  This RFA,
Molecular Interventions for Environmentally Induced Disease Prevention,
is related to the priority area of environmental health.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report:
Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington DC 20402-9325, telephone (202)
783-3238.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, 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.
Applications from minority individuals and women are encouraged.
Foreign applicants are not eligible for the First Independent Research
Support and Transition (FIRST) Award.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research grant (R01) and the FIRST Award (R29).  Responsibility for the
planning, direction, and execution of the proposed project will be
solely that of the applicant.  The total project period for
applications submitted in response to the present RFA may not exceed
five years.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-initiated
applications and be reviewed according to the customary NIH peer review
procedures.

FUNDS AVAILABLE

The estimated funds (total costs) available for the first year of
support for the entire program is $1.5 million.  The expected number of
awards is 8-12.

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 in the financial plans of the NIEHS, awards pursuant to
this RFA are contingent upon the availability of funds for this
purpose.

RESEARCH OBJECTIVES

The ultimate goal and scope of this research program is the support of
studies that will advance knowledge to diminish the risk of disease
development.  There are potentially many approaches that may have
application to clinical solutions to ameliorate environmental toxicant
effects and/or to intercede in disease pathways.

Many diseases are thought of as multistage in process, while others are
judged as multi-event.  It is recognized that the environment may play
a role in certain disease processes, although actual causative agents
have been shown in only a few instances.  Whereas cancer is a paradigm
for multistage/multi-event processes, the reasonable and testable
supposition is that there are other environmentally influenced chronic
disease processes (e.g., atherosclerosis, Alzheimer's disease, and
multiple sclerosis).  Therefore, by identifying early, fundamental
targets that could be control points of biochemical cascades of many
subsequent events, a more effective and ubiquitous management of
disease processes could be achieved.

The focus of this RFA is on the development and use of biomarkers to
assess the effectiveness of intervention studies.  Biomarkers, as
indicators of molecular and cellular events in biological systems, may
allow epidemiologists and other health professionals to better examine
the relationships between environmental hazards and human health
effects.

Biomarkers fall into three basic categories:  biomarkers of dose,
susceptibility, and effects.  It is important to determine the
mechanism of biomarker induction in humans and to help establish the
utility of biomarkers as indicators of toxic exposure.  Biomarkers of
exposure can be used to quantify an individual's exposure to and uptake
of environmental agents potentially related to disease.  Biomarkers of
internal dose can provide information not only on individual exposure
and uptake, but also on metabolic activation and detoxification
parameters that may be related to disease susceptibility.  Such studies
would also address the relationship of a biomarker to a disease
process, i.e., does exposure lead to effect.  As such, it is critical
to link molecular intervention studies to related molecular
epidemiology studies.  The NIEHS is interested primarily in biomarkers
correlated with non-cancer endpoints.  Although applications related to
cancer endpoints are acceptable, they will be weighted for programmatic
balance.

The following examples of areas of research interest are not intended
to be complete, and investigators are encouraged to study these or
other topics that meet the objectives of this announcement:

Development of Biomarkers and Their Validation for Use in
Exposure/Disease Relationships.

o  The knowledge of the mechanism(s) of biomarker induction in humans
to help establish the utility as indicators of toxic exposure and to
address the relationship to a disease process.  The modulation of the
levels of the biomarkers may correlate with the interventive/protective
properties of an interceding agent.

o  Biomarkers of internal dose are of particular interest because they
have the potential to detect enzymatic differences between individuals
that may relate to disease susceptibility.  It may be possible to
modulate these enzymatic activities, e.g., inhibit metabolic activation
processes or enhance detoxification processes, by interventions with
specific agents, or by changes in exposure patterns or lifestyles.
Biomarkers of internal dose can be used to assess the results of these
interventions or changes in lifestyle.

Use of Biomarkers in Prevention and Treatment Studies.

o  Molecular intervention studies related directly to epidemiology,
especially in the development and use of molecular techniques for
identifying affected individuals.  Biomarkers have the potential to
derive better risk models; intervention models with variable, yet
predictable, risk may permit the validation of biomarker measurements
to better extrapolate exposure to individual risk.  Data from such
studies should also lead to a better understanding of inter- and
intra-individual variability.

The scope of these studies may range from prevention of internal
exposure to the toxic agent, to treatment of effects at the cellular
and molecular level, to genetic control of the disease-regulating and
-controlling events.  Studies should be innovative, providing new
insight into the molecular basis of biomarker induction and the
concomitant modulation:  (1) the molecular identification and
quantification of exposure to environmental agents; (2) the
amelioration of environmental agent-induced biological perturbations;
and (3) the linkage of an environmental agent exposure to a specific
disease or disease process.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be required to include
minorities and women in study populations so that research findings can
be of benefit to all persons at risk of the disease, disorder or
condition under study; special emphasis should be placed on the need
for inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale for
its choice.  In addition, general and racial/ethnic issues should be
addressed in developing a research design and sample size appropriate
for the scientific objectives of the study.  This information should be
included in the form PHS 398 in Sections 1-4 of the Research Plan and
summarized in Section 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However, NIH
recognizes that it may not be feasible or appropriate in all research
projects to include representation of the full array of United States
racial/ethnic minority populations (i.e., Native Americans (including
American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks,
Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and prevention strategies), diagnosis, or treatment of diseases,
disorders or conditions, including, but not limited to, clinical
trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned to the applicant without review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed and the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional business offices and from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Room 449, Bethesda, MD  20892, telephone (301)
496-7441.

The RFA label available in the PHS 398 (rev. 9/91) application form
must be affixed to the bottom of the face page of the application.
Failure to use this label may 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 2a
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 photocopies, in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to:

Mr. David L. Mineo
Grants Management Officer
Grants Management Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
104 T.W. Alexander Drive
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-1373

Applications must be received by November 24, 1992.  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 announcement 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by NIH staff for
completeness and responsiveness.  Incomplete applications will be
returned to the applicant without review.  If the application is not
responsive to the RFA, NIEHS staff will contact the applicant to
determine whether to return the application to the applicant or submit
it for review in competition with unsolicited applications at the next
review cycle.

Those applications judged to be competitive will undergo further
scientific merit review.  Those applications that are complete and
responsive will be evaluated in accordance with the criteria stated
below for scientific/technical merit by an appropriate peer review
group convened by the NIEHS.  The second level of review will be
provided by the the National Advisory Environmental Health Sciences
Council.

Review criteria for this RFA are generally the same as those for
unsolicited research grant applications.

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal Investigator
and staff, particularly, but not exclusively, in the area of the
proposed research;

o  availability of resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research.

The subject of this RFA may overlap with interests of other Institutes,
Centers, and Divisions (ICDs).  Applicants will, therefore, be assigned
according to extant PHS Referral Guidelines.  If developing programs
deal with clinical populations, applicants might wish to consider
utilization of General Clinical Research Center (GCRC) facilities.
More information on the GCRC program can be obtained from the National
Center for Research Resources.

AWARD CRITERIA

The anticipated date of award is July 1, 1993.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

William A. Suk, Ph.D., M.P.H.
Program Administrator
Scientific Programs Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-0797
FAX:  (919) 541-2843

Direct inquiries regarding fiscal matters to:

Mr. David L. Mineo
Grants Management Officer
Grants Management Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-1373

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.894.  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, 43 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.

.

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