Full Text ES-94-003

TOXIC SUBSTANCE EFFECTS ON DEVELOPMENTAL GENE EXPRESSION

NIH GUIDE, Volume 22, Number 39, October 29, 1993

RFA:  ES-94-003

P.T. 34

Keywords: 
  Environmental Effects 
  Toxicology 
  PHYSIOLOGICAL/DEVELOPMENT PROCESS 
  0765014 


National Institute of Environmental Health Sciences

Letter of Intent Receipt Date:  December 15, 1993
Application Receipt Date:  January 21, 1994

PURPOSE

The National Institute of Environmental Health Sciences (NIEHS) in
conjunction with the National Toxicology Program invites applications
to conduct research on the effects of environmental toxicants on gene
expression during development.  The etiology of a large percentage of
birth defects are unknown.  However, it is very likely that the
origin of many of the observed developmental abnormalities can be
attributed to an environmental component.  Thus, the mechanism
whereby these agents or conditions cause these developmental defects
is unclear and there is suggestive evidence that some toxic agents
may be responsible for disrupting the normal pattern of gene
expression during developmental stages.

This Request for Applications (RFA) is issued to stimulate research
at the interface between developmental biology and developmental
toxicology in order to further our knowledge of how environmental
agents alter the basic processes of development and contribute to
birth defects in human populations.  The research supported will
focus upon the development of experimental paradigms and research
strategies for characterizing alterations in patterns of gene
expression induced by exposure to environmental toxicants during
mammalian development.

HEALTHY PEOPLE 2000

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,
Toxic Substance Effects on Developmental Gene Expression, 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 or local
governments, and eligible agencies in the Federal government.
Applications from minority individuals and women are encouraged.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) award.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research project grant (R01) and FIRST award (R29).  Responsibility
for planning, direction, and execution of the proposed project will
be solely that of the applicant.  The total project period for
applications may not exceed three years for R01s.

FUNDS AVAILABLE

The estimated funds (total costs) available for the first year of
support for entire program is $1.0 million.  The expected number of
awards is four to five.

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.
Support will not be provided under this RFA for research activities
focussed exclusively on clinical trials or the initiation of
large-scope epidemiologic studies.

RESEARCH OBJECTIVES

Developmental processes are guided by a precise coordination of gene
expression.  These genes have been shown to be involved in the
regulation of processes such as axis specification, cell lineage
determination, cell migration, cell differentiation and segmentation.
It can be assumed that disruptions in the normal pattern of gene
expression brought on by exposure to environmental toxicants (i.e.,
environmental and industrial chemicals, agents, and physical entities
such as heat and light), could lead to structure/function defects
and/or to death of the conceptus.  Indeed, there is suggestive
evidence that alterations in gene expression is at least part of the
teratogenic action of a growing number of agents and conditions
including TCDD, diethylstilbestrol (and other estrogenic compounds
such as certain pesticides and environmental estrogens), heat shock
(hyperthermia), valproic acid, and heavy metals (cadmium, lead,
etc.).  Understanding the mechanisms of toxicity brought on by these
exposures could help define how gene expression is altered and how
this leads to abnormal development.  Furthermore, developmental
defects caused by genetic perturbations are likely to share similar
developmental pathways as an environmental perturbation which causes
the same defect.  Genetic models may therefore be useful in
delineating the action of environmental toxicants on gene expression.

Identification of critical developmental genes, their specific
function, and their regulation is proceeding rapidly at a cellular,
biochemical, and molecular level through the efforts of developmental
biologists using new and novel techniques.  Thus it is an opportune
time for an integration of the development biology and development
toxicology fields.

A key component of this RFA is the cross fertilization between
molecular biologists/embryologists and developmental toxicologists.
Thus, applicants are encouraged to have elements of both toxicology
and molecular biology in the experimental design.  It should be noted
that simply screening for genes altered by environmental agents is,
in itself, not enough to qualify for consideration under this RFA.
Defining the gene must be only the first step in defining the role of
alteration in that gene in development.

This RFA is not limited to any particular stage of development,
organ, developmental abnormality or toxicant; the main criteria for
consideration is the relevance of the environmental toxicant and the
developmental abnormality to human health and the integration of
biology with toxicology.  The applications must be more than an
exchange of ideas; they must show a commitment to the
interdisciplinary approach.  it is hoped that the resulting
collaborations, "hybrid" thinking, and cross trained scientists will
continue to expand these initial efforts to define the site and
mechanism of action of developmental toxicants in order to better
protect the public health via awareness of prevention and
intervention.

SPECIAL REQUIREMENTS

Applicants should request funds for one trip annually to the NIEHS
for a meeting to discuss important new findings and a sharing of
research progress.

STUDY POPULATIONS

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

NIH policy is that applicants for NIH 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.  In addition, gender 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 preventive 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.

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.

Animal Welfare Considerations

Investigators are encouraged to consider alternative methods and
approaches in their research applications that do not require the use
of whole animals, use alternative species such as nonmammals or
invertebrates, reduce the number of animals required, and incorporate
refinements to procedures that will result in the elimination of
further minimization of pain and distress to animals.

LETTER OF INTENT

Prospective applicants are asked to submit, by December 15, 1993, a
letter of intent that includes a descriptive title of the proposed
project, 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 applications, the information
that it contains allows NIEHS staff to estimate the potential review
workload and to avoid possible conflict of interest in the review.

The letter of intent is to be sent to Dr. Jerrold Heindel at the
address listed under INQUIRIES.

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 offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone (301) 594-7378.

Applications must be received by January 21, 1994.  If an application
is received after that date, it will be returned to the applicant.

Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.

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:

Dr. Ethel Jackson
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
104 TW Alexander Drive, MD 3-04
Research Triangle Park, NC  27709

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by NIH staff for
completeness and responsiveness.  Incomplete applications will be
returned to the applicant without further consideration.  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.

Applications may be triaged by an NIEHS peer review group on the
basis of relative competitiveness.  The NIH will withdraw from
further competition those applications judged to be non-competitive
for award and notify the applicant Principal Investigator and
Institutional official.  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 National Advisory
Environmental Health Sciences Council.

Review criteria for RFAs 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.

Primary and secondary assignments of applications submitted in
response to this RFA will be made using the customary referral
guidelines.

AWARD CRITERIA

This anticipated date of award is July 1, 1994 .

INQUIRIES

We welcome the opportunity to clarify any issues or questions from
potential applicants, therefore, written and telephone inquiries
concerning this RFA are encouraged.

Direct inquiries regarding programmatic issues and address the letter
of intent to:

Jerrold J. Heindel, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
104 T.W. Alexander Drive
Research Triangle Park, NC  27709
Telephone:  (919) 541-0781

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
104 T.W. Alexander Drive
Research Triangle Park, NC  27709
Telephone:  (919) 541-1371

AUTHORITY AND REGULATIONS

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, 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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