Full Text ES-96-006
 
THE USE OF TRANSGENIC MODEL SYSTEMS IN MOLECULAR TOXICOLOGY
 
NIH GUIDE, Volume 25, Number 7, March 8, 1996
 
RFA:  ES-96-006
 
P.T. 34

Keywords: 
  Toxicology 
  Animal Breed. & Facil., Scientific 
  Environmental Effects 

 
National Institute of Environmental Health Sciences
 
Letter of Intent Receipt Date:  May 10, 1996
Application Receipt Date:  June 10, 1996
 
PURPOSE
 
A major goal of the National Institute of Environmental Health
Sciences (NIEHS) is to foster research that will increase the
knowledge of the diverse health effects of exposure to environmental
agents.  It is likely that many common diseases, including cancer,
lung disease, neurodegenerative diseases, cardiovascular diseases,
and developmental abnormalities or dysfunctions, have an
environmental component.  Further, there is a critical need for a
thorough understanding of the action of environmental agents on human
health at the genome level.  Recent advances in molecular biology
permit novel approaches for the identification of genes involved in
environmentally associated diseases.  Accordingly, the objective of
this request for applications (RFA) is to encourage innovative,
mechanistically based research using transgenic technologies to
investigate the alterations of gene expression induced by
environmental agents in specific target cells and organs, and to
determine how this response varies at critical times during exposure.
These studies would undoubtedly contribute to the development of
specific therapies designed to enhance or decrease the susceptibility
of individual cell types to specific environmental agents, and could
form the basis for treatment of a variety of human diseases.
 
The NIEHS is the principal Federal funding agency that supports
research examining human health consequences of exposure to physical
and chemical toxicants in the environment.  Research supported by
NIEHS spans many disciplines, including toxicology, molecular and
cellular biology, epidemiology, and clinical research.
 
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,
The Use of Transgenic Model Systems in Molecular Toxicology, 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 Summary Report:  Stock No. 017-001-
00473-1) through the Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (telephone (202) 5120-1800).
 
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, unit of State or local governments
and eligible agencies of the Federal government.  Applications from
minority individuals and women are encouraged.
 
MECHANISM OF SUPPORT
 
Only applications using the NIH individual research project grant
(R01) award mechanism will be accepted in response to this RFA.
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The requested
direct costs for the R01 applications  submitted in response to this
RFA may not exceed $200,000 per year.  This RFA is a one time
solicitation.
 
FUNDS AVAILABLE
 
The total estimated funds available for the first year of support for
the entire program is $1.5 million.  The expected number of awards is
six to eight.  The level of support is dependent on the receipt of
sufficient number of applications of high scientific merit.  Although
this program is provided for within the financial plans of the NIEHS,
awards pursuant to this RFA are contingent upon the availability of
funds for this purpose.
 
RESEARCH OBJECTIVES
 
Background
 
The impact of environmental agents on human health and well being has
been clearly established.  Exposure to environmental pollutants,
because of their genotoxic and non-genotoxic potential, is likely to
cause genetic and/or cellular perturbations leading to disease.
 
Perhaps the best examples of gene environment interactions at the
molecular level have come from studies of metabolic enzymes and DNA
repair proteins.  In the first case, the Phase I and Phase II enzymes
have been identified as critical components in the oxidative
metabolism of virtually all environmental chemicals.  In addition to
their role as a major detoxification system, it has become
increasingly recognized that these enzymes are pivotal in many
subcellular biosynthetic reactions and in regulating the effectors of
many critical life processes, including cell growth, differentiation,
programmed cell death or apoptosis, homeostasis, and neuroendocrine
functions.  Foreign chemicals can compete with the endogenous
ligands, acting as either agonists or antagonists, in stimulating
growth, perturbing differentiation, or evoking any numerous other
signals that would lead to environmentally associated diseases.
 
Somatic cell genetics has been used to identify genes necessary for
the induction of these enzymes by toxic agents.  For example,
resistance to aryl hydrocarbon toxicity has been ascribed to several
factors including: mutational alterations of the cytochrome P450
(CYP) genes, transcriptional deficiencies, mutations in regulatory
sequences, mutations in other genes required for the normal
translocation of the inducer receptor complex into the nucleus, and
mutations of the AH receptor.
 
Adding to this intricacy, it is known that the regulation and
expression of the CYP genes varies as a function of age and sex.
Striking tissue specific expression has also been detected.  It is
clear that this phenomenon is dependent on hormonal or diffusible
factors, cell cell contact, and/or the differentiated states of cells
in the intact animal.
 
The CYP system represents an excellent tool to study gene environment
interactions.  However, it must be emphasized that numerous
polymorphisms exists within other xenobiotic metabolizing enzyme
families (e.g. glutathione transferase, UDP glucuronosyltransferases,
paraoxonases, dehydrogenases, n acetyl transferases, and flavin
containing dehydrogenases).  It is the complex interplay of these and
other enzyme families within any individual which will ultimately
determine a particular response to a given chemical and potential for
toxicity.
 
The molecular details of how metabolic genes are activated by
xenobiotic agents during development must await further
characterization of these genes.  The transgenic technologies now
available allow for the determination of what role receptors, trans
acting transcriptional control factors, and enhancer elements have in
the altered expression of the genes.
 
The DNA repair pathways represent another well studied system of gene
environment interaction.  Mammalian cells can regulate their DNA
repair machinery in response to genotoxic damage.  Thus, gene
expression for many  DNA repair proteins is increased in response to
exposure of cells to genotoxic agents.  In addition, the expression
pattern of DNA repair proteins varies from tissue to tissue and with
the differentiated state of the cells, perhaps reflecting variable
capacity for DNA repair.  It is believed that strategically
regulating the transcriptional activation of these genes may allow
for an enhancement of the cell s defense against DNA damaging agents.
 
The plausible consequences of damage to the human genome from
industrial and environmental chemicals is of serious concern, and
hence the study of mutational phenomenon and modeling of cell
susceptibility to such agents is of toxicological importance.  In
this context, a more thorough understanding of the cellular
mechanisms which are involved in the processing of environmentally
induced DNA damage is needed.
 
The availability of the technology to produce whole animals with
recoverable shuttle vectors with target genes makes possible the
study of physiologically relevant parameters in exposure to
environmental pollutants.  Some of these factors include dose rate
effects, tissue and organ specificity, age related effects, and
diseased versus normal differences.  These factors can be thoroughly
examined in vivo since transgenic technologies provide the
experimental system needed to evaluate them.  The NIEHS is issuing
this RFA in recognition of the potential of transgenic technologies
in helping to elucidate the molecular mechanisms by which
environmental agents cause disease.
 
Research Goals
 
Transgenic animals genetically designed animals created by the
introduction of DNA coding for specific genes into the genome of pre
implantation embryos are model systems that provide a tool to
identify and characterize the expression of targeted genes.  For
example, this technology has facilitated the identification of
chemically induced mutations and has helped in determining the
mechanism of such mutations.  It has helped to elucidate the
mechanisms responsible for tissue specific and developmentally
regulated gene expression, and has been instrumental in identifying
signal transduction pathways and hormonal factors that modulate the
activity of genes.  However, with the exception of very few specific
genes (e.g., AH receptor, methyl guanine methyl transferase,
methallothioneins, and CYP1A1) the transgenic technologies have not
been extensively utilized to investigate how environmental agents
alter gene expression and cause disease.
 
Therefore, this RFA is issued to encourage research that uses
transgenic animal model systems to study molecular toxicology.  It is
anticipated that these investigations will allow innovative
approaches in understanding the mechanism of gene alteration by
environmentally relevant xenobiotic agents at the genome level, and
the establishment of the nature of the xenobiotic induced gene
expression in specific target cells and organs. Collaborative
research efforts between investigators skilled in transgenic
technologies and members of the environmental health research
community, as well as scientists from closely related disciplines,
are especially encouraged.
 
Because the NIEHS has issued a Program Announcement, PA-90-22
"Development and Utilization of Transgenic Animal and Cell Models in
Studies of Environmental Mutagenesis and Associated Health Effects,"
applications proposing the development and/or use of transgenic
models to screen suspected cancer causing chemicals will be
considered non-responsive to this RFA.
 
The following areas of research interest are not intended to be
complete, and investigators may study these and other topics that
meet the objectives of this RFA:
 
o  Research efforts may be directed at the creation of new transgenic
animals with specific genes whose expression is altered by
environmental agents, the induced responses are tissue and organ
specific, and a relationship between toxicant exposure in target
organs and subsequent development of disease sequelae may be
established.  For example,
 
 - new transgenic animals may be developed for the identification and
characterization of genes that are involved in modulation of the
cellular signaling pathways that lead to the xenobiotic induced
health effects.
 
- transgenic animals could be designed to improve our  understanding
of the correlation between chemical induction or suppression of
programmed cell death or apoptosis and subsequent health
consequences.
 
o  Transgenic animals could be used to study the over expression or
inappropriate expression of xenobiotic inducible genes in order to
understand the molecular basis of tissue specific and stage specific
gene expression following exposure to the environmental agent.
 
o New transgenic animals could also be used to study the regulation
of DNA repair with emphasis on the identification and
characterization of novel systems, and the molecular dissection of
the genetic elements responsible for the cellular response.  For
example, studies may be designed to:
 
- investigate cell and tissue specific expression of the DNA repair
genes induced by xenobiotic agents,
 
- study the interactions between the environmentally induced repair
pathways, transcriptional induction, cell cycle arrest, and DNA
replication.
 
Research studies directed toward potential implications of
environmental agents in non cancer disease endpoints are strongly
encouraged.  Therefore, new transgenic models may be developed for
the identification of environmental agents that cause non cancer
health effects, including, but not limited to, neurological,
reproductive/developmental, immunological or cardiovascular diseases.
Studies proposing the development and/or use of transgenic animals
for the screening of cancer causing agents are not appropriate for
this RFA.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by May 10, 1996, 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 consultants, the
participating institutions, and the number and title of the RFA in
response to which the application may be submitted.  It is important
to consider during the planning phase of the application, that the
requested direct costs for the R01 applications submitted in response
to this RFA may not exceed $200,000 per year.
 
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 is helpful in planning for the review of
applications.  It allows NIEHS staff to estimate the potential review
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
Telephone:  (919) 541-7826
FAX:  (919) 541- 2503
 
SPECIAL REQUIREMENTS
 
Applicants should request funds for one trip per year to the NIEHS in
Research Triangle Park, North Carolina for an annual meeting of
grantees.
 
APPLICATION PROCEDURES
 
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 Grants Information Office, Office of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714,
email:  girg@drgpo.drg.nih.gov.
 
The RFA label available in the PHS 398 application form 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 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.
 
Submit a signed, typewritten original of the application, including
the checklist, and three signed, clear, and single sided photocopies
in one package to:
 
DIVISION OF RESEARCH GRANTS
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 also 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
 
Applications must be received by June 10, 1996.  If an application is
received after that date, the Division of Research Grants (DRG) may
contact the applicant to determine whether it will be returned to the
applicant or reviewed with unsolicited applications for the next
regular receipt date.  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.  In addition, DRG will not accept any application that
is essentially the same as one already reviewed.  This does not
include the submission of substantial revisions of applications
already reviewed, but such applications must include an introduction
addressing the previous critique.
 
REVIEW CONSIDERATIONS
 
Because the scope of the research proposed in response to this RFA
encompasses the interest of several NIH institutes and centers,
applications might receive dual assignments based on the established
PHS referral guidelines.  Applications will be administratively
reviewed by NIH staff for completeness and responsiveness to this
RFA.  Applications found to be incomplete or non responsive to this
RFA will be returned to the applicant without further consideration.
Those applications that are complete and responsive to this 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.  Those applications
judged by the study section panel to be non competitive will be
administratively withdrawn from competition.  Those applications
judged to be competitive, deemed to have the highest scientific
merit, generally the top half of the applications under review, will
be discussed at the study section meeting, assigned a priority score,
and receive a second level review by the EHS national advisory
council.
 
Review Criteria
 
The following criteria will be considered:
 
o  scientific, technical, or medical significance and originality of
the proposed research as it relates to the utilization of transgenic
models to increase our knowledge of health effects of environmental
toxicants;
 
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 key personnel, particularly in the area of
transgenic technologies;
 
o  availability of resources necessary to perform the research; and
 
o  appropriateness of the proposed budget and duration in relation to
the proposed research.
 
AWARD CRITERIA
 
The anticipated date of award is September 1996.  The following will
be considered in making funding decisions:
 
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.
 
INQUIRIES
 
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:
 
Jose M. Velazquez, Ph.D.
Chemical Exposures and Molecular Biology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233, 104 Alexander Drive, MD 3 04
Research Triangle Park, NC  27709
Telephone:  (919) 541-4500
FAX:  (919) 541-2843
Email:  velazqu1@niehs.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
Research Triangle Park, NC  27709
Telephone:  (919) 541-7628
FAX:  (919) 541-2860
Email:  mineo@niehs.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No.93.113, 93.114 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.
 
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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