STRUCTURE-FUNCTION RELATIONSHIPS OF ENVIRONMENTALLY RELEVANT GENETIC VARIANTS

Release Date:  May 29, 1998

RFA:  ES-98-007

P.T.

National Institute of Environmental Health Sciences
National Institute on Aging

Letter of Intent Receipt Date: July 13, 1998
Application Receipt Date: August 13, 1998

PURPOSE

The National Institute of Environmental Health Sciences (NIEHS) is the
principal Federal funding agency that supports research focused on
understanding the mechanisms for human health consequences of exposure to
physical and chemical agents in the environment.  As part of this mission, the
NIEHS initiated the Environmental Genome Project (EGP) to establish how
genetic polymorphisms influence susceptibility or resistance of individuals
following exposure to environmental agents. By understanding how genetic
polymorphisms in the general population affect individual responses to
environmental agents, scientists can better predict health risks and policy
makers will have a science-based framework for the development of
environmental policies to protect susceptible individuals.

The National Institute on Aging (NIA) is a cosponsor of this Request for
Applications (RFA) and is interested in environmentally relevant polymorphisms
in genes that also have implications for understanding individual
susceptibility to aging.

The objective of this RFA is to encourage multi-disciplinary projects to
identify and characterize the gene products coded by allelic variants of
environmental responsive genes (ERG).

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, Structure-Function
Relationships of Environmentally Relevant Genetic Variants, 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 Superintended of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone (202) 512-
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, units of State or local governments and eligible
agencies of the Federal government.  Applications from minority individuals
and women are encouraged.

MECHANISM OF SUPPORT

This RFA will use the NIH individual research project grant (R01) 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
three years. The direct cost per year for R01 grants may not exceed $500,000
without prior discussion with the program officer listed under the INQUIRIES. 
The anticipated award date is April 1, 1999.

This RFA is a one-time solicitation. Unsolicited competing continuation
applications will compete with all investigator-initiated applications and
will be reviewed according to customary peer review procedures.  For
administrative reasons all applications received in response to this RFA will
be assigned initially to NIEHS.  After discussions between the participating
Institutes and before review, applications will be reassigned to the
Institute(s) that are programmatically most appropriate.  Applications may
receive dual assignments based on the established PHS guidelines.

FUNDS AVAILABLE

The funds available for the first year of support for this RFA are expected to
be $3,500,000 in Fiscal Year 1999.  Although the actual number may vary, the
anticipated number of awards is seven to fifteen.  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 rapid increase in our understanding of molecular biology coupled with the
technology and data emerging from the Human Genome Project offers the
opportunity to exploit a new direction in environmental health science
research.  To this end, the NIEHS launched the Environmental Genome Project
(EGP) to focus research on understanding the role of environmental responsive
genes on human susceptibility to environmental agents.  This RFA, which is an
integral part of the EGP, is to encourage researchers to apply the new tools
and technologies in molecular, biochemical, cellular, and structural biology
to understand the biological significance of genetic polymorphisms in
environmental responsive genes.  Extensive background information on the NIEHS
EGP is available at following URL: http://www.niehs.nih.gov/envgenom/home.htm
and in the NIH GUIDE (January 9, 1998).  Based on the extant data, the NIEHS
is most interested in genes controlling the distribution and metabolism of
toxicants, genes for DNA repair pathways, genes for the cell cycle control
system, genes for cell death and differentiation, and genes for the signal
transduction systems controlling the expression of the genes in the other
categories.

The NIEHS's EGP initiative is broader in scope and it is anticipated that the
Project will include additional susceptibility genes as they are discovered. 
This RFA is intended to encourage fundamental studies to identify the
biological impact of genetic polymorphisms in humans.  Such data can be used
as the basis for population-based epidemiological investigations for the
identification of both the ERG alleles and the risk of disease resulting from
exposure to environmental agents.

Identification and Characterization of Polymorphisms

Although many diseases may be caused by relatively rare mutations which result
in total or near complete loss of biological functions, for many gene
products, such as cellular enzymatic activities, it is clear now that common
polymorphisms of the same genes may cause significant reduction of the
cellular enzymatic activity, but to a level which does not lead to overt
symptomology of disease.  Polymorphisms of this type result in an apparently
benign "pseudo-deficiency" of the metabolically important enzyme causing the
individual to possess only minimal levels of the enzyme activity, rather than
the excess of activity found in the majority of people.  These individuals
when exposed to certain environmental agents may experience a pathologic
response at exposure levels that do not affect the general population as a
result of the enzyme deficiency.

For example, more than 60 genes code for the cytochrome P450 (CYP) enzyme
superfamily, which is involved in the metabolism of almost all chemicals to
which we are exposed in our internal and external environments.  The CYP gene
family codes for enzymes that are actors in a long pathway to detoxify and
excrete xenobiotic chemicals (i.e., synthetic compounds foreign to living
systems, such as drugs and insecticides). Looking specifically at the CYP2A6
genes in individuals of various ethnic backgrounds, investigators found two
sequence variants.  Variant one had a single amino acid change, and the
heterozygous state resulted in a reduction of activity to about 50% to 80%.
Homozygotes range from no activity up to 50% activity.  A second variant has
several differences in its sequence.  There are no homozygotes for this
variant, since it does not produce functional protein. This suggests that
there is not an easy way to understand the correlation between variant
sequence and phenotypic expression.

In a similar fashion, DNA repair genes, discovered more than 30 years ago, are
also important to toxicology.  Several genes involved in different DNA repair
pathways, such as base or nucleotide excision repair, have been cloned,
mapped, and the cDNAs isolated.  In many cases, the genomic sequences have
been determined.  Functions that have been ascribed to several of the DNA
repair genes include helicase, endonuclease, polymerase, ligase, and other
activities not fully understood but somehow involved in recombination and
repair processes.

One of the DNA repair genes -ERCC2- is interesting because it has variable
expression in individuals and is associated with three different diseases. 
The most severe of these diseases is Xeroderma Pigmentosum type D, which is
characterized by high sensitivity to UV light, high cancer incidence, and some
neurological disorders.  Another of the diseases, Cockayne's Syndrome, is
characterized by slight photosensitivity and severe neurological defects but
does not have a high cancer incidence.  The third ERCC2 disease,
trichothiodystrophy, presents a defect in the metabolism that causes
brittleness of hair, pale skin, slight photosensitivity in about 50% of the
patients, and some minor neurological defects. ERCC2 is one protein in a multi
protein complex and is part of a transcription factor complex necessary for
gene transcription into mRNA. Protein folding and interaction in the complex
may affect the form and phenotype produced.

To understand the functions of gene sequences, researchers can use a suite of
techniques including standard biochemical approaches, structural approaches,
or animal models such as knockout technologies in mice.  In knockouts, a
particular gene is disabled in the mouse, and any resulting changes in the
animal are noted.

Many novel human genes are being identified through comparisons with sequences
from other species.  In mouse-human comparisons, researchers use gene probes
that will identify both human and mouse clones.  For the DNA repair gene
XRCC1, there are 17 exons in human and the same number of highly conserved
exons in the mouse.  Interestingly, some noncoding regions are also conserved. 
What function do these highly conserve, noncoding regions perform? Are they
actually putative regulatory regions?

As we have seen in the previous examples, understanding the biological
significance of genetic polymorphisms is of utmost importance if we will ever
be able to use DNA variation as an indicator of disease or susceptibility.
More important, certain environmental factors might help trigger a disease
onset. Therefore, individual variabilities in DNA sequences (polymorphims) of
environmental responsive genes might help explain why some individuals in a
population are susceptible to some environmental agents, and why others are
resistant.

Specific Research Goals

The NIEHS and the NIA launching this EGP initiative because it is anticipated
that data generated from the studies will allow for rapid developments of
innovative approaches to elucidate the mechanisms of the xenobiotic-induced
molecular alterations in specific target cells and organs. Collaborative
research efforts between investigators in environmental health sciences and in
molecular and structural biology, and/or molecular modeling disciplines are
especially encouraged.

Summary of major research objectives for this RFA:

o  biochemical and structural biological studies of the proteins coded by the
allelic variants of candidate genes. These studies may include:
characterization of enzyme activities, determination of protein folding and
post-translational modifications, and cellular localization.

o  evaluation of the functional significance of single nucleotide
polymorphisms or other allelic variations in candidate genes and their
regulatory regions.

o  characterization of the molecular mechanisms controlling temporal and
cellular regulation of expression of the allelic variants of a specific class
of genes. The studies could include determination of RNA expression patterns
that contain information about which sets of transcripts are expressed, at
what level, in cell and tissue-specific manner at different stages of
development, differentiation or time in the cell cycle.

o  functional genomic studies to assess the expression patterns and functions
of these classes of environmental responsive genes at the organ/tissue/cell
levels.

o  studies on protein-protein interactions to understand how a specific
allelic variant of one class of gene interacts with other allelic variants of
a different class of genes belonging to the same or different cellular
pathways.

SPECIAL REQUIREMENTS

Investigators conducting biomedical research frequently develop unique
research resources.  The policy of the PHS is to make available to the public
the results and accomplishments of the activities that it funds.  All
applications must adhere to the PHS policy for the distribution of unique
research resources produced with PHS funding, which was published in the NIH
Guide for Grants and Contracts, Vol. 25, No. 23, July 12, 1996, and is
available at the following URL: 
https://grants.nih.gov/grants/guide/notice-files/not96-184.html.

Post-Award Management

Since it is anticipated that during the award period, technologies will
improve and the rate of progress and focus of the projects may change, NIEHS
plans to hold annual meetings of the grantees awarded through this RFA. 
Travel funds (up to $2,000 per year) for Principal Investigators to attend the
annual meeting should be included in the requested travel budgets.  The
meeting will be coordinated by NIEHS Program officials to establish research
priorities, review research progress and experimental difficulties, coordinate
resource and data sharing, and discuss new technological developments
applicable to this research program.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of 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 103-43).

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 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

LETTER OF INTENT

Prospective applicants are asked to submit, by July 13, 1998, 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, consultants, 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 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
Research Triangle Park, NC  27709
Telephone:  (919) 541-7826
FAX:  (919) 541-2503
Email:  jackson4@niehs.nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in
applying for these grants.  These forms are available at most institutional
offices of sponsored research and may be obtained from the Division of
Extramural Outreach and Information Resources, National Institute of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, Email: GRANTSINFO@NIH.GOV.

If IRB or IACUC review is unavoidably delayed beyond submission of the
application, a follow-up IRB certification and/or IACUC verification from an
official signing for the applicant organization must be sent to and received
by the Scientific Review Administrator of the Special Emphasis Panel by
October 13, 1998.  If IRB certification and/or IACUC verification is not
received by October 13, 1998, the application will be considered incomplete
and returned to the applicant.

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:

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.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O.Box 12233, 111 T. W. Alexander Drive, EC-24
Research Triangle Park, NC  27709

Applications must be received by August 13, 1998.  If an application is
received after that date, the Center for Scientific Review (CSR) may contact
the applicant to determine whether it will be returned to the applicant or be
reviewed with unsolicited applications for the next regular receipt date.  The
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 include 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 CSR and
responsiveness by the NIEHS.  Incomplete and/or non-responsive to the RFA will
be returned to the applicant for submission through the regular mechanisms. 
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
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, assigned a priority score, and receive a second
level review by the appropriate National Advisory Council(s).

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 review, comments on the following aspects of the application will
be made 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 the assignment of the overall score.

o  Significance:  Does this study address an important problem?  If the aims
of the applications are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
the field of environmental health sciences?

o  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?

o  Innovation:  Does the project employ novel concepts, approaches, or
methods?  Are the aims original and innovative?  Does the project challenge
current paradigms or develop new methodologies or substantially improve
existing technologies?

o  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)?

o  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?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

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

o  The proposed plans for the distribution of data/materials generated by the
research program.

The application of creative and innovative (high risk/high impact)
experimental approaches and the development of interactive strategies and
collaborative teams to the research goals of this RFA are encouraged.

Schedule

The following is the schedule planned for this initiative.  It should be noted
that this schedule may be changed without notification due to factors that
were unanticipated at the time of the announcement.  Contact the program
official below regarding any changes in the schedule.

Letter of Intent Receipt Date:  July 13, 1998
Application Receipt Date:       August 13, 1998
Initial Scientific Review:      October 21-23, 1998
Advisory Council Review:        February 1-2, 1999
Anticipated Date of Award:      April 1, 1999

AWARD CRITERIA

The anticipated date of award is April 1, 1999.  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 RFA.

INQUIRIES

Written and telephone inquires 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 Velazquez, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, 111 Alexander Drive, MD EC-21
Research Triangle Park, NC  27709
Telephone:  (919) 541-4998
FAX:  (919) 541-4937
Email:  velazqu1@niehs.nih.gov

Huber Warner, Ph.D.
Biology of Aging Program
National Institute on Aging
Bethesda, MD  20892
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  warnerh@exmur.nia.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, 111 T.W. Alexander Drive, MD EC-22
Research Triangle Park, NC  27709
Telephone:  (919) 541-1373
FAX:  (919) 541-2860
Email:  mineo@niehs.nih.gov

Mr. Joseph Ellis
Grants Management Office
National Institute on Aging
Gateway Building, Room 2N212
Bethesda, MD  20892
Telephone:  (301) 496-1472
FAX:  (301) 402-0066
Email:  ellisj@exmur.nia.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.113, 93.114, and 93.15.  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 Public Health Service (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.

Return to Volume Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.