[Federal Register: October 3, 2007 (Volume 72, Number 191)]
[Notices]
[Page 56358-56360]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr03oc07-60]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Toxicology Program (NTP); Host Susceptibility Program
(HSP); Genetic Variation and the Basis for Individual Susceptibility to
Environmental Toxicant Associated Disease: Request for Information
AGENCY: National Institute of Environmental Health Sciences (NIEHS),
National Institutes of Health (NIH).
ACTION: Request for information.
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SUMMARY: The NTP is developing the Host Susceptibility Program (HSP), a
new research program, to identify and functionally validate genes
associated with environmental exposure. This program will make
available NTP expertise and resources to investigate the genetic basis
for population-level differences in susceptibility to environmental
toxicants and/or disease based upon gene and environment interactions.
This research will be designed to ultimately lead to a better
understanding of why some individuals are more susceptible than others
to exposure to an environmental toxicant resulting in disease and
morbidity. Asthma, cardiovascular disease, cancer, diabetes, and
obesity are examples of diseases associated with multiple interacting
genes that are influenced by exposure to environmental agents. Through
this Request for Information, extramural and intramural scientists are
invited and encouraged to provide information and comment relevant to
this proposed programmatic research approach in order to help guide
further development and refinement of the goals of the NTP HSP.
Information on this initiative can be submitted electronically through
the HSP Request for Information Web site at: (http://ntp.niehs.nih.gov/go/32130
) or by contacting Dr. John E. French (see FOR FURTHER
INFORMATION CONTACT below).
DATES: The deadline for response is October 31, 2007.
ADDRESSES: Responses can be submitted electronically at the HSP Request
for Information Web site: http://ntp.niehs.nih.gov/go/32130.
FOR FURTHER INFORMATION CONTACT: Other correspondence should be
directed to Dr. John E. French, Host Susceptibility Program, NIEHS,
P.O. Box 12233, MD EC-17, Research Triangle Park, NC 27709, (fax) 919-
541-0947, (email) hsp@niehs.nih.gov. Courier address: Dr. John E.
French, Host Susceptibility Program, 111 T.W. Alexander Drive, Building
101, Room F167, Research Triangle Park, NC 27709.
SUPPLEMENTARY INFORMATION:
Background
The NTP was established as a cooperative effort to (1) coordinate
toxicology testing programs within the federal government, (2)
strengthen the science base in toxicology, (3) develop improved testing
methods, and (4) provide information about potentially toxic chemicals
to health, regulatory, and research agencies, scientific and medical
communities, and the public. To meet these goals, NTP designs and
conducts large-scale laboratory animal research and testing programs
and analyzes and reports their findings to assess potential hazards to
human health from exposure to environmental chemicals.
Recently, the NTP led and funded a haplotype mapping project with
Perlegen Sciences to resequence 15 isogenic strains of mice selected
for their potential genetic diversity. Along with the public sequence
of isogenic C57BL/6J, analysis of 16 sequenced strains has revealed,
conservatively, more than 8 million single nucleotide polymorphisms in
this initial analysis of laboratory and wild-derived isogenic mouse
strains (Frazer et al., 2007). Identification and analysis of mouse
haplotypes will provide a valuable tool for haplotype-phenotype
association studies in genetically diverse strains that can be used to
predict human genetic variants of functional significance (http://mouse.perlegen.com/mouse/index.html
). Toward that goal, the NTP is
developing a multidisciplinary research program on genetic
susceptibility to environmental exposures. This effort will partner
extramural and/or intramural researchers with NTP scientists by
creating research partnerships using NTP R&D contract resources. This
research program is not a funding opportunity or a grant program.
The intent of HSP is to provide researchers access to NTP R&D
contract resources and NTP expertise in public health toxicology.
Participation by extramural and/or intramural scientists will be based
on competitive peer
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review of proposed research projects. NTP scientists will work with
extramural and/or intramural investigators to define and refine the
most effective and cost-efficient experimental protocols for
accomplishing the experimental aims and for linking environmental
exposure with toxicity leading to disease. Development of approved
projects will proceed sequentially from hypothesis through specific
aims, based upon a consensus derived experimental plan. Continued
support of research projects will depend upon satisfactory completion
of each phase of the research plan.
Via this partnership, extramural and/or intramural investigators
will have access to NTP contract resources to investigate the
relationship between exposure to environmental toxicants and
development of quantitative measures of toxicity and disease, using
genetically diverse experimental animal models. Using research
partnerships, HSP scientists aim to develop the tools and means
necessary to accomplish the multidisciplinary tasks that are often
rate-limiting to individual research groups that may be interested in
investigating environmental toxicant exposure and genetic
susceptibility to disease and determining allelic variants of causally
related genes and their potentially dysregulated signaling pathways.
Once a project has been peer reviewed and approved, NTP staff will
interact directly with the Principal Investigator(s) (PIs) of the
approved projects to refine the research using NTP contracted
resources. NTP R&D contractors will perform approved tasks under the
direction of NTP staff. Those tasks necessary to accomplish the
experimental aims of any particular study are expected to vary from
project to project. In some cases, NTP may only support one or two key
missing steps necessary to complement the research; in other cases, it
may be necessary to supply the entire scope of experimental tasks
needed to complete the specific aims. Examples of tasks that can be
supported by NTP contracts and staff include, but are not necessarily
limited to:
Facilitating animal model selection (multiple-isogenic
strains, heterogeneous, outbred stocks, etc.).
Providing strain-specific data on absorption,
distribution, metabolism, and excretion of metabolic products of
environmental toxicants.
Defining or optimizing of exposure route, dose and dose
schedule of environmental toxicants using range-finding studies to
determine quantitative measures of acute toxicity in vivo in an
appropriate animal model.
Quantitatively identifying variants of toxicity
(phenotyping) in multiple isogenic strains, genetically engineered
strains, and/or genetically defined outbred stocks.
Developing appropriate experimental design protocols for
toxicity, biomarkers, expression arrays, clinical and histopathology,
and statistical analysis.
Acquiring test agent(s) in quantities sufficient for non-
GLP acute and prechronic toxicity investigations, development of
analytical methods for determination of quantity and purity of test
substances, production and stability (storage) of dosage forms.
Developing, optimizing, and conducting study and route
specific toxicology and toxicity assays for correlation between
toxicity and histopathologic determinants.
Output from such collaborative research activities, which may
include providing biological samples and/or data (genotyping,
quantitative measures of toxicity, expression phenotypes, etc.), is to
be made fully available to the originating principal investigator (or
his/her replacement, in case of withdrawal) for continued support of
the research project developed within the partnership. Data and samples
are to be transferred to extramural or intramural collaborators under
terms of a negotiated NIH Materials Transfer Agreement.
Information Requested
The NTP is soliciting information from the extramural and
intramural research communities on the strategies, resources, and tools
necessary to enable this cooperative research program on genetic
variation and individual susceptibility to environmental toxicant
exposure and associated polygenic diseases to progress. Please respond
online at the HSP Request for Information Web page (http://ntp.niehs.nih.gov/go/32130
) to any or all of the following questions by
October 31, 2007.
1. In general, what are the utility and limitations of using model
organisms (e.g., multiple strains of isogenic mice, heterogeneous mouse
stocks, etc.) to investigate and establish the genetic determinants of
biological response?
2. Are there particular environmental toxicants associated with
human disease where this research approach is immediately applicable
and useful to the identification of causally related genes and their
allelic variants?
3. Similarly, are there particular physiologic or pathogenic
pathways and/or disease endpoints for which the proposed research
approach is likely to be especially insightful in advancing our
understanding of gene-environment interactions?
4. What computational, statistical, and bioinformatic methodologies
might be particularly useful for determining toxicity phenotypes and
identifying associated genes, pathways, and networks?
5. What high-data content technologies, platforms, and statistical
approaches might be particularly valuable and critical to elucidating
the genetic basis for toxicity and disease based upon the experience
and knowledge gained over the past decade?
6. Are there high-throughput assays and screens using cell-based
systems that might be employed to examine the role of genetic variation
in human exposure?
7. Are in vitro and in vivo assays and genetic models for
functional validation of genes useful in permitting orthologous human
genes and their allelic variants to be identified and tested in large-
scale human populations with defined environmental exposures?
8. Is the competitive research partnership approach described for
the HSP using NTP R&D expertise in toxicology and contract resources
viable and of general interest to researchers interested in these
questions? Why or why not?
9. Are there specific concerns over intellectual property or
research collaboration issues in a research partnership that should be
addressed and negotiated?
All responses to individual questions within this Request for
Information are optional. The information collected will be analyzed
and considered for use in the further development of the NTP HSP. The
summarized data (without identifiers) may appear in internal reports.
Although the NIH will provide safeguards to prevent the release of
identifying information, there is no guarantee of confidentiality. This
Request for Information is for planning purposes and should not be
construed as a solicitation for applications or as an obligation on the
part of the Government. The Government will not pay for the preparation
of any information submitted or for the Government's use of that
information. Acknowledgement of receipt of responses will not be made,
nor will respondents be notified of the Government's assessment of the
information received. No basis for claims against the Government shall
arise as a result of response to this Request for Information, or in
the
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Government's use of such information as part of our evaluation process.
Reference
Frazer, K.A., E. Eskin, H.M. Kang, M.A. Bogue, D.A. Hinds, E.J.
Beilharz, R.V. Gupta, J. Montgomery, M.M. Morenzoni, G.B. Nilsen,
C.L. Pethiyagoda, L.L. Stuve, F.M. Johnson, M.J. Daly, C.M. Wade,
and D.R. Cox. A sequence-based variation map of 8.27 million SNPs in
inbred mouse strains. Nature 2007 July 29 Epub.
Dated: September 24, 2007.
Samuel H. Wilson,
Acting Director, National Institute of Environmental Health Sciences
and National Toxicology Program.
[FR Doc. E7-19462 Filed 10-2-07; 8:45 am]
BILLING CODE 4140-01-P