NOT-ES-07-009: Request for Information (RFI): Genetic Variation and the Basis for Individual Susceptibility to Environmental Toxicant Associated Disease

Request for Information (RFI): Genetic Variation and the Basis for Individual Susceptibility to Environmental Toxicant Associated Disease

Notice Number: NOT-ES-07-009

Key Dates
Release Date: September 6, 2007
Response Date: October 14, 2007

Issued by
National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.nih.gov/)

The NTP is developing the Host Susceptibility Program, a new research program to identify and functionally validate genes associated with environmental exposure. This effort is designed to facilitate gene-environment interaction research conducted by the extramural or intramural research communities. This program will make NTP resources available to these research communities to investigate the genetic basis for population-level differences in susceptibility to environmental toxicants and/or disease. This research will 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.

This research program is not a funding opportunity or a grant program. This program is being designed 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 review of proposed research projects. NTP scientists will work with successful 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. Through this RFI, extramural and intramural scientists are invited and encouraged to provide information and comment relevant to this proposed research approach in order to help guide further development and refinement of the goals of the NTP Host Susceptibility Program.

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 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 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.

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. This program aims to accomplish the multidisciplinary tasks that are often rate-limiting to many individual research groups that may be interested in investigating environmental toxicant exposure, genetic susceptibility to disease, and determination of allelic variants of causally related genes and their potentially dysregulated signaling pathways. Once a project has been approved, NTP staff will interact directly with the Principal Investigator(s) (PIs) of the approved projects. 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 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 to any or all of the questions below at the Host Susceptibility Program Request for Information webpage by October 14, 2007, at (http://ntp.niehs.nih.gov/go/32130).

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?
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?
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?
What computational, statistical, and bioinformatic methodologies might be particularly useful for determining toxicity phenotypes and identifying associated genes, pathways, and networks?
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?
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?
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?
Is the competitive research partnership approach described for the Host Susceptibility Program 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?
Are there specific concerns over intellectual property or research collaboration issues in a research partnership that should be addressed and negotiated?

Responses

All responses to individual questions within this RFI are optional. The information collected will be analyzed and considered for use in the further development of the NTP Host Susceptibility Program. 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 shall 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 Government’s use of such information as part of our evaluation process.

Submit responses by October 14, 2007 at http://ntp.niehs.nih.gov/go/32130

Inquiries

Direct inquiries regarding this notice to:
John E. French, Ph.D.
Host Susceptibility Initiative
National Toxicology Program
Division of Intramural Research
National Institute of Environmental Health Sciences
111 T. W. Alexander Drive, Rall Bldg/Rm F167
P.O. Box 12233 (MD F1-05)
Research Triangle Park, NC 27709
Phone: (919) 541-2569
Fax: (919) 541-1460
Email: french@niehs.nih.gov

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.

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