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U.S. Environmental Protection Agency
Office of Research and Development
National Center for Environmental Research
Science to Achieve Results (STAR) Program

CLOSED - FOR REFERENCES PURPOSES ONLY

Computational Toxicology and Endocrine Disruptors: Use of Systems Biology in Hazard Identification and Risk Assessment

Opening Date: August 15, 2003
Closing Date: January 21, 2004

Summary of Program Requirements
Introduction
Background
Specific Areas of Interest
References
Funding
Eligibility
Standard Instructions for Submitting an Application
Sorting Codes
Contact

Get Standard STAR Forms and Instructions (http://www.epa.gov/ncer/rfa/forms/)
View NCER Research Capsules (http://www.epa.gov/ncer/publications/topical/)
View research awarded under previous solicitations (http://www.epa.gov/ncer/rfa/archive/grants/)

SUMMARY OF PROGRAM REQUIREMENTS
General Information

Program Title: Computational Toxicology and Endocrine Disruptors: Use of Systems Biology in Hazard Identification and Risk Assessment

Synopsis of Program:
The U.S. Environmental Protection Agency (EPA), through its Science to Achieve Results (STAR) program, is seeking applications proposing innovative approaches for incorporating computational methods into hazard identification and risk assessment. These proposals should incorporate a systems biology approach with chemical effects assessment using traditional and novel techniques, which could include genomics, proteomics, and metabonomics. The proposals should focus on one, or both, of the following investigational areas:

(1) Development of integrative, quantitative models of the function of the hypothalamic-pituitary-gonadal or hypothalamic-pituitary-thyroid axes with emphasis on the descriptions of the normal physiological processes and mechanisms of perturbation following exposure to xenobiotics (e.g., endocrine disrupting chemicals), in rats or a commonly used small fish toxicology model (e.g., fathead minnow, medaka, zebrafish).

(2) Cross-species extrapolation of integrative, quantitative models of the perturbed hypothalamic-pituitary-gonadal or hypothalamic-pituitary-thyroid axes following exposure to xenobiotics from rats to humans or a commonly used small fish toxicology model (e.g., fathead minnow, medaka, zebrafish) to other vertebrates (i.e., within the same class or across classes). The cross-species extrapolation should be based on models as described in item (1). Proposals should demonstrate the existence of these models and their validity.

Contact Person:
Elaine Francis; Phone: 202-564-6789; email: francis.elaine@epa.gov

Applicable Catalog of Federal Domestic Assistance (CFDA) Number(s): 66.509

Eligibility Information:
Institutions of higher education and not-for-profit institutions located in the U.S., and Tribal, state and local governments, are eligible to apply. See full announcement for more details.

Award Information:
Anticipated Type of Award: Grant
Estimated Number of Awards: Three to five awards.
Anticipated Funding Amount: Approximately $2.4 million.
Potential Funding per Grant: $150,000 - 250,000 per year for a duration of up to three years and no more than a total of $750,000, including direct and indirect costs. Proposals with budgets exceeding the total award limits will not be considered.

Sorting Code:
The sorting code for applications submitted in response to this solicitation is:
2003-STAR-L1

Deadline/Target Dates:
Letter of Intent Due Date(s): None
Application Proposal Due Date(s): January 21, 2004

INTRODUCTION

The U.S. Environmental Protection Agency (EPA) is interested in the application of novel technologies, derived from computational chemistry, molecular biology and systems biology, in toxicological risk assessment. In assessing risk associated with exposure to a chemical or other environmental stressor, a number of scientific uncertainties exist along a “source-to-adverse outcome” continuum, beginning with the presence of the chemical in the environment, the uptake and distribution of the chemical in the organism or environment, the presence of the active chemical at a systemic target site, and the series of biological events that lead to the manifestation of an adverse outcome that can be used for risk assessment. The “Human Health Research Strategy” (www.epa.gov/sab/pdf/hhrs.pdf) developed by EPA’s Office of Research and Development (ORD) describes these scientific uncertainties and some of the multidisciplinary approaches that are needed to build linkages between exposure, dose and effects.

Recently ORD has initiated a new research program called “Computational Toxicology” (www.epa.gov/nheerl/comptoxframework/comptoxframeworkfinaldraft7_17_03.pdf) that will use emerging technologies to improve risk assessment and reduce uncertainties in this source-to-adverse outcome continuum. One of the strategic objectives of the Computational Toxicology Initiative is to develop improved linkages across the source-to-outcome continuum, including the areas of chemical transformation and metabolism, better diagnostic/prognostic molecular markers, improved dose metrics, characterization of toxicity pathways, metabonomics, systems biology approaches, modeling frameworks, and uncertainty analysis. This solicitation for research proposals is focused on development of systems biology-based models for key components of adverse health outcomes induced by environmental contaminants.

BACKGROUND

Conventional molecular biology strives to examine key events at ever increasingly finer levels of detail. ORD’s Computational Toxicology Initiative, as well as work being conducted by other institutions and organizations, will provide a wealth of information on effects of toxicants at multiple levels of biological organization by using genomic, proteomic, and metabonomic techniques. In order to be most useful, this information must be integrated into a coherent picture. To maximally utilize and integrate this large amount of information, an approach called systems biology has been developed. Systems biology uses computational methods to reconstruct an integrated physiologic and biochemical model of an organism’s or cell’s biology. The approach is similar to developing a wiring diagram for a complicated electrical system or an engineering diagram, such as one that shows the function and interaction of different parts of an automobile. In this regard, it is targeted at studying how normal biological processes are governed, and how alterations can lead to diseases or other unwanted outcomes. Understanding the functions of a normal cell or organism is key to understanding how toxicants can exert effects.

A systems biology approach will enable the integration of disparate data developed by biologists, computer scientists, chemists, engineers, mathematicians and physicists to construct models of organismal function and response to toxic insult. For any model, a choice must be made about scale and level of detail. In this case, models useful to the Agency most likely will be built from individual subcomponents assembled into a larger system. Once these models are developed, then hypotheses can be developed and tested through virtual simulations prior to designing targeted experiments to validate and inform the models. An integral part of the Computational Toxicology Initiative will be the use of relevant model organisms to expand our understanding of the regulation of biological processes and how toxicants can perturb these processes, with the goal of identifying the key mechanistic events for improved risk prediction.

SPECIFIC AREAS OF INTEREST

The brain-pituitary-gonadal axis and the brain-pituitary-thyroid axis represent two complex endocrine pathways important for reproduction and survival (Kalra, 1993; Stocco and Clark, 1996; Herbison, 1998; Couse and Korach, 1999; Terasawa and Fernandez, 2001; Foster et al, 2002, Viguerie and Langin, 2003; Zoeller, 2003). Growing evidence exists that these two axes are targets for a variety of environmental toxicants. For example, disruption of thyroid homeostasis may occur in response to environmental compounds that affect thyroid synthesis (iodine uptake or peroxidase inhibitors), transport (disrupting binding to thyroglobulin), excretion (phase I and phase II liver enzymes), uptake, and utilization (de-iodinate) (Zoeller, 2003). Of equal complexity, the hypothalamic-pituitary-gonadal axis, in both sexes, has been shown to be sensitive to disruption by environmental agents that affect gonadotropin secretion, steroidogenesis, receptor binding or signal transduction (Stoker et al., 2000, 2001; Goldman et al., 2000). Of particular interest is a better characterization of the mechanisms involved in toxicant-induced alterations in the hypothalamic control of gonadotropin releasing hormone (GnRH) (Cooper et al., 2000; Gore, 2001) and thyrotropin releasing hormone (TRH). Thus, there is a need for the development of protocols and techniques that provide quantitative measures of change within the GnRH and TRH neurons directly, as well as those that quantify changes in the neuronal systems that regulate these cells.

Integrated studies need to be developed that merge the rich basic literature detailing the molecular and biochemical mechanisms involved in the normal functioning of the gonadal and thyroid axes with studies evaluating and characterizing the adverse effects of environmental chemicals on these systems. These efforts should be facilitated by the application of a systems biology approach that could eventually lead to the development of predictive models. Furthermore, due to the complex nature of the regulatory processes of these neuroendocrine axes, incorporation of new technologies are needed so that multiple molecular and biochemical parameters can be evaluated to determine how classes of environmental toxicants affect the systems’ homeostasis. It is envisioned that the development and application of these techniques will assist in the identification and interpretation of changes in the synthesis of reproductive and/or thyroid hormones, hormonal release/clearance, steroid and thyroid receptor regulation (e.g., synthesis, binding, activation) and the hypothalamic peptides and neurotransmitters involved in the regulation of gonadotropin releasing hormone and thyroid releasing hormone.

EPA is seeking applications proposing innovative approaches for incorporating computational methods into hazard identification and risk assessment. These proposals should incorporate a systems biology approach with chemical effects’ assessment using traditional and novel techniques, which should include genomics, proteomics, and metabonomics, as well as formal mathematical descriptions of the relevant physiology and pharmacodynamic aspects. The proposal should focus on one, or both, of the following investigational areas:

(1) Development of integrative, quantitative models of the function of the hypothalamic-pituitary-gonadal or hypothalamic-pituitary-thyroid axes with emphasis on the descriptions of the normal physiological processes and mechanisms of perturbation following exposure to xenobiotics (e.g., endocrine disrupting chemicals), in rats or a commonly used small fish toxicology model (e.g., fathead minnow, medaka, zebrafish).

(2) Cross-species extrapolation of integrative, quantitative models of the perturbed hypothalamic-pituitary-gonadal or hypothalamic-pituitary-thyroid axes following exposure to xenobiotics from rats to humans or a commonly used small fish toxicology model (e.g., fathead minnow, medaka, zebrafish) to other vertebrates (i.e., within the same class or across classes). The cross-species extrapolation should be based on models as described in item (1). Proposals should demonstrate the existence of these models and their validity.

The tools of modern molecular biology, including genomics, proteomics and/or metabonomics should help to elucidate the interrelationships among the key components of the endocrine system under study, how these hormonal pathways maintain homeostasis and, ultimately, how these systems react in response to toxic insults. It would be beneficial if the dose metric input into the model were derived from a similar physiologically based toxicokinetic model. The models may initially be developed for one sex of the adult organism, but should be adaptable to either sex, and to other life stages (particularly the developing organism). Development, testing, and validation of these models will require collaboration among molecular biologists, endocrinologists, and mathematical biologists.

REFERENCES

Cooper, R.L., T.E. Stoker., L. Tyrey,, J.M. Goldman, and W.K. McElroy (2000). Atrazine disrupts hypothalamic control of pituitary-ovarian function. Toxicological Sciences. 53:297-307.

Couse, J.F., and K.S. Korach (1999). Estrogen receptor null mice: What have we learned and where will they lead us? Endocrine Review. 20:358-417.

Foster, D.L., V. Padmanabhan, R.I. Wood, and J.E. Robinson (2002). Sexual differentiation of the neuroendocine control of gonadotropin secretion: Concepts derived from sheep models. Reproduction Suppl. 59:83-99.

Goldman, J.M., S.C. Laws, S.K. Balchak, R.L. Cooper, and R.J. Kavlock (2000). Endocrine disrupting chemicals: Prepubertal exposures and effects on sexual maturation and thryroid activity in the female rat. A review of the EDSTAC recommendations. Critical Reviews in Toxicology. 30:135-196.

Gore, A.C. (2001). Environmental toxicant effects on neuroendocrine function. Endocrine. 14:235-240.

Herbison, A. E. (1998). Multimodal influence of estrogen upon gonadotropin-releasing hormone neurons. Endocrine Reviews. 19:302-330.

Kalra, S.P. (1993). Mandatory neuropeptide-steroid signaling for the preovulatory luteinizing hormone-releasing hormone discharge. Endocrine Reviews. 14:507-538.

Stocco, D.M. and B.J. Clark (1996). Regulation of the acute production of steroids in steroidogenic cells. Endocrine Reviews. 17:221-244.

Stoker, T.E., L.G. Parks, L.E. Gray, and R.L. Cooper (2000). Effects of endocrine disrupting chemicals on puberty in the male rat: A review of the EDSTAC recommendations. Critical Reviews in Toxicology. 30:197-252.

Stoker T.E., J.M. Goldman, and R.L. Cooper (2001). Delayed ovulation and pregnancy outcome: Effect of environmental toxicants on the neuroendocrine control of the ovary. Environmental Toxicolology and Pharmacology. 9:117-129.

Terasawa, E., and D.L. Fernandez (2001). Neurobiological mechanisms of the onset of puberty in primates. Endocrine Reviews. 22:111-151.

Viguerie, N. and D. Langin (2003). Effect of thyroid hormone on gene expression. Curr Opin. Clin. Nutr. Metab. Care. 6:377-381.

Zoeller, R.T. (2003). Challenges confronting risk analysis of potential thyroid toxicants. Risk Analysis. 23:143-162.

FUNDING

It is anticipated that a total of approximately $2.4 million will be awarded, depending on the availability of funds. Approximately three to five awards will be made under this RFA. The projected award per grant is $150,000 to $250,000 per year total costs, for up to 3 years. Requests for amounts in excess of a total of $750,000, including direct and indirect costs, will not be considered.

ELIGIBILITY

Institutions of higher education and not-for-profit institutions located in the U.S., and Tribal, state and local governments, are eligible to apply. Profit-making firms are not eligible to receive grants from EPA under this program.

National laboratories funded by federal agencies (Federally-funded Research and Development Centers, “FFRDCs”) may not apply. FFRDC employees may cooperate or collaborate with eligible applicants within the limits imposed by applicable legislation and regulations. They may participate in planning, conducting, and analyzing the research directed by the principal investigator, but may not direct projects on behalf of the applicant organization or principal investigator. The principal investigator's institution, organization, or governance may provide funds through its grant from EPA to a FFRDC for research personnel, supplies, equipment, and other expenses directly related to the research. However, salaries for permanent FFRDC employees may not be provided through this mechanism.

Federal agencies may not apply. Federal employees are not eligible to serve in a principal leadership role on a grant, and may not receive salaries or in other ways augment their agency's appropriations through grants made by this program. However, federal employees may interact with grantees so long as their involvement is not essential to achieving the basic goals of the grant. EPA encourages interaction between its own laboratory scientists and grant principal investigators for the sole purpose of exchanging information in research areas of common interest that may add value to their respective research activities. This interaction must be incidental to achieving the goals of the research under a grant. Interaction that is “incidental” does not involve resource commitments.

The principal investigator’s institution may enter into an agreement with a federal agency to purchase or utilize unique supplies or services unavailable in the private sector. Examples are purchase of satellite data, census data tapes, chemical reference standards, analyses, or use of instrumentation or other facilities not available elsewhere. A written justification for federal involvement must be included in the application, along with an assurance from the federal agency involved which commits it to supply the specified service.

Potential applicants who are uncertain of their eligibility should contact Tom Barnwell in NCER, phone (202) 564-0824, email:barnwell.thomas@epa.gov

STANDARD INSTRUCTIONS FOR SUBMITTING AN APPLICATION

The Standard Instructions for Submitting a STAR Application including the necessary forms will be found on the NCER web site, http://www.epa.gov/ncer/rfa/forms/.

SORTING CODES

The need for a sorting code to be used in the application and for mailing is described in the Standard Instructions for Submitting a STAR Application. The sorting code for applications submitted in response to this solicitation is: 2003-STAR-L1

The deadline for receipt of the applications by NCER is no later than 4:00 p.m. ET, January 21, 2004.

CONTACT

Further information, if needed, may be obtained from the EPA official indicated below. Email inquiries are preferred.

Elaine Francis
202-564-6789
francis.elaine@epa.gov


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