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OHSU Named to $37 Million Research Consortium

   Portland, Ore.

Grant award makes OHSU one of five centers studying gene-environment contributions to disease

Oregon Health & Science University (OHSU) has been selected as one of five university research centers to pioneer development of the National Institutes of Health Toxicogenomics Research Consortium (TRC). Toxicogenomics is a leading-edge scientific discipline that seeks to understand the role of gene-environment interactions in disease and dysfunction. The OHSU component -- spearheaded by the Center for Research on Occupational and Environmental Toxicology (CROET), in concert with the School of Medicine's Department of Pediatrics and Doernbecher Children's Hospital -- will focus on neurotoxicogenomics and child health. Other participants in this national consortium include researchers at the Massachusetts Institute of Technology, the Fred Hutchinson Cancer Research Center at the University of Washington, Duke University and the University of North Carolina.

"It is an honor for OHSU to take part in this national consortium, partnering with some of the finest research institutions across the country," said OHSU President Peter Kohler, M.D. "The selection of OHSU for this important project is further evidence that the university is becoming an institution with research that deserves national recognition."

OHSU received the center grant as a cooperative agreement from the National Institute of Environmental Health Sciences (NIEHS), a component of the National Institutes of Health (NIH). NIEHS and CROET at OHSU have complementary missions of reducing the burden of disease and dysfunction by defining how environmental and occupational agents adversely impact health. Last year NIEHS awarded CROET a Superfund Basic Research center grant that will interact with the new TRC initiative. NIEHS has slated a total of $37 million to fund the TRC for an initial period of five years. OHSU has been approved to receive $7.25 million, one-fifth of which will be used to fund collaborative studies at the Boston Biomedical Research Institute.

"We are excited by this opportunity to help shape the emerging science of toxicogenomics, and to contribute to a priority area of human health focused on disease prevention and intervention at an early treatable stage," said Peter Spencer, Ph.D., F.R.C.Path., principal investigator for the OHSU TRC research site, and CROET senior scientist and director.

Charles Roberts, Ph.D., professor of pediatrics in OHSU's School of Medicine and director of research at Doernbecher, serves as co-principal investigator. "This award complements

Doernbecher's recent designation as a Biotechnology Center by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and demonstrates our commitment to genomics research, which will be a cornerstone of the planned Pediatric Research Institute," noted Roberts.

Srinivasa R. Nagalla, M.D., assistant professor of pediatrics in OHSUiss School of Medicine and director of the OHSU-NIDDK Biotechnology Center, will lead the genomics component of the new TRC site and will also serve as principal investigator for one of the three basic research projects supported by this award.

To conduct their research, scientists at OHSU and other participating TRC centers will utilize gene- and protein-profiling technologies. These groundbreaking methods will allow the consortium to understand at a fundamental level how cells of various organisms respond to environmental factors. Chemicals that disrupt human brain development and induce neurodegeneration are the common interest of scientists in the CROET-Pediatrics research partnership at OHSU. The university's bioinformatics resources will also play an important role in this research by organizing and compiling the tremendous amount of data generated by the research programs.

One of the consortium's goals is to develop standards and practices for the newly developed science of toxicogenomics that will allow researchers to generate consistent data in a suitably equipped laboratory anywhere in the world. The five participating centers will seek inter-laboratory validation of experimental results by conducting specific experiments using common research protocols. A TRC Steering Committee, with membership from the five cooperating university centers, the NIEHS and a NIEHS-appointed contractor, will oversee the research collaboration. The Steering Committee will apply its collective knowledge to accelerate the pace of discovery and promote the identification of gene-expression signatures associated with chemical-induced disorders, such as organic solvent neuropathy. Gene signatures will be entered into a publicly accessible NIH Environmental Genome database for use in developing strategies to prevent and treat environmental diseases.

OHSU's research cooperative agreement with NIEHS will receive advice and input from a committee of distinguished scientists, nurses and physicians representing the fields of molecular toxicology, developmental neurobiology, environmental and legal medicine, and biomedical ethics.

In addition to the national research projects, each consortium site will conduct its own set of fundamental molecular and cellular research studies. OHSU's research projects involve investigations into factors that affect the developing and maturing nervous system. One project, led by Roberts, uses taxol, a drug originally isolated from the Pacific yew tree that fights childhood brain cancer but also causes nerve damage as an unwanted toxic side effect. A second, led by Nagalla, uses DNA-damaging agents that disrupt brain development and which are linked epidemiologically to adult-onset neurodegenerative diseases such as amyotrophic lateral sclerosis and Parkinsonism-dementia. The third, led by Harvard associate professor of neurology, Jeffrey Miller, Ph.D., examines the actions on brain development of man-made chemicals, including an insecticide and fungicide.

Results gained through the synergistic interactions of researchers in the TRC will help improve public health through better risk detection and earlier intervention in disease processes. CROET researchers see benefits in sorting out why some chemicals are bad actors and others not, and how workplace chemicals and other exposures interact to trigger illness.

"Exposures early in life may result in health disorders evident at birth, during development or in later life," said Spencer. "A greater understanding of the impacts of natural and synthetic chemicals on human development will minimize illness in the population and provide for a healthier workforce."

Other CROET scientists who are participating in the new research center include Richard Allen, Ph.D.; Gregory Higgins, Ph.D.; Michael Lasarev, M.S.; Glen Kisby, Ph.D; and Mohammad Sabri, Ph.D. Additional members of the research center include School of Medicine researchers Stephen Back, M.D. (Pediatrics); Christopher Dubay, Ph.D. (Medical Informatics); and Jodi Lapidus, Ph.D. (Public Health).

Pediatrics also sees benefit in the development of new and safer drugs to fight childhood disease. "In the past drugs were only tested for adult use before they were approved by the Food and Drug Administration (FDA). Recently the FDA announced new regulations stating that all drugs used to treat pediatric disease must specifically be tested for this purpose," explained Nagalla. "Using microarray technology, scientists will be able to determine the long-term genetic impacts of therapeutic drugs. By understanding the key genes involved in a disease and the genetic impacts of compounds used to treat the disease, researchers will be better suited to prescribe drugs that will not impact development," he noted. "In the future scientists also may use this information to design new, more targeted drugs that impact the very specific genes involved in the disease, without affecting other genes."


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