Press Release

EMBARGOED FOR RELEASE:
Wed., Aug. 31, 2005, 1 p.m., EST
Contact: Tom Capezzuto
(973) 972-7273
E-mail: capezzta@umdnj.edu

At UMDNJ-Robert Wood Johnson Medical School
UMDNJ Researchers Find Genomic Link in Systemic Inflammation;
Finding May Result in Individualized Trauma Treatment
--Study Published in Aug. 31 On-Line Nature Publication--

9/1/05—Researchers at the University of Medicine and Dentistry of New Jersey (UMDNJ) have identified genomic changes in white blood cells associated with systemic inflammation that may result in improved and individualized treatment of complex traumatic injuries.

The researchers say the study represents a breakthrough in comprehending why some individuals recover well from traumatic injuries while others can have life-threatening inflammatory complications that may develop long after the original injury.

The finding, led by physicians from the UMDNJ-Robert Wood Johnson Medical School in New Brunswick and the Stanford Genome Technology Center in Palo Alto, California, is the key component of a published report that appears in the Aug. 31 on-line publication of the journal Nature.

The project is funded by a five-year, $37 million grant from the National Institute of
General Medical Sciences (NIGMS), a component of the National Institutes of Health, through what are termed "glue grants," which bring together researchers from disparate disciplines that include trauma, surgery, genomics, bioinformatics and computers to address complex trauma- related problems.

In the report, researchers from 22 national sites describe their investigations over the past four years into how the process of systemic inflammation--an immune response that affects the entire body--alters the expression of genes within the white blood cells, which are key both to fighting infections and initiating inflammation.

The Nature paper describes one of the group’s initial experiments, led by Dr. Stephen F. Lowry, chair of the Department of Surgery at the UMDNJ-Robert Wood Johnson Medical School, which focused on the physiologic mechanism behind a systemic inflammatory response that sweeps through the body in response to a defined stimulus.

"This study is singularly unique in that it focuses on interpretation of the genome-wide response to systemic inflammation in the context of a fully predictable recovery, something that cannot be done routinely in severely injured patients because clinical outcomes often are unpredictable in these patients," Dr. Lowry said.

In the study conducted three years ago, healthy volunteers were injected with bacterial endotoxin, which produced a widespread, but controlled, inflammatory response that quickly subsides. Blood samples were taken at various intervals after participants received the endotoxin and the expression levels of genes in white blood cells were analyzed and compared with those of control participants.

"We found that expression levels of more than 3,700 genes in white blood cells changed significantly during the hours after endotoxin injections, while expression levels in control participants were unchanged," said Dr. Steve Calvano, an associate professor of surgery at the UMDNJ-Robert Wood Johnson Medical School and study co-investigator.

"For more than half the identified genes, expression was decreased, including several
genes involved in the function of mitochondria, sub-cellular energy-producing structures," Dr. Calvano said. Based on these findings, the researchers suggest that reduced activity of these key immune cells may occur, leading to increased risk of infection during systemic inflammation.

Since each gene can interact with many others in complex patterns, the researchers turned to a database of information on thousands of human, rat and mouse genes. They were able to construct inflammation-associated molecular networks involving interactions between more than 8,000 genes.

"Hundreds of these genes and pathways were not previously known to be associated with the inflammatory process," and after the data is made available to other interested researchers, they will provide the nucleus for many other studies of the genomic response to inflammation," Dr. Calvano noted.

"Not only has this work identified novel pathways of inflammation, it also demonstrates an approach to getting more meaning out of the data provided by a microarray of gene expression profiles," said Dr. Ronald Tompkins, chief of the Burns Service at Masssachusetts General Hospital, John Francis Burke professor of surgery at Harvard Medical School and national leader of the study.

"This work represents a major step in understanding inflammation in severely injured or burned patients," said Dr. Jeremy M. Berg, director of the NIGMS. "We hope this knowledge will eventually help physicians better predict patient outcomes and tailor treatments accordingly."