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Genomic basis of inflammation could
lead to improved trauma treatment
Study provides first steps toward
individualized treatment of serious injuries
BOSTON - August 31, 2005 - A multi-institutional research
collaborative has begun to decipher the complex interplay of genes
that underlies the body's response to major injuries. In a report
to appear in the journal Nature, researchers from the Inflammation
and Host Response to Injury program describe their investigation
into how the process of systemic inflammation - an immune response
which affects the entire body - alters the expression of genes within
white blood cells. The findings are a first step towards the overall
goal of understanding why some individuals recover well from traumatic
injuries while others can have dangerous inflammatory complications
that may develop long after the original injury.
"Some of the most serious problems facing patients with major
burns or trauma result from out-of-control inflammation, a process
we still do not understand well," says Ronald Tompkins, MD,
Sc.D., chief of the Burns
Service at Massachusetts General Hospital (MGH) and national
leader of the project. "By looking at how people respond to
injury on a genomic and proteomic level, we hope someday to be able
to tailor treatments to patients' individual needs and keep the
inflammatory response from doing more harm than good."
The project is supported by the National
Institute of General Medical Sciences (NIGMS) through what are
called "glue grants," so named because they bring together
researchers from different institutions and across several fields
- for example trauma medicine, genomics, bioinformatics and computers
- to address complex scientific problems. The inflammation team
incorporates scientists from 22 research centers who have been working
together for four years.
The Nature paper, which is receiving early online release,
describes one of the group's initial experiments, led by researchers
from the University
of Medicine and Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson
Medical School and the Stanford
Genome Technology Center. To examine the physiologic mechanism
behind systemic inflammation, healthy volunteers were injected with
bacterial endotoxin, which produces a widespread but controlled
inflammatory response that subsides quickly. Blood samples were
taken at several points after participants received endotoxin, and
the expression levels of genes in circulating white blood cells
were analyzed and compared with those of control participants using
technologies that tested almost 45,000 probes, representing more
than 30,000 possible human genes.
The researchers found that expression levels of more than 3,700
genes in white blood cells changed significantly during the hours
after endotoxin administration, while gene expression in control
participants was unchanged. More than half the identified genes
were expressed at lower levels, including several genes involved
in the function of mitochondria - subcellular structures that produce
the cells' energy - suggesting reduced activity of these key immune
cells.
Since each gene can interact with many others in complex patterns,
the researchers turned to a database of information on thousands
of human, mouse and rats genes, compiled from more than 200,000
scientific articles with technology developed by Ingenuity Systems
Inc. Using that tool 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.
"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 microarray gene expression profiles. We're
hoping to determine what tools are going to be most effective in
producing real knowledge from these lists of perturbed genes,"
says Tompkins, who is the John Francis Burke Professor of Surgery
at Harvard Medical School.
"This work represents a major step in understanding inflammation
in severely injured or burned patients. We hope this knowledge eventually
will help physicians better predict patient outcomes and tailor
treatments accordingly," said Jeremy M. Berg, PhD, director
of the NIGMS, one of the National Institutes of Health.
The senior authors of the Nature paper are Stephen Lowry,
MD, chair of Surgery at UMDNJ - Robert Wood Johnson Medical School,
and Ronald Davis, PhD, professor of Biochemistry and Genetics and
director of the Stanford Genome Technology Center (SGTC). The lead
authors are Steve Calvano, PhD, UMDNJ-RWJMS, and Wenzhong Xiao,
PhD, SGTC; co-authors are Daniel Richards, Ramon Felciano, PhD,
Raymond Cho, and Richard Chen of Ingenuity Systems Inc.; Henry Baker,
PhD, Kevin Tschoeke, MD, and Lyle Moldawer, PhD, University of Florida;
Bernard Brownstein, PhD, and Perren Cobb, MD, Washington University
School of Medicine; Carol Miller-Graziano, PhD, University of Rochester
School of Medicine; and Michael Mindrinos, PhD, SGTC
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $450 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Media Contacts: Sue
McGreevey, MGH Public Affairs
Tom Capezzuto, UMDNJ - Robt.
Wood Johnson Med.School
Physician Referral Service: 1-800-388-4644
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