IUPS/APS Newsroom March 29-April 6
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Contact: Donna Krupa
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SERPINE2 Identified As Novel
Candidate Gene For COPDSusceptibility, Especially With Smoking
Major
tissue, cell protease inhibitor’s role in lung previously unrecognized
San Diego (April 3, 2005) – Using a combination of
genetic linkage, microarray gene expression and genetic association studies,
a group of Brigham and Women’s Hospital/ Harvard Medical School researchers
have identified a serine protease inhibitor clade E, member 2, or SERPINE2,
“as a novel candidate susceptibility gene for COPD,” according to Sorachai
Srisuma, who is presenting the research at the 35th Congress of the
International Union of Physiological Sciences in San Diego, March 31 - April
5, 2005.
The collaborative, multi-disciplinary team includes:
Sorachai Srisuma, Dawn L. DeMeo, Brigham H. Mecham, Edwin K. Silverman,
Scott T. Weiss, Kathleen J. Haley, John J. Reilly, Steven D. Shapiro, and
Thomas J. Mariani. Mariani, head of the lab where Srisuma works, said the
gene is “the most promising susceptibility candidate due to its biological
relevance, its expression correlation with disease characteristics, and the
allelic association in COPD families and replication in non-familial COPD
patients.”
*Paper presentation: “Expression of Serine
Proteinase Inhibitor E2, a novel candidate COPD susceptibility gene, in the
lung,” 12:30 p.m.-3 p.m. Tuesday April 5, Physiology 936.4/board #A490. On
view 7:30 a.m. - 4 p.m.
First major study to seek SERPINE2’s physiological
role in lung
Srisuma said SERPINE2 “was of particular interest due
to its pattern of expression and relationship to alpha-1-antitypsin, the
only gene proven to modify risk to COPD (chronic obstructive pulmonary
disease). Our team of human genetic epidemiologists, led by Dawn DeMeo and
Edwin Silverman, previously identified a region on chromosome 2 they thought
might contain a gene conferring susceptibility to COPD.
“We used DNA chips, or gene expression microarrays, to
identify genes within this region that were expressed in the lung,” Srisuma
noted. “Subsequently we showed that specific cells in the lungs express
SERPINE2, and that its expression is altered in individuals with certain
clinical characteristics of COPD. Furthermore, specific forms of the gene,
termed polymorphisms or SNPs, were more common in people who developed COPD,”
he said. Taken together, “these data strongly suggest SERPINE2 is a gene
capable of modifying COPD risk, particularly in response to smoking,” he
added.
SERPINE2 is a major tissue and cell-associated
inhibitor of thrombin and plasmin, but not elastase, Srisuma noted. But no
significant study of this protease inhibitor’s expression in normal or
diseased lungs had been undertaken previously. “In an effort to begin to
gain insight into the physiological role of SERPINE2 in the lung, we
investigated the temporal and spatial expression pattern of the gene in
mouse and human lungs,” he said.
Analysis of two independent microarray data sets
describing normal mouse lung development revealed prominent SERPINE2
expression, which was maximal during formation of the airspaces, which is
related to lung maturation. Immunostaining was performed to identify the
location of SERPINE2 within the lung.
SERPINE2 shows analogous pattern in diseased human,
normal mouse lungs
Prominent immunolocalization of SERPINE2 was observed
in a cell-associated pattern within bronchiolar airway epithelial cells and
in an extracellular matrix-associated pattern in the vascular adventitia.
Immunohistochemistry in human lungs demonstrated an analogous staining
pattern. “ Our studies revealed cell-specific and developmentally-regulated
expression of SERPINE2 in the lung, which supports further investigation of
this gene’s role in human lung diseases,” Srisuma said.
Next steps. Already the group has characterized
where and when SERPINE2 is expressed in the lung at various developmental
stages. “We are also investigating the specific role of SERPINE2 mutations
in lung function and the risk of developing COPD in humans and genetically
modified animals,” Srisuma noted. “We hope this line of investigation will
show how SERPINE2 affects the risk of developing COPD and how smoking
contributes to this process,” he added.
In the future, Srisuma will pursue a project
identifying potential biomarkers in COPD patients from New England and also
in his native Thailand. When he completes his current post-doctoral
fellowship and returns home, a collaborative study will proceed related to
lung development and pathogenesis of COPD and pediatric lung diseases.
Scope of the problem, hope for behavior change
About 16 million Americans suffer from COPD, a chronic
inflammatory disorder characterized by a gradual loss of lung function.
Strongly associated with cigarette smoking, COPD is the only disease among
the top 10 causes of death in the U.S. with an increasing rate of newly
diagnosed cases. Already the fourth leading cause of death in the U.S.,
some believe it could be the leading cause of death worldwide by 2010. So
far, there is no cure for COPD, and doctors can only relieve symptoms.
Similar to diseases like cancer and heart diseases,
people who smoke (or breathe second-hand smoke) have an increased risk of
developing COPD, including emphysema and chronic bronchitis. Certain
individuals are more susceptible than others, in that they have an increased
risk of developing disease in response to smoking. For instance, people
with a rare form of the protein made by the gene alpha-1-antitrypsin have a
high risk of developing COPD if they smoke. Individuals with the common
form of this protein have a low risk of developing emphysema, but increase
their chances of getting disease if they smoke.
Srisuma said that nearly all individuals are thought to
have other genes that contribute to their risk of developing COPD.
Researchers have previously identified some candidate susceptibility genes
and further studies may help identify people with increased risk of disease.
“The identification of individuals with increased risk would be beneficial,”
he said, “if they can modify their smoking behavior. Further research also
may hasten the detection diseased individuals, which will be especially
useful if it also leads to potential therapies,” Srisuma added.
***
The 35th Congress of the International Union of
Physiological Sciences is in San Diego, March 31 - April 5, 2005. The
Congress (http://www.iups2005.org/)
is organized by the six member societies of the U.S. National Committee of
the IUPS,
the American Physiological Society,
the Society for Neuroscience,
the Microcirculatory Society,
the Society of General Physiologists,
the Biomedical Engineering Society, and
the Society for Integrative and Comparative Biology, under the auspices
of the U.S. National Academy of Sciences.
The IUPS conference, held every four years, runs
concurrently this year with Experimental Biology 2005 at the San Diego
Convention Center.
The American Physiological Society (APS), which is
hosting IUPS, was founded in 1887 to foster basic and applied science, much
of it relating to human health. The Bethesda, MD-based Society has more than
10,000 members and publishes nearly 4,000 articles every year in its 14
peer-reviewed journals. In May, APS received the Presidential Award
for Excellence in Science, Mathematics and Engineering Mentoring (PAESMEM).
***
Editor’s Note: For further information or to
schedule an interview with a member of the research team, please contact
Donna Krupa at the IUPS/APS newsroom @ 619.525.6228 (March 31-April
6), or (703) 967-2751 (cell) or (301) 634-7209 (office), or Stacy Brooks at
240.432.9697 (cell) or 301.634.7253 (office).
A searchable online program for IUPS and EB is at
http://www.faseb.org/meetings/eb2005/call/default.htm
