CONTACT: BECKY SOGLIN
Iowa City IA 52242
(319) 335-6660; fax (319) 384-4638
Release: Feb. 14, 2001
UI researchers receive $1.5 million Cystic Fibrosis Foundation grant
IOWA CITY, Iowa -- University of Iowa researchers have received a $1.5 million,
three-year grant from the Cystic Fibrosis Foundation for three collaborative
projects that will use genomic-based approaches to search for new therapeutic
strategies for treating cystic fibrosis (CF).
The disease affects multiple organs; however, it is chronic lung disease
that causes the most serious problems. CF alters the normal defense mechanisms
in play at the lung-lining surface, leading to increased susceptibility to
bacterial infection. This chronic infection results in inflammation and tissue
damage. Characteristically, people with CF eventually become infected with
Pseudomonas bacteria that are impossible to eradicate.
The recent sequencing of the human genome and many bacterial genomes, in
concert with human epithelial (surface cell) and bacterial model systems,
has opened many new research opportunities for CF investigators, said Paul
McCray, M.D., UI associate professor of pediatrics, who will direct the collaborative
"This research will help us understand how cystic fibrosis changes
cells that line the airway surface and will allow us to identify the genes
and pathways that are altered in cells affected by CF," McCray said.
"Furthermore, we will work to identify the gene expression patterns in
Pseudomonas aeruginosa biofilms, which contribute to the characteristic antibiotic-resistant
lung infections seen in people with CF."
One of the three project goals is to create a DNA library of an estimated
25,000 genes in airway surface cells. This DNA library will be used as a tool
to better understand how mutations in the gene that codes for a specialized
protein change the functions of cells affected by CF. The specialized protein
of interest is the CF transmembrane conductance regulator (CFTR).
"We hope to identify primary and secondary effects of CF mutations,"
said McCray, who will be on this first project team led by Bento Soares, Ph.D.,
UI associate professor of pediatrics, and physiology and biophysics. Other
UI researchers participating in this project are Joseph Zabner, M.D., associate
professor of internal medicine; Lance Prince, M.D., Ph.D., fellow in pediatrics;
and Michael Welsh, M.D., UI professor of internal medicine and physiology
and biophysics, and a Howard Hughes Medical Institute investigator.
The serious lung and digestive problems associated with CF are caused by
malfunctioning ion channels, or pores, that normally regulate salt and water
secretions to protect the lungs. The CFTR protein makes the channel. However,
in people with CF, the gene that codes for the CFTR protein is mutated. As
a result, the CFTR protein is faulty and gets degraded before it can reach
the cell surface, where it normally functions as an ion channel.
"We want to learn how the presence of the defective protein changes
gene expression in CF cells," McCray said. "Instead of just looking
at the CFTR gene, we will look at all the genes in the cell. The ability to
do this on such a large scale draws on advances in molecular medicine."
The team will use a gene-profiling technique called microarray hybridization
to study the thousands of genes and determine which are expressed (turned
on) in the lung-lining cells. By comparing healthy cells and CF cells, the
investigators hope to identify different groups of genes that are altered
in people with CF and try to understand how these changes impact the disease
"It will be somewhat like a very large fishing expedition," McCray
said. "But we hope to bring home a fish or two."
The second project funded by the grant will be led by E. Peter Greenberg,
Ph.D., Virgil L. and Evalyn Shepperd Endowed Professor of Molecular Pathogenesis
and UI professor of microbiology. Greenberg will search for genes involved
in the antibiotic resistance of Pseudomonas aeruginosa biofilms.
By marshalling the forces of many groups of bacteria, biofilms can withstand
attack from antibiotics and the body's immune system. In addition, CF patients'
own immune systems seem to overreact to the bacteria, damaging tissue and
eventually destroying the lungs. These bacterial clusters are a leading cause
of illness and death for people with CF.
"A major problem for people with cystic fibrosis is that the bacteria
in their lungs is drug-resistant," McCray said. "As a result, it
gets harder to treat CF lung disease by using antibiotics."
Greenberg will grow biofilms of P. aeruginosa bacteria under antibiotic
pressure and see which bacterial genes are "turned on." This information
might then be used against the biofilms. The ability to disable or "turn
off" certain genes might in turn disable the biofilm and thereby halt
potentially lethal infections. Like the first project, this project will use
microarray techniques, also known as gene-chip technology, to measure gene
expression in the bacteria.
The third project funded by the CF Foundation grant focuses on bioinformatics,
or computer technologies, that will link and display the findings, perform
electronic data management, and search databases for possible therapeutic
applications of the results.
This work will be done in the laboratory of Thomas L. Casavant, Ph.D., professor
of electrical and computer engineering in the UI College of Engineering, using
computer techniques developed by his team. His lab's current Web site can
be visited at http://genome.uiowa.edu.
"All the data generated in these studies will be made available to
the cystic fibrosis research community through a Web site," McCray said.
"By achieving the three goals, we believe that new strategies for treating
cystic fibrosis will likely emerge."
The Cystic Fibrosis Foundation previously has funded UI research in cystic
fibrosis. The organization helps support 10 research centers nationwide, including
the UI Cystic Fibrosis Foundation Research and Development Program Center.
The foundation's Web site can be visited at http://www.cff.org/.
University of Iowa Health Care describes the partnership between
the UI College of Medicine and the UI Hospitals and Clinics and the patient
care, medical education and research programs and services they provide.