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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 efforts.

"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 process.

"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.