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| |  Protein Fragments May Help Alleviate Cystic Fibrosis WASHINGTON, MD -- May 20, 1997 -- Fragments of proteins that form tiny channels in cell membranes show promise as a potential new drug therapy for cystic fibrosis. NIGMS grantee Dr. John Tomich of Kansas State University and his colleagues have used these protein fragments to create functional membrane channels in laboratory-grown cells. Such channels are defective or absent in people with cystic fibrosis. If the technique proves clinically effective, it could underlie a new treatment for the disease. The scientists describe their findings in the May 1997 issue of the American Journal of Physiology: Cell Physiology. Cystic fibrosis (CF) is the most common fatal genetic disease in the United States, affecting approximately 30,000 people. About half die by age 30 In 1989, scientists determined that the major cause of CF is a flaw in the gene that codes for a protein called cystic fibrosis transmembrane conductance regulator (CFTR). Like other "channel proteins," CFTR molecules form passageways through which essential electrically charged atoms flow into and out of cells. Specifically, CFTR controls the flow of chloride ions (a component of salt) across lung, intestine, and pancreatic duct cell membranes. When CFTR is faulty, lung cells do not secrete enough fluid and an abnormally thick, sticky mucus accumulates in the airways, impairing breathing and promoting bacterial infection. Dr. Tomich and his colleagues have extensively researched the structure and activity of channel proteins similar to CFTR, especially a chloride channel protein found in the brain. Most significantly, they found that short, synthetic segments of these proteins form ion channels just like the entire proteins. Medicinal chemists often search for the smallest functional unit of a molecule, since smaller molecules are easier to deliver as drugs. If researchers can develop a mini-protein that forms functional chloride channels in people with cystic fibrosis, there's a chance it could alleviate symptoms of the disease. In order for the protein fragments to serve as chloride channels, they must be taken up by cells. Dr. Tomich and his coworkers discovered that they can increase this uptake -- and thus the passage of chloride and the secretion of fluid -- by adding extra molecules of the amino acid lysine to one end of the mini-proteins. If the same technique proves effective in the lung cells of people with cystic fibrosis, it may prevent the cells from being clogged with mucus. One challenge will be to incorporate the synthetic mini-proteins into a therapeutic delivery system, such as an inhaler. The scientists have applied for a patent on the method of using the brain protein to form chloride channels. The next steps will be to repeat the laboratory experiments using rat and human lung cells, and eventually--if the technique continues to show promise--to design clinical trials in people with cystic fibrosis. Dr. Tomich's collaborators on the paper include Dr. Lawrence Sullivan and Dr. Jared Grantham of the University of Kansas Medical Center; Darren Wallace and Kyle Henderson, graduate students in Dr. Sullivan's laboratory; and Dr. Takeo Iwamoto of Kansas State University. Dr. Tomich's basic research on synthetic, channel-forming protein fragments that laid the foundation for the present work was carried out in collaboration with Dr. Mauricio Montal of the University of California, San Diego. This research was supported by two components of the National Institutes of Health, the National Institute of General Medical Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases, as well as by the Cystic Fibrosis Foundation.
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