The proteomics research includes awards to scientists at the University of Colorado Health Science Center; University of North Carolina at Chapel Hill; Oregon Health & Science University, Portland; The Hospital for Sick Children, Toronto; Mayo Clinic, Scottsdale, Ariz.; and the University of California, San Francisco. Two of these projects feature partnerships with industry leaders in this biotechnology field: Proteome Systems Limited, Sydney, Australia and Affinium Pharmaceuticials, formerly Integrative Proteomics, Toronto.
Proteomics, the study of proteins made by genes, is changing the landscape of biomedical research. Proteins are the workhorses of the cell, creating and directing cell functions; therefore, abnormal protein interactions are associated with malfunctioning cells that characterize diseases like CF. Correcting the defective protein should yield the same result as adding a healthy gene — correcting faulty cells. Now armed with genetic maps for humans and other organisms, scientists are gaining vast new knowledge about cells based on studying proteins.
“By investing in proteomics, the CF Foundation begins a new strategy in our search for a cure and new therapies for CF,” said Robert J. Beall, Ph.D., president and chief executive officer of the CF Foundation and CFFTI. “We are particularly hopeful about the potential of this technology because it offers the possibility of discovering drugs to intervene at the root of the disease.”
Recently, automation of established methods to analyze proteins has made the technology more rapid and comprehensive. Recognizing this evolution in proteomics technology, the CF Foundation decided the time was right to make use of this powerful biomedical research strategy in CF. This research requires the expertise of many fields of science, from protein chemistry, to epithelial cell biology, to cell physiology.
In CF, an abnormal version of the protein, Cystic Fibrosis Transmembrane conductance Regulator (CFTR), is produced by the inherited CF gene. This gene and its protein are found in cells that line certain organs (epithelial cells), including the lungs and the pancreas. When normal, CFTR forms a molecular channel for the flow of chloride particles through the cell membrane. When faulty, the protein fails to perform its job — either not at all or insufficiently — chloride cannot escape the cell and too much sodium enters. The result: lining organs abnormally thick, sticky CF mucus that causes major problems in the airways and digestive tract.
Researchers know that the CFTR protein interacts with a large number of other proteins in the cell but are just beginning to understand what those proteins might be and how those interactions might be important in CF. Many proteins intermingle with the CFTR protein during all of its functions, including synthesis, folding and transportation to the cell membrane.
“Scientists will compare such protein interactions in mutant [disease-associated] versus normal CFTR,” said Melissa Ashlock, M.D., director of drug discovery at the CF Foundation. “The ultimate goal is to identify novel targets for new CF drugs. These targets could then be developed into high-throughput screens, or tests, to facilitate the accelerated discovery of novel drugs,” she continued. “A CF therapy that can promote normal function of CFTR, in theory, could prevent the disease’s progressive and fatal symptoms from developing.”
As many of the mutant CFTR proteins are processed, they are “misfolded,” and cannot therefore reach the cell membrane, where they need to be to perform their job effectively. However, these mutant CFTR proteins often retain partial function, and restoring some of that activity may help “correct” the defect in CF cells. It is believed that many protein-protein interactions are involved in determining the processing, regulation and function of CFTR. Although some of these interactions are known, many more remain undiscovered.
Some of these proteins may represent novel targets for new drugs to promote better processing of mutant CFTR. The results of these studies will provide the groundwork for collaborations with biotechnology companies that will translate the findings into drug design and testing strategies.
Another use of proteomics in this new CF Foundation research strategy involves identifying proteins that could function as “biomarkers” of the disease’s status, such as a patient’s degree of lung damage or response to treatment. An example of a common biomarker is the “PSA” test to detect prostate cancer.
The CF Foundation was created in 1955 to assure the development of the means to cure and control CF and to improve the quality of life for people with the disease. The CF Foundation’s proteomics research initiative is part of its innovative Therapeutics Development Program, which supports the full spectrum of CF drug development from discovery to clinical evaluation. Matching milestone-driven awards to support CF drug discovery and development are offered to biotechnology companies and academic institutions through this program. Promising new drugs are then streamlined through clinical trial evaluations in the CF Foundation’s Therapeutics Development Network, which is comprised of network of specialized CF care centers.
CFFTI is a nonprofit affiliate of the CF Foundation that operates drug discovery, development and evaluation efforts. CFFTI is made up of industry and academic researchers and members of the CF Foundation Board of Trustees. Total support of CFFTI is provided by the CF FoundationThe CF Foundation provides total support of CFFTI. For more information on the CF Foundation and CFFTI, please visit www.cff.org.