NEWS

 Cystic Fibrosis Foundation opens new research door with Protoeomics at University of North Carolina, Chapel Hill

BETHESDA, Maryland -- Cystic Fibrosis Foundation Therapeutics, Inc. (CFFTI), the drug discovery and development arm of the Cystic Fibrosis Foundation, today announced that it has awarded $1.79 million to scientists at the University of North Carolina at Chapel Hill (UNC) to harness the power of the cutting-edge field of proteomics in the search for new therapeutic strategies for cystic fibrosis (CF).

CF researchers are poised to use proteomics, an innovative area of biomedical science, to discover potential therapeutics for CF and to form new diagnostic tools. Genomics, which is the technology used to identify genes, has provided the complete genetic maps for organisms from bacteria to human beings. These genes, in turn, produce proteins that serve as the cell’s machinery. Scientists are using proteomics technology to identify all of the proteins in a cell or tissue and to study their functions and the interactions among these proteins. Proteins direct cellular functions, and abnormal protein interactions have been associated with disease, including CF.

Although most of the tools used in proteomics are not new, only recently has automation of these methods been possible, allowing for more rapid, continuous use. 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.

Recently, the CF Foundation gave a proteomics research award to M. Jackson Stutts, Ph.D., associate professor of medicine in the department of pulmonary and critical care medicine at the UNC School of Medicine.

"By supporting proteomics, the CF Foundation opens a brand new door in our search for a cure or control 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 proteomics because it offers the possibility of discovering drug targets to correct the root cause of the disease."

A protein produced by the CF gene — Cystic Fibrosis Transmembrane conductance Regulator (CFTR) — normally is found in cells that line certain organs (epithelial cells), including the lungs, the pancreas and the sweat ducts. CFTR’s function is to form a channel for the flow of chloride particles through the cell membrane. In CF, the protein fails to perform its job — either not at all or insufficiently — leading to an imbalance of salt and water at the inner lining of these organs. Abnormally thick, sticky mucus develops, causing the progressive respiratory and digestive problems that characterize CF.

Most CF gene mutations encode CFTR proteins that are "misfolded" as they are processed. Therefore, very few reach the cell membrane, where they need to be to perform their job. 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.

Stutts’s study aims to identify as many of the proteins as possible that interact with CFTR in cells lining the airways. Some of these proteins may represent novel targets for new drugs to promote better processing of mutant CFTR. The results of this study will provide the groundwork for collaborations with biotechnology companies that will translate the findings into drug screening and drug design strategies.

Proteomics has the potential to accelerate our understanding of the formation and function of CFTR, explained Stutts. "The life cycle of a CFTR molecule involves interactions with many different other proteins within multiple subcellular compartments. Some of these interactions are known, but it is thought that many more remain undiscovered. It is among these undiscovered interactions of CFTR that we hope to recognize junctures that can be manipulated to improve CFTR function," he said.

To accomplish such a monumental task, a group of investigators with expertise in protein chemistry, epithelial cell biology and epithelial cell physiology have been assembled, including Christoph Borchers, Ph.D., assistant professor in the department of biochemistry; and Sharon L. Milgram, Ph.D., associate professor in the department of cell and developmental biology, both at the UNC medical school; and Jack Riordan, Ph.D., Richard O. Jacobson professor of molecular medicine and professor of biochemistry and molecular biology at the Mayo Clinic, Scottsdale, Ariz., who was co-discoverer of the gene that causes CF.

In addition, this proteomics endeavor is complemented by the state-of-the-art scientific resources at UNC, including the UNC Mass Spectrometry Core Facility, as well as a supply of many types of human airway epithelial cell lines (a type of cells where CFTR is found). These cell lines are available, thanks to the cutting-edge work of Scott Randell, Ph.D., assistant professor of medicine and cell and molecular physiology at UNC.

"For the proteomics approach we proposed, large quantities of airway epithelial cells are essential," said Stutts. "However, to identify proteins interacting with CFTR in these cells requires a method of isolating CFTR and associated proteins. This is possible because of highly specific antibodies against CFTR developed by our collaborator, Dr. Jack Riordan. His expertise is key to recognizing and understanding any novel interactions of CFTR that our proteomics efforts uncover."

Another use of proteomics in this new CF Foundation–funded 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. These studies will be carried out at several other institutions and companies.

The CF Foundation’s support for proteomics research in Chapel Hill follows the announcement last year of a public-private investment in a campuswide genome sciences initiative representing at least $245 million over the next decade. That commitment included a $25 million anonymous gift to create the Michael Hooker Center for Proteomics to help place UNC at the forefront of this rapidly emerging scientific field.

UNC already has a robust history of taking a leading role in many of the CF Foundation’s research and patient care initiatives. The UNC CF care center is the site of one of the CF Foundation’s eight Therapeutics Development Centers, which coordinate clinical trials of cutting-edge new treatments. It is also the location of the first-of-its-kind CF National Bioinformatics Center, where functional genomics data from CF research around the world are consolidated into a central repository, to promote information sharing. Furthermore, the UNC CF care center has been a part of the 10-member CF Research Development Program since it began in the 1980s. Scientists from many disciplines are brought together through this program to maximize their collective expertise for CF. UNC also is the site of one of seven Gene Therapy Centers, where the technology to make CF gene therapy a success is being developed.

Contact: Allison M. Tobin
Director of Media Relations
Cystic Fibrosis Foundation
(301) 841-2665

Mike McFarland
University Relations
University of North Carolina at Chapel Hill
(919) 962-8593