Cystic Fibrosis:

Regulation of expression of the CFTR Gene.  The cystic fibrosis transmembrane conductrance regulator (CFTR) gene shows a complex pattern of expression, with temporal and spatial regulation that is not accounted for by elements in the promoter.   The gene is expressed at high levels in intestinal epithelia and at much lower levels in cells within the respiratory epithelium, where the tissue-specific control mechanisms are apparently different.  Using a combined approach of DNase1 hypersensitive site (DHS) mapping and comparative genomics we identified candidate regulatory elements flanking the gene and within introns.  The major focus of current research is to determine 1) the tissue-specific trans-acting factors that interact with these cis-acting elements; 2) how these elements interact with the CFTR gene promoter and 3) the alterations in chromatin structure and modifications that are associated with CFTR expression.

Function of MUC4 airway mucin.
The normal health of all epithelial surfaces in the human body is dependent on the presence of a surface layer of adequately hydrated mucus.  The major protein components of this mucus layer are mucus glycoproteins, mucins, which may either be attached to the cell membrane or secreted from the epithelial surface.  In addition to serving as a barrier that protects and lubricates the epithelium, mucins function as adhesion/anti-adhesion molecules, in invasion and metastasis and in intracellular signaling.  We are working on the major membrane-associated mucin in the airway, MUC4, to determine its role in airway epithelial function in health and disease.  We predict that this molecule acts as an extracellular sensor of airway environment and can have a profound effect on intracellular processes.

Function of MUC6 pancreatic mucin.
The normal functions of mucin glycoproteins may be usurped by cancer cells.  We are dissecting the biological properties of an abundant secreted mucus glycoprotein, MUC6, that is found at several organ sites, including the pancreas, but about which very little is currently known.  We are evaluating the hypothesis that MUC6 functions in the normal pancreatic duct to maintain epithelial integrity, protect the epithelium from enviornmental insults and contribute to the repair of epithelial damage. However, in the early stages of pancreatic cancer, aberrant expression of MUC6 may contribute to progression of this devastating disease.

Collagen XV as a tumor suppressor.
Collagen XV is a proteoglycan found in the basement membrane zones of a number of tissues but its precise functions remain to be elucidated.  Our published data on cervical cancer epithelial cells support the hypothesis that human collagen XV is a dose-dependent suppressor of tumorigenicity.  We predict that the hypothesis will be applicable to other epithelial tumors and are currently testing our hypothesis in the epithelium of the pancreatic duct.  Pancreatic adenocarcinomas are generally highly metastatic and are associated with an extremely poor prognosis in comparison to many other cancers.  The initiating events that underlie the escape of a pancreatic tumor cell, from its site of origin in the ductal epithelium, through the basement membrane of the pancreatic duct are fundamental to the progression of the pancreatic adenocarcinoma.  Elucidation of the key molecular events involved in this escape are a central focus of this project.