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MOLECULAR AND CELLULAR LABORATORY
Nancy McNamara, O.D., PhD.
Molecular Mechanisms of Squamous Metaplasia in Dry Eye
Severe ocular surface diseases, such as Stevens-Johnson Syndrome (SJS), ocular cicatricial pemphigoid (OCP) and Sjögren’s syndrome (SS) present some of the most challenging clinical cases facing eye care providers today. These patients experience numerous problems, including symblepharon formation, corneal vascularization, and squamous metaplasia. Squamous metaplasia, by definition, is a phenotypic change whereby epithelial cells initiate synthesis of specialized, squamous cell-specific proteins including small proline-rich protein, SPRR1B to form the cornified envelope (keratinization). While SPRR1B expression is a normal feature of external squamous tissues (i.e., skin, scalp, footpad, vaginal epithelia), it is a sign of pathology when present in mucosal tissues such as the bladder, lung or ocular surface. Very little is known about the molecular mechanisms mediating squamous metaplasia and efforts to inhibit it have so far been unsuccessful. Recent work suggests that squamous metaplasia is caused by proinflammatory activity of the ocular surface. They have discovered that SPRR1B expression in increased in human patients with Sjögren’s syndrome (SS) as well as an animal model of dry eye disease (shown below) in areas of lissamine green-positive staining. They have defined specific mediators of inflammation that cause squamous metaplasia and have shown a link between these mediators and increased expression of SPRR1B. This work includes a combination of translational and basic science research that is helping us to improve our understanding of the pathogenesis of squamous metaplasia and will open the possibility of developing novel treatments to prevent pathological keratinization.
Animal model of dry eye disease (bottom row) demonstrates increased lissamine
green staining (left panel) and increased expression of SPRR1B in the cornea
(bottom right panel, SPRR1B labeled red) compared to controls (top row).
Novel Drug Therapies to Alleviate Mucus Hypersecretion in Cystic Fibrosis
Ninety-five percent of the morbidity and mortality associated with cystic fibrosis lung disease occurs as a result of chronic infection and mucus hypersecretion that leads to airway obstruction. Ongoing efforts by drug companies to inhibit mucus hypersecretion in response to diverse injury-inducing stimuli have met with little success. The long-term goal of this project is to develop novel therapeutics that inhibit mucus hypersecretion in cystic fibrosis. Specifically, Dr. McNamara and colleagues are exploring different methods for assaying mucus secretion for high throughput screening of chemically diverse compounds that inhibit hypersecretion. These studies are designed to yield results that are readily translatable to the development of human drug therapy.
Smoke-Induced Lung Cancer: Role of EGFR, MUC1 and Catenins
The World Health Organization reports that approximately 1.25 billion people smoke cigarettes on a daily basis (Proctor, 2001) and smoking will cause roughly 10 million deaths per annum by the year 2030 (WHO. Tobacco or Health: 1999). Approximately one-quarter of these deaths will be from lung cancer. While smoke has deleterious effects on virtually every organ of the body, the primary target is the lungs and more than 90% of lung cancers occur as the result of tobacco smoke.
In order to identify drug targets that can be exploited by pharmaceutical companies to alleviate or prevent the effects of smoke-induced lung cancer, one must first understand the pathogenesis of the disease at a molecular level. To do this, Dr. McNamara and colleagues have used a new experimental model of smoke-induced lung cancer that is fast, easy and reproducible and offers the opportunity to perform manipulations of cells at the molecular level during the process of tumor induction by smoke. Using this model, they are able to study several important events that mediate the transformation of normal lung cells to tumor cells. For example, tobacco smoke elicits the dissolution of cell-cell junctions, and early step in tumorigenesis. Interestingly, dissociation of the junction in response to smoke is accompanied by liberation of one of the junction proteins, ß-catenin. In epithelial cells ß-catenin normally exists in a complex with E-cadherin. In response to smoke, ß-catenin is released by E-cadherin and appears to enter the nucleus and modulate tumorigenic gene transcription.
Lung epithelial cells exposed to smoke for 3 days adopt a pleiomorphic shape suggestive of tumorigenesis. Note lateral junctions between control cells (left panel) and smoke-induced translocation of b-catenin (labeled green) to cell nuclei (right panel, arrowheads).
In this respect, the dissolution of junctions mimics effects of an embryonic signaling pathway known as Wnt that is important in development. The aberrant induction of developmental
signaling pathways us a hallmark of tumorigenesis. Further investigation will help to gain insight into the relevant molecular mechanisms that mediate smoke-induced loss of intercellular junctions and induction of the Wnt signaling pathway.
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