294 Re-engineering the Functions of a Terminally Differentiated Epithelial Cell in Vivo BRUCE J. BAUM, a,d SONGLIN WANG, a EDNA CUKIERMAN, b CHRISTINE DELPORTE, a HIDEAKI KAGAMI, a YITZHAK MARMARY, a PHILIP C. FOX, a DAVID J. MOONEY, c AND KENNETH M. YAMADA b a Gene Therapy and Therapeutics Branch and b Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA c Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109–2136, USA ABSTRACT: Because of their easy access, and important role in oral homeo- stasis, mammalian salivary glands provide a unique site for addressing key is- sues and problems in tissue engineering. This manuscript reviews studies by us in three major directions involving re-engineering functions of salivary epithe- lial cells. Using adenoviral-mediated gene transfer in vivo, we show approaches to i) repair damaged, hypofunctional glands and ii) redesign secretory func- tions to include endocrine as well as exocrine pathways. The third series of studies show our general approach to develop an artificial salivary gland for clinical situations in which all glandular tissue has been lost. INTRODUCTION An age-old clinical axiom states that the mouth is the gateway to the body. In- deed, many systemic diseases present with clinical signs easily recognizable in the open mouth. 1 Analogously, the mouth provides several advantages for the applied scientist or clinician interested in tissue engineering, but none is more important than ease of access. For many years, we have been studying mechanisms by which salivary glands produce their secretions. 2,3 Salivary glands have provided a valuable experimental model for generations of scientists interested in neurofunctional controls, from Claude Bernard and Ivan Pavlov to the present day. They are highly responsive epi- thelial tissues whose function can be readily and non-invasively measured. 4,5 In humans there are three major pairs of salivary glands (parotid, submandibular, and sublingual). These glands consist almost entirely of well-differentiated epithe- lial cells that exist as a monolayer bordering on an extensively arborized lumen. 6 Each of these major glands has a direct exit into the mouth through a single main excretory duct. Thus, from an open mouth the cannulation of the duct orifice, a pro- cedure which in humans requires no anesthesia, affords direct access to the luminal membrane of virtually every epithelial cell in this secretory tissue. It is our belief that d Author for correspondence: GTTB, NIDCR, NIH, 10 Center Drive, MSC 1190, Building 10, Room 1N113, Bethesda, MD 20892; 301-496-1363 (voice); 301-402-1228 (fax); bruce_j_baum@nih.gov (e-mail).