Dry eye syndrome affects millions of people worldwide and is one of the most common ocular diseases. Dry eye syndromes are relatively common among the aging population and in women. Though the pathogenesis of dry eye likely involves multiple components, lacrimal gland dysfunction and tear deficiencies are major components. The absence of tears, in severe cases, can lead to abrasion of the corneal surface and blindness. Though lacrimal gland physiology has been well studied, relatively very little is known about the regulatory mechanisms that shape lacrimal gland development. Our long-term goal is to define these regulatory mechanisms and to build a comprehensive model of glandular development. Acquisition of this knowledge will be critical for devising alternative treatment options for patients with lacrimal gland disorders such as dry eye syndromes. Our previous studies have shown that FGF-10, a member of the fibroblast growth factor (FGF) family, is both necessary and sufficient for initiation of differentiation of lacrimal and Harderian glands in the murine eye. These studies established FGF-10 as an important component of the signaling system that induces glandular growth and Differentiation. Mutations in FGF-10 in human patients have been shown to be the underlying cause for aplasia of the lacrimal and salivary glands (ALSG) syndrome, a condition characterized by irritable eyes and dryness of the mouth. These findings underscore the importance of FGF-10 signaling to human lacrimal gland development. The objective of this application is to build on our previous studies and define the roles of downstream components of the FGF-10 signaling pathway that are critical for glandular differentiation. We will focus our efforts on Ras, a downstream effector of FGF-10 signaling (Aim 1), Sprouty, a downstream target and antagonist of FGF-10 signaling (Aim 2), and Edar (ectodysplasin receptor), a downstream target of FGF-10 signaling (Aim 3). These studies will be performed by gain- and loss-of-function studies in mice. As the FGF-10 signaling pathway has been shown to be a critical regulator of branching and epithelial-mesenchymal interactions in multiple organ rudiments including the lungs and limbs, a clear understanding of the mechanistic details of the FGF-10 signaling pathway will have broad significance in the field of developmental biology. In addition, the proposed studies will, in the long-term, allow the development of novel therapeutic approaches for treatment of patients with dry eye syndromes.
