Dry eye syndrome is a chronic lack of sufficient lubrication in the eye due to malfunction or damage to the lacrimal gland. Dry eye may occur as a part of the natural aging process, as a side effect of many medications, as an effect of environmental causes (dry climate or pollution), or as result of an autoimmune disease (Sjogren's syndrome). Though lacrimal gland function has been well studied, relatively little is known about the mechanisms that regulate lacrimal gland development. Our long-term goal is to define these mechanisms and to create a comprehensive model of lacrimal gland development that could be critical for designing alternative treatments for patients with lacrimal gland disorders. Our previous studies showed that members of the fibroblast growth factor (FGF) family are important regulators of lacrimal gland morphogenesis. In particular we found that FGF-10 was necessary for lacrimal and Harderian gland development. Moreover, recent studies have identified mutations in FGF10 in patients with aplasia of the lacrimal and salivary glands (ALSG) and in lacrimo-auriculo-dento-digital (LADD) syndrome. Together these studies established that FGF signaling is important for lacrimal gland development. Over the past two years, we have made significant advances in understanding how structural differences in various FGFs are incorporated into their functional properties. Thus we showed that differences in the binding of FGF7 and FGF10 to heparan sulfate (HS) within the extracellular matrix result in the formation of different gradients that dictate distinct functional activities of these FGFs during branching morphogenesis. These data for the first time connected the structural differences of FGFs with their biological function in LG branching morphogenesis. Our preliminary studies have also shown that FGFs cooperate with canonical Wnt/2-catenin signaling and the homeodomain transcription factor Barx2 in regulating of lacrimal gland morphogenesis. We now propose to focus our efforts on defining structural basis for distinct functions of different FGFs in LG branching morphogenesis (Aim 1). In this aim we will perform a comprehensive functional study of mutations in FGF3 and FGF10 structure. In addition, we will evaluate the regulatory connections between FGF and Wnt signaling pathways and the transcription factor Barx2 in controlling lacrimal gland cell proliferation and differentiation (Aim 2). Understanding the mechanistic details of the FGF signaling in lacrimal gland morphogenesis will have broad significance in the field of developmental biology and will, in the long-term, help the development of novel therapeutic approaches for treatment of patients with dry eye conditions.
In this application we will focus on understanding the regulatory mechanisms that control lacrimal gland branching and repair. Our long-term goal is to define these mechanisms and to create a comprehensive model of lacrimal gland development that could be critical for designing alternative treatments for patients with lacrimal gland disorders.
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