Stimulus-Secretion Coupling in Diseased Lacrimal Gland

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Inflammatory diseases of the lacrimal gland such as Sj¿gren's syndrome, sarcoidosis, and chronic graft versus-host disease or simply as occurs with advanced age, lead to inadequate secretion of the aqueous layer of the tear film, which is a leading cause of keratoconjunctivitis sicca (KCS) or dry eye syndromes. Common denominators for these diseases are the phenotypic signs of chronic inflammation (injury) of the lacrimal gland with loss of parenchymal tissue (the tear secreting acinar and ductal epithelial cells) and the inability of the gland to repair itself. To date there are no cures for dry eye syndromes. We recently discovered that the lacrimal gland contains label retaining slow cycling progenitor cells that are involved in repair following experimentally induced injury. We also discovered that during the repair phase, cells with a mesenchymal stem cell (MSC) phenotype are generated through induction of epithelial-to-mesenchymal transition (EMT). MSCs actively participate in lacrimal gland repair to generate acinar and ductal epithelial cells and restore adequate tear production. In the present proposal, we are capitalizing on these discoveries by hypothesizing that: 1) lacrimal gland repair mechanisms are compromised in animal models of autoimmune-driven lacrimal gland deficiencies largely because their extracellular matrix is disrupted, 2) manipulation of matrix metalloproteinases (MMPs), especially MMP2 and/or 9 expression/activity may improve lacrimal gland regeneration, and 3) that delivery of exogenous stem cells will accelerate the healing process of inflamed lacrimal glands. To test these hypotheses, we propose the following specific aims: 1-Iinvestigate changes in the extracellular matrix, cell adhesion molecules and matrix modifying enzymes in chronically inflamed lacrimal glands; 2-Test the hypothesis that manipulation of MMP2 and 9 expression and/or activity would improve healing of chronically inflamed lacrimal glands; 3-To use genetic cell lineage tracing to further characterize the phenotype of the cells involved in initiation of EMT and mesenchymal-epithelial transition (MET) during experimentally induced injury to the lacrimal gland; and 4-Test the potential of cultured MSCs to accelerate repair of diseased lacrimal glands when delivered in vivo to animal models of autoimmune lacrimal gland deficiency. There are currently no cures for severe dry eye resulting from loss of the moisture producing cells of the lacrimal glands. The studies described here, if successful, will lead to new strategies to halt, and maybe reverse, the loss of these cells which will restore normal tear production and alleviate the ocular surface discomfort associated with dry eye syndromes.