Stimulus-Secretion Coupling in Diseased Lacrimal Gland

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DESCRIPTION (provided by applicant): Inflammatory diseases of the lacrimal gland such as Sjvgren'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. The hallmarks of lacrimal gland inflammation are the presence of leukocytic infiltrates, loss of acinar epithelial cells (the secreting cells), and increased production of proinflammatory cytokines. Lacrimal gland epithelial cells are terminally differentiated and hence are believed to be unable to proliferate. We discovered that murine lacrimal gland epithelial cells can proliferate in response to tissue insult. The overall goal of this application is to decipher the mechanisms that govern murine lacrimal gland regeneration following experimentally induced inflammation. The knowledge gained will unravel new strategies to promote regeneration of inflamed human lacrimal glands that would restore adequate aqueous tear production. Based on our preliminary data and reports in the literature, we hypothesize that experimentally induced inflammation of the lacrimal gland triggers acinar cell apoptosis that subsequently induces acinar cell differentiation from ductal cells or ductal cell-associated stem/progenitor cells with ensuing proliferation mediated by the increased production of fibroblast growth factor 10 (FGFI 0) and/or bone morphogenetic protein 7 (BMP7). We propose three specific aims: 1 -Determine if lacrimal gland epithelial cells are lost by apoptosis or necrosis during experimentally induced inflammation; 2-Determine which cells are responsible for the regeneration of the murine lacrimal gland following experimentally induced inflammation; and 3- Determine which effector molecules are responsible for triggering lacrimal gland repair following experimentally induced inflammation and investigate if these factors could trigger/accelerate lacrimal gland repair in disease states. 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. PUBLIC HEALTH RELEVANCE There are currently no cures for severe dry eye resulting from loss of the moisture producing cells of the lacrimal glands. We discovered that murine lacrimal gland epithelial cells can proliferate in response to tissue insult. The overall goal of this application is to decipher the mechanisms that govern murine lacrimal gland regeneration following experimentally induced inflammation. The knowledge gained will unravel new strategies to promote regeneration of inflamed human lacrimal glands that would restore adequate aqueous tear production.