Stimulus-Secretion Coupling in Diseased Lacrimal Gland

泪腺的炎症性疾病，如干燥综合征、结节病和慢性 移植物抗宿主病或只是由于高龄而发生，导致分泌不足的 泪膜的水层，这是干性角结膜炎(KCS)或干眼的主要原因 综合症。这些疾病的共同特征是慢性炎症的表型标志。 泪腺(损伤)实质组织丢失(泪液分泌腺泡和导管上皮) 细胞)和腺体自我修复的能力。到目前为止，干眼症还没有治愈方法。 我们最近发现泪腺含有保留慢循环祖细胞的标记。 它们参与了实验性损伤后的修复。我们还发现，在 在修复阶段，通过诱导产生具有间充质干细胞(MSC)表型的细胞 上皮向间充质转化(EMT)。MSCs积极参与泪腺修复生成 腺泡和导管上皮细胞，恢复足够的泪液分泌。在目前的建议中，我们是 利用这些发现，假设：1)泪腺修复机制是 在自身免疫驱动的泪腺缺陷的动物模型中受到损害，主要是因为他们的 细胞外基质被破坏，2)对基质金属蛋白酶(MMPs)，特别是MMP2的调控 和/或9的表达/活性可以促进泪腺再生，以及3)外源基因的传递 干细胞将加速发炎的泪腺的愈合过程。为了检验这些假设，我们 提出以下具体目标：1-研究细胞外基质、细胞黏附的变化 慢性炎症泪腺中的分子和基质修饰酶；2-检验假设 操纵MMP2和9的表达和/或活性将促进慢性炎症的愈合 泪腺；3-使用遗传细胞谱系追踪进一步表征细胞的表型 在实验诱导过程中参与EMT的启动和间充质-上皮转化(MET) 泪腺损伤；以及4-测试培养的MSCs加速疾病修复的潜力 将泪腺体内注射给自身免疫性泪腺缺陷动物模型。 目前还没有治愈由于失去产生水分的细胞而导致的严重干眼症的方法。 泪腺的位置。这里描述的研究，如果成功，将导致新的战略停止，以及 也许可以逆转，这些细胞的丧失将恢复正常的泪液产生，并缓解眼部 与干眼综合征相关的表面不适。

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.