Stimulus-Secretion Coupling in Diseased Lacrimal Gland

描述（由申请人提供）：泪腺炎症性疾病，如Sjvgren综合征、结节病、慢性移植物抗宿主病，或仅仅发生在老年，导致泪膜水层分泌不足，这是干燥性角膜结膜炎（KCS）或干眼综合征的主要原因。泪腺炎症的特征是存在白细胞浸润，腺泡上皮细胞（分泌细胞）的丢失，促炎细胞因子的产生增加。泪腺上皮细胞是终末分化的，因此被认为不能增殖。我们发现小鼠泪腺上皮细胞可在组织损伤的反应中增殖。本应用程序的总体目标是破译控制小鼠泪腺再生的机制后，实验诱导炎症。所获得的知识将揭示新的策略，以促进再生发炎的人泪腺，将恢复足够的水泪液生产。根据我们的初步数据和文献报道，我们假设实验诱导的泪腺炎症触发腺泡细胞凋亡，随后诱导腺泡细胞从导管细胞或导管细胞相关的干细胞/祖细胞分化，随后由成纤维细胞生长因子10 （FGFI 0）和/或骨形态发生蛋白7 （BMP7）的增加介导增殖。我们提出了三个具体目标：1 -确定泪腺上皮细胞是否在实验诱导的炎症中因凋亡或坏死而丢失；2 .确定实验性诱导炎症后小鼠泪腺再生的细胞；3-确定哪些效应分子负责触发实验性诱导炎症后的泪腺修复，并研究这些因素是否可以触发/加速疾病状态下的泪腺修复。由于泪腺分泌水分的细胞减少而导致的严重干眼症，目前还没有治愈方法。这里所描述的研究，如果成功，将带来新的策略来阻止，甚至可能逆转这些细胞的损失，这些细胞将恢复正常的泪液产生，减轻与干眼综合征相关的眼表不适。由于泪腺产生水分的细胞丧失而导致的严重干眼症目前尚无治愈方法。我们发现小鼠泪腺上皮细胞可在组织损伤的反应中增殖。本应用程序的总体目标是破译控制小鼠泪腺再生的机制后，实验诱导炎症。所获得的知识将揭示新的策略，以促进再生发炎的人泪腺，将恢复足够的水泪液生产。

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.