Stimulus-Secretion Coupling in Diseased Lacrimal Gland

描述（由申请人提供）：泪腺的炎性疾病，如干燥综合征、结节病和慢性移植物抗宿主病，或仅发生于高龄，导致泪膜水层分泌不足，这是干燥性角结膜炎（KCS）或干眼综合征的主要原因。泪腺炎症的标志是存在白细胞浸润、腺泡上皮细胞（分泌细胞）损失和促炎细胞因子产生增加。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以增殖，以应对组织的侮辱。本申请的总体目标是解释在实验诱导的炎症后支配小鼠泪腺再生的机制。所获得的知识将揭示新的策略，以促进发炎的人类泪腺的再生，从而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干/祖细胞分化，随后通过增加成纤维细胞生长因子10（FGF 10）和/或骨形态发生蛋白7（BMP 7）的产生介导增殖。 我们提出了三个具体目标：1 -确定在实验诱导的炎症过程中泪腺上皮细胞是否因凋亡或坏死而丢失; 2-确定哪些细胞负责实验诱导的炎症后小鼠泪腺的再生;及3-确定哪些效应分子负责在实验诱导的炎症后触发泪腺修复，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。目前还没有治疗由泪腺的产湿细胞损失引起的严重干眼症的方法。这里描述的研究，如果成功，将导致新的策略来阻止，甚至逆转，这些细胞的损失，这将恢复正常的泪液产生，并减轻与干眼症相关的眼表不适。公共卫生相关性目前还没有治疗由泪腺的产湿细胞损失引起的严重干眼症的方法。我们发现，小鼠泪腺上皮细胞可以增殖，以应对组织的侮辱。本申请的总体目标是解释在实验诱导的炎症后支配小鼠泪腺再生的机制。所获得的知识将揭示新的策略，以促进发炎的人类泪腺的再生，从而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.