Stimulus-Secretion Coupling in Diseased Lacrimal Gland

患病泪腺中的刺激-分泌耦合

• 批准号: 7584767
• 负责人: DRISS ZOUKHRI
• 金额: $ 50万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7584767
• 关键词: Acinar Cell; Agonist; Apoptosis; Attention; Autophagocytosis; Cell Differentiation process; Cell Proliferation; Cells; Coupling; Data; Data Reporting; Development; Disease; Dry Eye Syndromes; Ductal; Ductal Epithelial Cell; Elderly; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Exocrine Glands; Film; Funding; Genes; Goals; Growth; Growth Factor; Human; Inflammation; Inflammatory; Interleukin-1; Keratoconjunctivitis Sicca; Knowledge; Lacrimal gland structure; Lead; Leucocytic infiltrate; Link; Literature; Mammary gland; Mediating; Mus; Mutation; Myoepithelial; Natural regeneration; Necrosis; Organ; Pancreas; Phase; Play; Process; Production; Proliferating; Role; Salivary Glands; Sarcoidosis; Sjogren' s Syndrome; Stem cells; Stimulus; Syndrome; Testing; Tissues; Wound Healing; aqueous; base; bone morphogenetic protein 7; cell type; chronic graft versus host disease; cytokine; eye dryness; fibroblast growth factor 10; gland development; human disease; lacrimal; neurotransmitter release; ocular surface; public health relevance; receptor; regenerative; repaired; response; stem

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.

描述（由申请人提供）：泪腺的炎症性疾病，例如Sjvgren的综合征，结节病和慢性移植与宿主病与宿主病的疾病，或者只是随着高龄而发生的，导致催泪膜水性层的分泌不足，这是科拉塔西加菌Istic sicca sicca sicca sicca sicca sicca Cyndrdry cyndrdry cyndry cyndry cyndry cyndry cyndry cyndry cyndry cyndrdry cyndrdry cyndrdry cyndrdry cyndrdry cyndrdry cyndrdry eyeclyndrdry eyeclyndrdry Dry Dry Dry。泪腺炎症的标志是白细胞浸润，腺泡上皮细胞的丧失（分泌细胞）以及促炎性细胞因子的产生增加。泪腺上皮细胞被终止分化，因此被认为无法增殖。我们发现，鼠泪腺上皮细胞可以响应组织侮辱而增殖。该应用的总体目标是破译在实验诱导的炎症后控制鼠泪腺再生的机制。获得的知识将揭示新的策略，以促进发炎的人泪腺的再生，这些腺可以恢复足够的水性撕裂产生。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会触发腺泡细胞凋亡，随后诱导腺泡细胞从导管细胞中诱导腺泡细胞的分化或导致细胞与型干细胞/祖细胞的分化，并与随之而来的祖细胞介导了fib的生产量增加了fib rol虫的生长，而FIB的产量增加了。蛋白7（BMP7）。 我们提出了三个特定的目的：1-确定性如果在实验诱导的炎症过程中因细胞凋亡或坏死而丢失了泪腺上皮细胞；在实验诱导的炎症之后，哪些细胞负责鼠泪腺的再生； 3-确定在实验诱导的炎症后，哪些效应分子负责触发泪腺修复，并研究这些因素是否可以在疾病状态下触发/加速泪腺修复。目前，由于流失的泪腺产生水分细胞而导致严重的干眼睛。如果成功的话，此处描述的研究将导致停止的新策略，也许会逆转这些细胞的丧失，这些细胞会恢复正常的泪液产生并减轻与干眼综合症有关的眼部表面不适。公共卫生相关性目前尚无严重干眼的治疗方法，这是由于流失的泪腺产生细胞而导致的。我们发现，鼠泪腺上皮细胞可以响应组织侮辱而增殖。该应用的总体目标是破译在实验诱导的炎症后控制鼠泪腺再生的机制。获得的知识将揭示新的策略，以促进发炎的人泪腺的再生，这些腺可以恢复足够的水性撕裂产生。