Stimulus-Secretion Coupling in Diseased Lacrimal Gland

患病泪腺中的刺激-分泌耦合

• 批准号: 8721960
• 负责人: DRISS ZOUKHRI
• 金额: $ 68.8万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721960
• 关键词: Accounting; Age; American; Animal Model; Animals; Artificial Tears; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biopsy; Blindness; Cell Adhesion Molecules; Cell Lineage; Cell-Cell Adhesion; Cells; Chemicals; Chronic; Cicatrix; Corneal Abrasion; Coupling; Data; Diagnosis; Disease; Dry Eye Syndromes; Ductal Epithelial Cell; Elderly; Enzymes; Epidemiologic Studies; Epithelial; Epithelial Cells; Extracellular Matrix; Eye; Eye diseases; Feeling; Film; Functional disorder; Genes; Genetic; Gland; Goals; Healed; Health; Homeostasis; Human; In Vitro; Individual; Inflammation; Inflammatory; Injury; Keratoconjunctivitis Sicca; Knowledge; Label; Lacrimal gland structure; Lead; Left; Location; MMP2 gene; MMP9 gene; Matrix Metalloproteinases; Mesenchymal; Mesenchymal Stem Cells; Mesenchyme; Messenger RNA; MicroRNAs; Molecular Profiling; Mus; Natural regeneration; Patients; Phase; Phenotype; Photophobia; Postmenopause; Process; Production; Regulation; Salivary Glands; Sarcoidosis; Signal Pathway; Stem cells; Stimulus; Syndrome; Tail; Technology; Testing; Tissues; Transgenic Mice; Ulcer; United States; Veins; Vimentin; Vision; Woman; aging population; aqueous; chronic graft versus host disease; epithelial to mesenchymal transition; experience; eye dryness; healing; improved; in vivo; inhibitor/antagonist; injured; intense pain; irritation; mouse model; ocular surface; palliative; protein expression; public health relevance; repaired; research study; stem; stem cell niche; stem cell therapy; tissue repair; transcription factor; transcriptome sequencing

DESCRIPTION (provided by applicant): 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.

描述（由应用提供）：肺腺的炎症性疾病，例如SJ¿这些疾病的常见分母是肺腺慢性感染（损伤）的表型迹象，且实质性组织失去（撕裂的分泌性腺泡和导管上皮细胞）和导管上皮细胞）以及可修复纤维的无能为力。迄今为止，还没有干眼症的治疗方法。我们最近发现，泪腺含有保留慢速循环祖细胞的标签，这些标记是在实验诱导的损伤后参与修复的标签。我们还发现，在修复阶段，具有间充质干细胞（MSC）表型的细胞是通过诱导上皮到间质转变（EMT）而产生的。 MSC积极参与泪腺修复，以产生腺泡和导管上皮细胞并恢复足够的泪液产生。在本提议中，我们通过假设：1）在自身免疫性驱动的心腺纤维腺体模型中妥协了泪腺修复机制，从而利用了这些发现，这在很大程度上很大程度上是因为它们的细胞外基质被中断，2）可能改善了MMMMPS和MMMMPS，尤其是MMMP），MMMMP），MMMP），MMMP）腺再生和3）外源干细胞的递送将加速发炎的泪腺的愈合过程。为了检验这些假设，我们提出了以下特定目的：1- iInstect the细胞外基质的变化，细胞粘合剂分子和基质修饰酶的泪腺中的酶的变化； 2测试假说，操纵MMP2和9表达和/或活性将改善慢​​性发炎的泪腺的愈合； 3使用遗传细胞谱系追踪在实验诱导的泪腺损伤过程中，进一步表征了参与EMT和间质上皮跃迁（MET）涉及细胞的表型； 4测试培养的MSC的潜力在体内递送到自身免疫性泪腺缺乏症的动物模型中时，可以加速泪腺的修复。目前，由于流失的泪珠的水分产生细胞而导致严重的干眼症。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。