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（由申请人提供）：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，或仅在高龄时发生，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。这些疾病的常见诱因是泪腺慢性炎症（损伤）的表型体征，伴随实质组织（分泌泪液的腺泡和导管上皮细胞）的损失以及腺体无法自我修复。到目前为止，还没有治愈干眼综合征的方法。 我们最近发现泪腺含有标记保留慢循环祖细胞，其参与实验诱导损伤后的修复。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细胞向间充质细胞转化（EMT）产生的。间充质干细胞积极参与泪腺修复，产生腺泡和导管上皮细胞，并恢复足够的泪液产生。在本提案中，我们利用这些发现，假设：1）泪腺修复机制在自身免疫驱动的泪腺缺陷的动物模型中受到损害，主要是因为它们的细胞外基质被破坏，2）基质金属蛋白酶（MMP），特别是MMP 2和/或MMP 9表达/活性的操纵可以改善泪腺再生，和3）外源性干细胞的递送将加速发炎的泪腺的愈合过程。为了验证这些假设，我们提出了以下具体目标：1-研究慢性炎症泪腺中细胞外基质、细胞粘附分子和基质修饰酶的变化：2-验证操纵MMP 2和MMP 9表达和/或活性将促进慢性炎症泪腺愈合的假设; 3-使用遗传细胞谱系追踪来进一步表征在实验诱导的泪腺损伤期间参与EMT和间充质-上皮转化（MET）起始的细胞的表型;和4-测试培养的MSC在体内递送至自身免疫性泪腺缺陷的动物模型时加速患病泪腺修复的潜力。 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。