Stimulus-Secretion Coupling in Diseased Lacrimal Gland

患病泪腺中的刺激-分泌耦合

基本信息

批准号：
8585380
负责人：
DRISS ZOUKHRI
金额：
$ 69.18万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
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/8585380
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 Molecular Profiling Mus Natural regeneration Patients Phase Phenotype Photophobia Postmenopause Process Production Regulation Salivary Glands Sarcoidosis Signal Pathway Sjogren&apos s Syndrome 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

项目摘要

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.

泪腺炎症性疾病，如 Sj¿格伦氏综合征、结节病和慢性抗宿主病或简单地说移植物随着年龄的增长而发生，导致分泌不足泪膜的水层，这是干燥性角结膜炎 (KCS) 或干眼症的主要原因这些疾病的共同点是慢性炎症的表型体征。泪腺（损伤）伴有实质组织损失（分泌泪液的腺泡和导管上皮）细胞）以及腺体无法自我修复，迄今为止，还没有治愈干眼综合症的方法。我们最近发现泪腺含有保留慢循环祖细胞的标记我们还发现，它们参与了实验引起的损伤后的修复。在修复阶段，通过诱导产生具有间充质干细胞 (MSC) 表型的细胞上皮间充质转化（EMT）积极参与泪腺修复以生成。在目前的建议中，我们正在研究腺泡和导管上皮细胞并恢复足够的泪液产生。利用这些发现假设：1）泪腺修复机制是在自身免疫驱动的泪腺缺陷的动物模型中受到损害很大程度上是因为它们细胞外基质被破坏，2）基质金属蛋白酶（MMPs）的操纵，尤其是MMP2 和/或9表达/活性可以改善泪腺再生，并且3)外源性的递送干细胞将加速发炎泪腺的愈合过程为了检验这些假设。提出以下具体目标： 1-I研究细胞外基质、细胞粘附的变化慢性发炎泪腺中的分子和基质修饰酶；2-检验假设；操纵 MMP2 和 9 的表达和/或活性将改善慢性炎症的愈合泪腺；3-使用遗传细胞谱系追踪来进一步表征细胞的表型参与实验诱导过程中 EMT 和间质-上皮转化 (MET) 的启动泪腺损伤；以及 4-测试培养的 MSC 加速病变修复的潜力当体内递送至自身免疫性泪腺缺陷动物模型时，泪腺。目前尚无治疗因水分产生细胞丧失而导致的严重干眼症的方法这里描述的研究如果成功，将导致新的策略停止和也许可以逆转这些细胞的损失，从而恢复正常的泪液产生并减轻眼部不适与干眼综合症相关的表面不适。