Pathogenesis of Conjunctival Squamous Metaplasia

结膜鳞状上皮化生的发病机制

基本信息

批准号：
8449581
负责人：
Stephen C Pflugfelder
金额：
$ 37.17万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-08-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8449581
关键词：
Address Adoptive Transfer Aging Area Award Binding Boxing CD4 Positive T Lymphocytes Cell Density Cell Differentiation process Cell Maturation Cell secretion Cells Cellular Structures Conjunctival Epithelium Cornea Data Disease Employee Strikes Environment Epithelial Cells Equilibrium Eye Eye diseases Film Functional disorder Genetic Transcription Glycoproteins Goals Goblet Cells Grant Homeostasis Human Immune system Interferon Type II Interferons Interleukin-13 Intervention Knockout Mice Knowledge Lubrication MUC5AC gene Maintenance Mediating Medical Microspheres Modeling Molecular Mucins Mucous body substance Mus Pathogenesis Phosphorylation Production Quality of life Receptor Signaling Regulation Role Route STAT6 gene Severities Signal Transduction Sjogren&apos s Syndrome Societies Squamous Metaplasia Stress Supplementation Symptoms Testing Therapeutic Transcript Transcription Repressor/Corepressor Visual Work aqueous conjunctiva corneal epithelium cost cytokine density eye dryness interleukin-13 receptor irritation neutralizing antibody novel novel strategies ocular surface public health relevance receptor research study response

项目摘要

DESCRIPTION (provided by applicant): This proposal investigates the mechanisms responsible for loss of mucus-producing conjunctival goblet cells in dry eye. Dry eye is one of the most prevalent medical conditions that decreases quality of life due to irritation symptoms and visual disturbance at a great cost to society. A hallmark of aqueous tear deficiency is loss of conjunctival goblet cells. Goblet cell secretions are essential for maintaining a stable tear film. Our preliminary data indicated that goblet cells are components of the ocular mucosal immune system and that goblet cell maturation and mucus secretion is regulated by T-helper cytokines. The T-helper 2 cytokine IL-13 promotes goblet cell maturation and mucus production while the Th1 cytokine interferon gamma inhibits goblet cell maturation. Interferon gamma increases in the conjunctiva in dry eye. This grant investigates the hypothesis that interferon gamma represses conjunctival goblet cell maturation by increasing expression of FoxA2, a transcriptional repressor of MUC5AC mucin, as well as the IL-13 decoy receptor, IL-13 receptor alpha 2 that avidly binds IL-13 and inhibits IL-13 signaling in goblet cells. Three specific gains are proposed to investigate this novel hypothesis. This proposal addresses a gap in knowledge regarding the mechanism of goblet cell loss in dry eye. At the conclusion of this project, we will better understand the molecular mechanisms by which interferon gamma antagonizes the goblet cell promoting activity of IL-13. We will also determine whether IL-13 supplementation and/or interferon gamma neutralization have therapeutic potential for promoting goblet cell maturation in dry eye. The end product of this project will be a fundamental new understanding of the regulation of conjunctival secretory function by these T-helper cytokines and novel strategies to maintain goblet cell promoting environment in the conjunctiva in dry eye disease.

描述（由申请人提供）：该提案研究了干眼症中产生粘液的结膜杯状细胞损失的机制。干眼症是最普遍的疾病之一，由于刺激症状和视力障碍而降低生活质量，给社会造成巨大损失。水性泪液缺乏的一个标志是泪液丧失结膜杯状细胞。杯状细胞分泌物对于维持稳定的泪膜至关重要。我们的初步数据表明，杯状细胞是眼粘膜免疫系统的组成部分，并且杯状细胞的成熟和粘液分泌受T辅助细胞因子的调节。 T 辅助细胞 2 细胞因子 IL-13 促进杯状细胞成熟和粘液产生，而 Th1 细胞因子干扰素 γ 抑制杯状细胞成熟。干眼症患者结膜中的干扰素 γ 增加。该资助研究了这样的假设：干扰素 γ 通过增加 FoxA2（MUC5AC 粘蛋白的转录抑制因子）以及 IL-13 诱饵受体（IL-13 受体 α2）的表达来抑制结膜杯状细胞成熟，该受体强烈结合 IL-13 并抑制杯状细胞中的 IL-13 信号传导。提出了三个具体成果来研究这一新颖的假设。该提案解决了有关干眼杯状细胞丢失机制的知识空白。在这个项目结束时，我们将更好地了解干扰素γ拮抗IL-13杯状细胞促进活性的分子机制。我们还将确定补充 IL-13 和/或干扰素 γ 中和是否具有促进干眼杯状细胞成熟的治疗潜力。该项目的最终产品将是对这些 T 辅助细胞因子调节结膜分泌功能的基本新认识，以及维持干眼病结膜杯状细胞促进环境的新策略。