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：
10438872
负责人：
Stephen C Pflugfelder
金额：
$ 53.18万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438872
关键词：
Adoptive Transfer Affect Age Agonist All-Trans-Retinol Award Benchmarking Blood Blurred vision Cell Culture Techniques Cell Lineage Cells Cessation of life Cornea Dendritic Cells Desiccation Development Disease Dry Eye Syndromes Environment Epithelial FDA approved Functional disorder Funding Gene Expression Gene Expression Profile Generations Goblet Cells Human ITGAM gene Immune Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interferons Interleukin-12 Label Lacrimal gland structure Location Mediating Medical Metaplasia Modeling Mononuclear Mouse Strains Mucous Membrane Mus Mutation Nuclear Pathogenesis Pathway interactions Phagocytes Pharmaceutical Preparations Phenotype Production Productivity Proteins Quality of life RXR RXRA gene Regulator Genes Retinoid Receptor Retinoids Severities Signal Transduction Squamous Metaplasia Stress Testing Therapeutic Tissues Tretinoin Vascularization Vision Vitamin A aqueous chemokine conditioning conjunctiva cytokine dietary supplements experimental study eye dryness genetic signature irritation keratinization loss of function macrophage migration monocyte mouse model novel novel strategies ocular surface preservation prevent receptor recruit response retinoic acid 4-hydroxylase

项目摘要

This proposal investigates the mechanisms by which retinoic acid, the active form of vitamin A suppresses production of inflammatory mediators that cause dry eye by monocyte derived cells in the conjunctiva. Dry eye is one of the most prevalent medical conditions affecting tens of millions in the US that decreases quality of life and productivity due to irritation and blurred vision. A hallmark of aqueous deficient dry eye is loss of conjunctival goblet cells. Goblet cells produce retinoic acid from vitamin A in tears. We hypothesize that retinoic acid signaling through the retinoid X receptor on monocytes suppresses desiccation stress induced production of IL-12 and IFN- , cytokines that cause goblet cell loss. Three specific aims are proposed to investigate this hypothesis in a mouse model of dry eye and in monocyte cell cultures. The proposed experiments investigate the novel suppressive activity of the retinoid X receptors on conjunctival monocytes and evaluate therapeutic activity of molecules that activate these receptors. These include drugs approved for other indications and dietary supplements. At the conclusion of this project, we will have a better understanding of the mechanisms by which retinoic acid maintains a healthy ocular surface and prevents development of dry eye. The benchmark accomplishments of this project will be a fundamental new understanding of the mechanisms that contribute to goblet cell loss and new approaches to utilize natural retinoid pathways prevent or treat dry eye disease.

该提案研究了视黄酸（维生素 A 的活性形式）的作用机制抑制单核细胞衍生细胞产生导致干眼的炎症介质在结膜中。干眼症是影响数十人的最普遍的疾病之一美国有数百万人因刺激和模糊而降低了生活质量和生产力想象。水液缺乏性干眼症的一个标志是结膜杯状细胞的丧失。杯状细胞从眼泪中的维生素A产生视黄酸。我们假设视黄酸信号通过单核细胞上的类视黄醇 X 受体抑制干燥应激诱导的 IL-12 产生和 IFN-，导致杯状细胞损失的细胞因子。提出了三个具体的调查目标这一假设在干眼小鼠模型和单核细胞培养物中得到证实。拟议的实验研究了类维生素A X 受体的新型抑制活性结膜单核细胞并评估激活这些单核细胞的分子的治疗活性受体。其中包括批准用于其他适应症的药物和膳食补充剂。在该项目结束后，我们将对维A酸的机制有更好的了解酸可以维持健康的眼表并防止干眼症的发生。基准该项目的成就将是对机制的根本性新理解导致杯状细胞损失，利用天然类维生素A途径的新方法可以预防或治疗干眼症。