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：
7386565
负责人：
Stephen C Pflugfelder
金额：
$ 33.08万
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 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7386565
关键词：
Affect Age Anti-Inflammatory Agents Apoptosis Blindness Blood Blood Cells CD4 Positive T Lymphocytes Cell Death Cell Differentiation process Cells Condition Conjunctival Epithelium Cornea Data Development Disease Disruption Environment Epithelial Epithelial Cells Epithelium Exposure to Eye Funding Gene Expression Genes Goals Goblet Cells Helper-Inducer T-Lymphocyte Hour Human Immune Immunophenotyping Inbred BALB C Mice Infiltration Inflammatory Intercellular adhesion molecule 1 Interferon Type II Interferons Interleukin-13 Investigation JUN gene Keratin Keratoconjunctivitis Keratoconjunctivitis Sicca MAP Kinase Gene Matrix Metalloproteinases Mediator of activation protein Mitogen-Activated Protein Kinases Mitogens Modeling Molecular Mucous Membrane Mucous body substance Mus Numbers Osmolar Concentration Pathogenesis Pathologic Processes Pathway interactions Patients Phase Phosphotransferases Play Population Predisposition Process Production Proteins Recruitment Activity Research Role Selectins Severities Signal Pathway Skin Squamous Metaplasia Stress Surface Testing Transglutaminases Vascular Endothelium Vision base biological adaptation to stress cell type chemokine conjunctiva corneal epithelium crosslink cytokine day density env Gene Products eye dryness ocular surface pro-apoptotic protein response stress activated protein kinase therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Our research has identified that exposure of the surface of the eye to a dry or high osmolarity environment initiates a 2 phase response. The first phase of this response is increased expression of a variety of stress response genes by the epithelial cells on the surface of the eye, including inflammatory mediators and factors that promote abnormal "skin like" differentiation and premature cell death. Our data suggests that dry eye induced changes in gene expression are due in part to activation of mitogen activated protein kinase (MARK) signaling pathways in the ocular surface epithelia, particularly the c-jun n-terminal kinase (JNK) pathway. The second phase of the ocular surface response is recruitment of inflammatory/immune cells from the blood to the surface of the eye. Among these cells are type 1 T helper lymphocytes (Th1) that produce interferon gamma, a cytokine that has been shown to alter mucosal epithelial differentiation and to decrease the number of mucus producing goblet cells in non-ocular mucosal tissues. Based on our preliminary findings, we hypothesize that each of these phases plays a key role in the pathogenesis of keratoconjunctivitis sicca (KCS), the sight-threatening ocular surface epithelial disease of dry eye. Three proposed Specific Aims will test this hypothesis. Aim 1 will confirm that dry eye and osmotic stress promote prduction of cornified envelope (CE) differentiation proteins and their cross-linking transglutaminases by the ocular surface epithelium, a process that results in an irregular poorly wettable surface that is a hallmark of keratoconjunctivitis sicca. It will investigate the role of MARK signaling pathways in the abnormal production of these cornified envelope precursors. Specific Aim 2 will investigate the mechanism by which CD4+ T cells are recruited to the conjunctiva (Phase 2) in dry eye and will characterize the type and cytokine profile of these cells. Specific Aim 3 investigates the hypothesis that cytokines produced by type 1 and type 2 helper T lymphocytes differentially modulate conjunctival goblet cell differentiation and production of differentiation associated factors by the ocular surface epithelia. These studies are likely to uncover key mediators in the pathogenesis of keratoconjunctivitis sicca and uncover disease relevant therapeutic targets for this condition that affects up to 15% of the population over the age of 45 and has the potential to cause blindness.

描述（由申请人提供）：我们的研究发现，眼睛表面暴露于干燥或高渗透压环境会引发两相反应。该反应的第一阶段是眼睛表面上皮细胞增加多种应激反应基因的表达，包括炎症介质和促进异常“皮肤样”分化和过早细胞死亡的因子。我们的数据表明，干眼引起的基因表达变化部分是由于眼表上皮细胞中有丝分裂原激活蛋白激酶（MARK）信号通路的激活，特别是c-jun n末端激酶（JNK）通路。眼表面反应的第二阶段是将炎症/免疫细胞从血液募集到眼睛表面。这些细胞中有 1 型 T 辅助淋巴细胞 (Th1)，可产生干扰素 γ，干扰素是一种细胞因子，已被证明可以改变粘膜上皮分化并减少非眼粘膜组织中产生粘液的杯状细胞的数量。根据我们的初步研究结果，我们假设每个阶段在干燥性角结膜炎（KCS）（一种威胁视力的干眼眼表上皮疾病）的发病机制中发挥着关键作用。提出的三个具体目标将检验这一假设。目标 1 将证实，干眼和渗透压会促进眼表上皮产生角质化包膜 (CE) 分化蛋白及其交联转谷氨酰胺酶，这一过程会导致不规则的、润湿性差的表面，这是干燥性角结膜炎的标志。它将研究 MARK 信号通路在这些角化包膜前体的异常产生中的作用。具体目标 2 将研究干眼症中 CD4+ T 细胞被募集到结膜（第 2 阶段）的机制，并将表征这些细胞的类型和细胞因子谱。具体目标 3 研究了以下假设：1 型和 2 型辅助 T 淋巴细胞产生的细胞因子差异调节结膜杯状细胞分化和眼表上皮细胞分化相关因子的产生。这些研究可能会揭示干燥性角结膜炎发病机制中的关键介质，并揭示这种疾病的相关治疗靶点，这种疾病影响着 45 岁以上人口的 15%，并有可能导致失明。