Pathogenesis of Conjunctival Squamous Metaplasia

结膜鳞状上皮化生的发病机制

• 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
• 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

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）：我们的研究已经确定，眼表暴露于干燥或高渗透压环境会引发2期响应。这种反应的第一阶段是增加眼表面上皮细胞对各种应激反应基因的表达增加，包括炎症介质和促进异常“皮肤”分化和过早细胞死亡的因素。我们的数据表明，干眼症诱导的基因表达变化部分是由于有丝分裂原活化蛋白激酶（MARK）信号传导途径的激活，尤其是C-JUN N末端激酶（JNK）途径。眼表反应的第二阶段是从血液到眼表的炎症/免疫细胞募集。在这些细胞中，有1型辅助淋巴细胞（TH1）产生干扰素γ，这是一种细胞因子，已显示出可改变粘膜上皮分化并减少非眼粘膜组织中产生杯状细胞的数量。根据我们的初步发现，我们假设这些阶段中的每个阶段在角膜结膜炎的发病机理中都起着关键作用，SICCA（KCS），即视力危及视力的眼表上皮疾病。提出的三个特定目标将检验这一假设。 AIM 1将证实，干眼和渗透应激会促进浓缩的包膜（CE）分化蛋白及其通过眼表上皮的交联转谷氨酰胺酶的交联，这一过程导致不规则较差的表面，这是Sicca的角膜结膜的标志。它将研究标记信号通路在这些蜂蜜包膜前体异常产生中的作用。具体目标2将研究干眼症中CD4+ T细胞募集到结膜（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调查了以下假设：1型和2型辅助辅助T淋巴细胞产生的细胞因子差异调节了结膜的杯状细胞分化和通过眼表上皮的分化相关因子的产生。这些研究可能会发现西卡氏病的发病机理和发现这种疾病的疾病相关的治疗靶标的关键介体，该疾病影响了45岁以上多达15％的人口，并有可能引起失明。