Molecular Mechanisms of Squamous Metaplasia in Dry Eye

干眼症鳞状上皮化生的分子机制

• 批准号: 8316282
• 负责人: Nancy A McNamara
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316282
• 关键词: Ablation; Anabolism; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Biological Markers; Biological Models; Blindness; CCL2 gene; CD4 Positive T Lymphocytes; Cells; Characteristics; Chronic; Clinical; Collaborations; Cornea; Couples; Cytology; Data; Development; Dichloromethylene Diphosphonate; Disease; Down-Regulation; Early Diagnosis; Effector Cell; Epithelial Cells; Epithelium; Event; Eye diseases; Fibrosis; Gene Chips; Genes; Genetic; Glycoconjugates; Goals; Goblet Cells; Histologic; Human; Immune; Immunosuppressive Agents; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Keratin; Keratoconjunctivitis Sicca; Keratopathy; Lacrimal gland structure; Left; Ligands; Link; Liposomes; Mediating; Mediator of activation protein; Molecular; Molecular Profiling; Monitor; Mononuclear; Morbidity - disease rate; Mucins; Mus; Nuclear; Ocular cicatricial pemphigoid; Organ; Pathogenesis; Pathological Staging; Patients; Phenotype; Polysaccharides; Process; Production; Proteins; Publishing; Research; Role; Severities; Severity of illness; Signal Transduction; Sjogren' s Syndrome; Skin; Specimen; Squamous Metaplasia; Staging; Stevens-Johnson Syndrome; Syndrome; Systemic disease; Testing; Vision; Work; aqueous; autoimmune exocrinopathy; base; chemokine receptor; corneal epithelium; cytokine; eye dryness; glycosylation; immunopathology; impression; in vivo; keratinization; mRNA Expression; macrophage; monocyte; mouse model; novel; ocular surface; palliative; prevent; proline-rich proteins; systemic autoimmune disease; transdifferentiation; treatment strategy

DESCRIPTION (provided by applicant): In systemic autoimmune diseases like Sj"gren's syndrome (SS), exocrinopathy of the lacrimal gland leads to an aqueous-deficient dry eye that is among the most common and debilitating clinical manifestations. As dry eye disease progresses, it initiates a multi-step, immune-mediated process that includes two pathological characteristics (1) transdifferentiation a nonkeratinized, mucosal ocular surface to a keratinized, "skin-like" epithelium; and (2) disruption of ocular surface and goblet cell mucins. This process, known as squamous metaplasia (SQM), is a devastating, end-stage consequence of dry eye disease that can cause considerable morbidity as advanced keratinzation couples with subepithelial fibrosis to cause corneal opacification and blindness. While immune-mediated inflammation has been implicated in the pathogenesis of SQM, little is known about the precise immunopathogenic mechanisms, leaving us with treatment strategies that are limited, costly and largely palliative. The goal of our research is to decipher how autoimmune-mediated inflammation provokes vision-threatening SQM. Using three model systems, (i) human patients with SS; (ii) a validated mouse model of spontaneous autoimmune exocrinopathy and keratopathy that mimics the clinical characteristics of SS; and (iii) in vitro studies of cultured corneal epithelial cells, our previous work demonstrated an essential role for autoreactive CD4+ T cells and their interplay with the proinflammatory cytokine IL-1 in the pathogenesis of SQM. Yet, the specific mechanism whereby CD4+ T cells and IL-1 promote SQM in autoimmune dry eye remains unknown. To deepen our understanding of the molecular and cellular pathogenic mechanism of immune-mediated SQM, and to identify possible targets for treatment, we seek to (i) determine how CD4+ cells work together with IL-1 to provoke SQM; and (ii) how IL-1 promotes transdifferentiation of the ocular surface epithelium to one that is mucin-depleted and pathologically keratinized. We hypothesize that autoantigen-primed CD4+ T cells work in collaboration with infiltrating monocytes to promote the local release of proinflammatory mediators (e.g., IL-1) that establish and sustain a chronic inflammatory state at the ocular surface. Once established, the local inflammatory response causes ocular surface damage and promotes SQM by disrupting, PAX6, the master regulator of ocular mucosal phenotype and altering the glycosylation and expression of ocular mucins. To test this hypothesis we will (Aim 1) explore infiltrating mononuclear cells as potential cellular intermediate linking antigen-primed CD4+ T cells to the local production of IL-1; (Aim 2) define how IL-1 directs the early stages of pathological keratinization, by studying its effects on the master gene controlling corneal phenotype, Pax6; and (Aim 3) characterize the mechanisms whereby IL-1 alters ocular mucins by identifying key genes regulating glycoconjugate biosynthesis. The overall impact of this work will include a better understanding of the immunopathology of SQM in autoimmune disease that is likely to uncover key events that aid in its early diagnosis and/or treatment.

描述（由申请人提供）：在干燥综合征（SS）等系统性自身免疫性疾病中，泪腺外分泌病会导致水液缺乏性干眼症，这是最常见且令人衰弱的临床表现之一。随着干眼症的进展，它启动了一个多步骤的免疫介导过程，包括两个病理特征（1）非角化粘膜眼表面转分化为角化、 “皮肤样”上皮细胞；（2）眼表面和杯状细胞粘蛋白的破坏，这一过程称为鳞状上皮化生（SQM），是干眼病的毁灭性终末期后果，晚期可导致相当高的发病率。角化与上皮下纤维化相结合，导致角膜浑浊和失明。虽然免疫介导的炎症与 SQM 的发病机制有关，但对其确切的发病机制知之甚少。免疫致病机制，给我们留下了有限、昂贵且很大程度上是姑息治疗的治疗策略。我们研究的目标是破译自身免疫介导的炎症如何引发威胁视力的 SQM。使用三个模型系统，(i) SS 人类患者； (ii) 经验证的自发性自身免疫性外分泌病和角膜病小鼠模型，模拟 SS 的临床特征； (iii) 培养的角膜上皮细胞的体外研究，我们之前的工作证明了自身反应性 CD4+ T 细胞及其与促炎细胞因子 IL-1 的相互作用在 SQM 发病机制中的重要作用。然而，CD4+ T 细胞和 IL-1 在自身免疫性干眼中促进 SQM 的具体机制仍不清楚。为了加深我们对免疫介导的 SQM 的分子和细胞致病机制的理解，并确定可能的治疗靶点，我们寻求 (i) 确定 CD4+ 细胞如何与 IL-1 一起作用来引发 SQM； (ii) IL-1 如何促进眼表上皮转分化为粘蛋白耗尽且病理性角化的上皮。我们假设自身抗原引发的 CD4+ T 细胞与浸润单核细胞协同作用，促进促炎介质（例如 IL-1）的局部释放，从而在眼表建立并维持慢性炎症状态。一旦建立，局部炎症反应会导致眼表损伤，并通过破坏眼粘膜表型的主要调节因子 PAX6 并改变眼粘蛋白的糖基化和表达来促进 SQM。为了检验这一假设，我们将（目标 1）探索浸润性单核细胞作为潜在的细胞中间体，将抗原引发的 CD4+ T 细胞与 IL-1 的局部产生联系起来； （目标 2）通过研究 IL-1 对控制角膜表型的主基因 Pax6 的影响，确定 IL-1 如何指导病理性角化的早期阶段； （目标 3）通过鉴定调节糖复合物生物合成的关键基因来表征 IL-1 改变眼部粘蛋白的机制。这项工作的总体影响将包括更好地了解 SQM 在自身免疫性疾病中的免疫病理学，这可能会发现有助于其早期诊断和/或治疗的关键事件。