Cellular and Molecular Mechanisms that Contribute to Ocular Surface Disease during Severe Allergic Inflammation

严重过敏性炎症期间导致眼表疾病的细胞和分子机制

• 批准号: 9919560
• 负责人: Daniel Raphael Saban
• 金额: $ 39.75万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919560
• 关键词: Address; Affect; Allergic; Allergic inflammation; American; Animal Model; Anterior; Antigen-Presenting Cells; Area; Blepharitis; Blindness; Bone Marrow; Bullous Pemphigoid; Cell Degranulation; Cells; Cellular biology; Chimera organism; Chronic; Clinical; Collaborations; Cornea; Cre-LoxP; Data; Defect; Dendritic Cells; Development; Disease; Disease model; Duct (organ) structure; Eosinophilia; Etiology; Event; Eye; Eye diseases; Fibrosis; Film; Flow Cytometry; Genetic Techniques; Gland; Glean; Grant; Health; Histologic; Homeostasis; Human; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immune system; Immunologics; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Keratoconjunctivitis; Lead; Lung; Lymphocyte; Lymphocyte Activation; Mediating; Mediator of activation protein; Medical; Medicine; Microscopy; Modeling; Molecular; Mucous Membrane; Mus; Ocular Rosacea; Oils; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Play; Plug-in; Process; Production; Psoriasis; Quality of life; Role; Secondary to; Series; Site; Stevens-Johnson Syndrome; System; T cell response; Technology; Thinking; Time; Transgenic Mice; Tumor-infiltrating immune cells; Work; adaptive immune response; adaptive immunity; base; bulbar conjunctiva; chronic graft versus host disease; clinical examination; conjunctiva; experimental study; in vivo; mast cell; meibomian gland; meibomian gland dysfunction; mouse model; neutrophil; novel; novel therapeutics; ocular surface; response; tool

ABSTRACT Inflammatory lid margin disease, which arises in chronic ocular surface inflammation, constitutes a major health problem in the U.S. and abroad. This type of inflammation, also referred to as blepharitis, can affect both the anterior and posterior aspects of the lid margin, and may include meibomian gland dysfunction (MGD). Long-term defects of the tear film and secondary impairments to the conjunctiva and cornea often develop due to MGD, as the meibomian gland is responsible for the oil (or meibum) production required for tear film homeostasis. Such debilitating blepharitis occurs regularly in patients with chronic forms of allergic eye disease, such as in atopic keratoconjunctivitis (AKC). Likewise, blepharitis occurs in ocular rosacea, chronic graft versus host disease, Stevens-Johnson Syndrome, and other chronic inflammatory ocular surface diseases. Our lab has previously established and validated a severe allergic eye disease (AED) mouse model. This AED model reproducibly develops various clinical sequelae consistent with AKC in humans, including corneal involvement, subepithelial fibrosis of the bulbar conjunctiva, and blepharitis (anterior and posterior). The utility of this model has proven to permit identification of unknown pathogenic events that mediate severe eye allergy, which is a disease with an unmet medical need. Along these lines, the aim of this grant is to elucidate the immunologic mechanisms that specifically cause blepharitis in the AED model. Experiments proposed go beyond the examination of classical allergic inflammation, such as mast cell degranulation, T helper 2 responses and eosinophilia. Instead, our preliminary data has led us to focus our efforts on the central role of the T helper 17 pathway. Experiments herein also seek to elucidate upstream mediators, including identification of the bona fide dendritic cell subsets, and their mediators, responsible for eliciting the T helper 17 pathway in this disease model. Our approach involves a myriad of in vivo genetic techniques to enable conditional/inducible depletion of specific dendritic cell subsets in a site specific manner. These strategies and others will empower us to pinpoint the mediators and their mechanisms that cause lid margin disease in the AED model. This timely and novel proposal is poised to catalyze our understanding of eye mucosal dendritic cells in disease and lymphocyte activation in blepharitis. Furthermore, information gleaned from these experiments could be relevant in the broader context of ocular surface inflammatory disease.

抽象的 在慢性眼表面炎症中引起的炎症盖缘疾病构成了主要 美国和国外的健康​​问题。这种类型的炎症，也称为睑缘炎，可能会影响 盖缘的前部和后方方面都可能包括梅博姆腺功能障碍（MGD）。 撕裂膜的长期缺陷和结膜和角膜的次要障碍通常会出现应有的 到MGD，因为梅博米亚腺负责撕裂膜所需的油（或梅布姆）生产 稳态。这种使人衰弱的骨性炎经常发生在患有慢性过敏性眼病的患者中， 例如在特应性角膜结膜炎（AKC）中。同样，眼睑炎发生在眼镜，慢性移植与 宿主疾病，史蒂文斯 - 约翰逊综合征和其他慢性炎症性眼表面疾病。我们的实验室 先前已经建立并验证了严重的过敏性眼病（AED）小鼠模型。这个AED模型 可重复发展与人类中AKC一致的各种临床后遗症，包括角膜介入， 鳞茎结膜的上皮下纤维化和骨炎（前后）。该模型的实用性 事实证明，可以识别介导严重眼睛过敏的未知病原事件，这是 有未满足的医疗需求的疾病。沿着这些线，这笔赠款的目的是阐明免疫学 在AED模型中特别引起骨性炎的机制。提出的实验超出了 检查经典过敏性炎症，例如肥大细胞脱粒，T辅助2反应和 嗜酸性粒细胞。相反，我们的初步数据使我们将精力集中在T助手17的核心角色上 路径。这里的实验还试图阐明上游介体，包括识别BONA FIDE树突状细胞子集及其介体负责在该疾病中引起T助手17途径 模型。我们的方法涉及无数的体内遗传技术，以实现有条件/诱导的耗竭 以特定方式以特定方式的特定树突状细胞亚群。这些策略和其他策略将使我们能够 查明介体及其在AED模型中引起盖缘疾病的机制。这个及时 新的建议有望催化我们对疾病和 淋巴炎淋巴细胞激活。此外，从这些实验中收集的信息可能是 与眼表炎性疾病的更广泛背景有关。