Cellular and Molecular Mechanisms that Contribute to Ocular Surface Allergy

导致眼表面过敏的细胞和分子机制

• 批准号: 8246069
• 负责人: Daniel Raphael Saban
• 金额: $ 9.7万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 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 2012-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246069
• 关键词: Affect; Allergens; Allergic; Allergic Conjunctivitis; Allergic inflammation; Allergic rhinitis; American; Antihistamines; Area; Biological; Cell Maturation; Cell physiology; Cellular biology; Classification; Communicable Diseases; Conjunctivitis; Contact Lenses; Dendritic Cells; Development; Drug Delivery Systems; Event; Experimental Models; Eye; Giant Papillary Conjunctivitis; Glycoproteins; Goals; Health; Health Care Costs; Histamine; Hypersensitivity; ITGAM gene; ITGAX gene; IgE; Immune; Immune response; Immunity; In Vitro; Inbred BALB C Mice; Investigation; Lung; Lymphocyte; Mast Cell Stabilizer; Measures; Mediating; Molecular; Mucous Membrane; Mus; Nose; Pathogenesis; Pharmaceutical Preparations; Pharmacotherapy; Play; Proteins; Quality of life; Role; Route; Signs and Symptoms; Staging; Surface; Symptoms; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Thrombospondin 1; Tissues; United States; Vision; Wild Type Mouse; Work; base; cytokine; in vivo; insight; novel; novel strategies; ocular surface; research study; therapeutic target; uptake

DESCRIPTION (provided by applicant): Allergic conjunctivitis (AC) affects nearly 30 million Americans, thereby constituting a major health problem and causing significant health care costs in the United States. In addition to perennial and seasonal forms of AC which can diminish quality of life, advanced forms of vernal or atopic AC can be sight-threatening as well. Unfortunately, current pharmacotherapies are only transiently effective and incapable of abolishing signs and symptoms. Antihistamines and mast cells stabilizers, for example, target IgE mediated released proinflammatory cytokines and histamines. However, this is preceded by important upstream activities not targeted by these drugs, namely the stimulation of T helper 2 lymphocytes by dendritic cells (DC). Thus, it is likely that novel strategies targeting DC function, may serve as a better means to treat AC. To this end, the overall goal of these proposed studies is to better understand conjunctival (conj) DCs and the mechanisms employed toward AC immunopathogenesis. It is currently understood that DCs originate from different lineages which yield distinct subsets and perform intrinsic or specialized functions and recent work from our lab has initiated the classification of subsets and respective ontogenies that constitute the conj DC network. This, for one, permits comparisons to DC subsets previously identified in other mucosal tissues, such as those constituting lung or gut, which also sustain allergic inflammation. Furthermore identification of such DC subsets in conj will facilitate Aim 1 of this study, which is to discern which DC subset(s) is immunopathogenic in AC and whether this is accomplished via proficient T cell stimulation and/or enhanced allergen uptake and presentation. Regarding T cell stimulation mediated by conj DCs, preliminary studies presented in this proposal demonstrate that thrombospondin (TSP)-1, a matricellular glycoprotein with immunoregulatory functions, inhibits DC maturation required for consequent T cell stimulation. Thus, Aim 2 of this proposal seeks to explore the role of TSP-1 deficiency in the immunopathogenesis of AC. In summary, results from these studies will provide further understanding of conj DC subsets and function, an area which is not only applicable to allergy but also to infectious diseases and other immune-related conditions afflicting the ocular surface. Furthermore identification of the immunopathogenic DC subset(s) in AC and their mechanisms will provide important insights for development of much needed therapeutic strategies to better treat AC. PUBLIC HEALTH RELEVANCE: Nearly 30 million Americans suffer from allergies that afflict the surface of the eye, thereby constituting a major health problem in the U.S. and causing significant health care costs. Unfortunately, current drug treatments (such as antihistamines), which target end-stage biological events that cause allergy, do not abolish this condition. The proposed research study seeks to investigate early-stage events that cause allergy and thereby may help to uncover more effective targets for treatment of ocular allergies.

描述（由申请人提供）：过敏性结膜炎（AC）影响了近3000万美国人，从而构成了一个重大的健康问题并在美国造成了巨大的医疗保健费用。除了多年生和季节性形式的交流形式可以降低生活质量外，春季或特应交流的先进形式也可以危及视力。不幸的是，当前的药物治疗仅是瞬时有效的，并且无法消除迹象和症状。抗组胺药和肥大细胞稳定剂，例如，靶向IgE介导的释放促炎细胞因子和组胺。然而，这是在这些药物中未针对的重要上游活性，即树突状细胞（DC）刺激T辅助2淋巴细胞。因此，针对DC功能的新型策略很可能是治疗AC的更好手段。为此，这些拟议的研究的总体目标是更好地了解结膜DC和用于AC免疫发病的机制。目前可以理解，DC源自不同的谱系，这些谱系产生不同的子集并执行固有或专业的功能，而我们实验室的最新工作启动了构成Conj DC网络的子集和各自的本基因的分类。一方面，这允许与先前在其他粘膜组织中鉴定出的DC子集进行比较，例如构成肺或肠道的DC子集，这些粘膜或肠道也具有过敏性炎症。此外，CONJ中此类DC子集的鉴定将促进本研究的目标1，这是为了辨别哪种DC子集在AC中具有免疫发育性，以及这是否是通过熟练的T细胞刺激和/或增强的过敏原摄取和表现来实现的。关于由CONJ DC介导的T细胞刺激，该提案中介绍的初步研究表明，血小板蛋白（TSP）-1是一种具有免疫调节功能的母细胞糖蛋白，抑制导致T细胞刺激所需的DC成熟。因此，该提案的目标2旨在探索TSP-1缺乏症在AC的免疫发病发生中的作用。总之，这些研究的结果将进一步了解Conj DC子集和功能，该区域不仅适用于过敏，还适用于感染性疾病和其他与免疫相关的疾病，困扰着眼表面。此外，在AC中鉴定免疫病DC子集及其机制将为开发急需的治疗策略提供重要的见解，以更好地治疗AC。 公共卫生相关性：将近3000万美国人遭受折磨眼睛表面的过敏症，从而构成了美国的主要健康问题并造成了巨大的医疗保健费用。不幸的是，针对导致过敏的终末期生物学事件的当前药物治疗（例如抗组胺药）不会废除这种情况。拟议的研究旨在研究引起过敏的早期事件，从而可能有助于发现更有效的眼部过敏靶标。