Paradigms of maintaining anterior segment homeostasis

维持眼前节稳态的范例

• 批准号: 10600479
• 负责人: A. Sue Menko
• 金额: $ 60.03万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600479
• 关键词: Angiogenesis Inhibitors; Anterior; Anti-Inflammatory Agents; Antigen Presentation; Appearance; Aqueous Humor; Autoimmune; Biological Assay; Bone Marrow; Cataract; Cells; Characteristics; Chronic; Coculture Techniques; Collagen; Cornea; Corneal Injury; Development; Disease; Embryo; Epithelium; Exfoliation Syndrome; Exhibits; Eye; Eye Development; Eye Injuries; Glaucoma; Grant; Growth; Homeostasis; Immune; Immune response; Immune system; Immunomodulators; Immunosuppression; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Iris; Life; Light; Link; Location; Macrophage; Maintenance; Mediating; Modeling; Molecular; Molecular Profiling; Mus; Myofibroblast; Ocular Pathology; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Phenotype; Population; Positioning Attribute; Production; Property; Proteins; Proteomics; Publishing; Resolution; Role; Sentinel; Site; Surface; T-Cell Activation; Time; Tissues; Trauma; Uveitis; Visual Acuity; Vitreous humor; Yolk Sac; angiogenesis; autoimmune uveitis; capsule; cell capsule; corneal repair; extracellular; immunoregulation; lens; lens capsule; migration; monocyte; preservation; prevent; recruit; regenerative repair; response; response to injury; restoration; self-renewal; wound healing

Project Summary/Abstract Inflammatory responses in the eye, such as following corneal wounding, and in autoimmune-mediated uveitis, must be controlled and resolved to preserve homeostasis and prevent damage. In all these conditions, we discovered that immune cells are recruited to the surface of the lens, many with characteristics associated with immunomodulation. The central location of the lens and its interface with most eye tissues via the adjacent aqueous and vitreous humors places it in the perfect position for these Lens Capsule Associated Immune Cells (LC-AICs) to present antigens and produce proteins that can exert immunosuppressive functions across the eye. In addition, we found that there are resident immune cells, the sentinels of the immune system, that become integrated within the lens during development. We now build on these findings with studies aimed at understanding the lineage and functions of lens resident immune cells and LC-AICs recruited from other ocular sites, their roles in maintaining homeostasis, and whether their long-term persistence is linked to pathogenic outcomes. In Aim 1, we will perform lineage tracing studies to determine their ontogeny. These studies will reveal whether these immune cell populations are long-lived, self-renewing and embryonic yolk-sac derived, or short-lived, bone marrow-derived typical of those recruited to tissues in response to injury and pathogenesis. Since tissue resident immune cells are immediate responders to injury and pathogenesis, we will investigate whether their activation in response to corneal wounding is linked to LC-AIC recruitment and regenerative repair of the cornea. In Aim 2, we will perform a detailed analysis of the immunomodulatory properties of the LC-AICs recruited to the lens post-corneal wounding and in uveitis. These studies will include a functional analysis to directly link the LC-AICs to the suppression of T-cell activation. We also examine the anti- inflammatory and anti-angiogenic properties of the bioactive matrix-derived molecules proteolytically released by LC-AICs as they migrate within the lens capsule. Our studies of the LC-AICs strongly support their important functions as immunomodulators in the eye, including our discovery that they persist integrated with the lens surface during the resolution of inflammation in uveitic eyes. However, their long-term persistence at the lens capsule surface beyond this time, and the ability of a subset to abrogate lens immune privilege and infiltrate the lens, suggests that their prolonged presence could lead to pathological outcomes. In Aim 3, we will determine the mechanisms by which LC-AICs cross the lens capsule to infiltrate the lens and their fate, including whether they can be agents of cataractogenesis by becoming collagen I-producing myofibroblasts. In addition, we will investigate the properties of the fibrillar network with which the LC-AICs maintained on the surface of the lens become entwined, and to which the iris becomes attached at late stages of uveitis, which could be linked to pathological outcomes of uveitis. Understanding these links could lead to new treatment options for patients with ocular pathologies associated with chronic inflammation.

项目概要/摘要 眼睛的炎症反应，例如角膜受伤后和自身免疫介导的葡萄膜炎， 必须加以控制和解决，以保持体内平衡并防止损害。在所有这些条件下，我们 发现免疫细胞被招募到晶状体表面，其中许多具有与 免疫调节。晶状体的中心位置及其通过相邻的眼组织与大多数眼组织的界面 房水和玻璃体液使其处于这些晶状体囊相关免疫的完美位置 细胞（LC-AIC）呈递抗原并产生可以在整个细胞中发挥免疫抑制功能的蛋白质 眼睛。此外，我们发现存在常驻免疫细胞，即免疫系统的哨兵， 在开发过程中集成到镜头中。我们现在以这些发现为基础进行研究，旨在 了解从其他眼部招募的晶状体驻留免疫细胞和 LC-AIC 的谱系和功能 位点、它们在维持体内平衡中的作用，以及它们的长期存在是否与致病性有关 结果。在目标 1 中，我们将进行谱系追踪研究以确定它们的个体发育。这些研究将 揭示这些免疫细胞群是否长寿、自我更新且源自胚胎卵黄囊，或者 寿命短暂，源自骨髓，是因损伤和发病机制而被招募到组织中的典型特征。 由于组织驻留免疫细胞是对损伤和发病机制的直接反应者，我们将研究 它们对角膜受伤的反应是否与 LC-AIC 募集和再生有关 角膜的修复。在目标 2 中，我们将对免疫调节特性进行详细分析。 角膜受伤后和葡萄膜炎中 LC-AIC 被募集至晶状体。这些研究将包括功能性 分析将 LC-AIC 与 T 细胞激活的抑制直接联系起来。我们还检查了反 蛋白水解释放的生物活性基质衍生分子的炎症和抗血管生成特性 当 LC-AIC 在晶状体囊内迁移时，它们会被 LC-AIC 所影响。我们对 LC-AIC 的研究有力地支持了他们的观点 作为眼睛免疫调节剂的重要功能，包括我们发现它们持续与 葡萄膜炎眼炎症消退过程中的晶状体表面。然而他们的长期坚持 超过这个时间的晶状体囊表面，以及子集废除晶状体免疫特权的能力和 渗入晶状体，表明它们的长期存在可能会导致病理结果。在目标 3 中，我们将 确定 LC-AIC 穿过晶状体囊渗透晶状体的机制及其命运， 包括它们是否可以通过成为产生胶原蛋白 I 的肌成纤维细胞而成为白内障发生的因素。在 此外，我们将研究 LC-AIC 维持在纤维网络上的纤维网络的特性 晶状体表面缠绕在一起，虹膜在葡萄膜炎晚期附着在晶状体表面， 可能与葡萄膜炎的病理结果有关。了解这些联系可能会带来新的治疗方法 患有与慢性炎症相关的眼部病变的患者的选择。