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.

项目总结/摘要 眼睛中的炎症反应，例如角膜损伤后，以及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，防止损害。在所有这些条件下，我们 发现免疫细胞被募集到透镜表面，许多具有与 免疫调节透镜的中心位置及其通过邻近的角膜组织与大多数眼组织的界面 房水和玻璃体液将其置于这些透镜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免疫系统中发挥免疫抑制功能的蛋白质。 the eye.此外，我们发现有常驻免疫细胞，免疫系统的哨兵， 在显影过程中结合在透镜内。我们现在在这些发现的基础上进行研究， 了解透镜驻留免疫细胞和从其他眼部募集的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 结果。在目标1中，我们将进行谱系追踪研究，以确定他们的个体发育。这些研究将 揭示这些免疫细胞群是否是长寿的、自我更新的和胚胎卵黄囊衍生的，或 短寿命、骨髓来源的典型的那些被募集到组织中以响应损伤和发病机制。 由于组织驻留免疫细胞是损伤和发病机制的直接反应者，我们将研究 它们对角膜损伤的反应是否与LC-AIC的募集和再生有关？ 修复角膜。在目标2中，我们将对免疫调节特性进行详细分析。 LC-AIC在角膜创伤后和葡萄膜炎中被募集到透镜。这些研究将包括一个功能 分析以将LC-AIC与T细胞活化的抑制直接联系起来。我们还研究了反- 蛋白水解释放的生物活性基质衍生分子的炎性和抗血管生成性质 当它们在透镜囊内迁移时通过LC-AIC。我们对LC-AIC的研究强烈支持他们的观点。 重要的功能，作为免疫调节剂在眼睛，包括我们的发现，他们坚持整合 在葡萄膜炎眼睛的炎症消退过程中的透镜表面。然而，他们的长期坚持， 透镜囊表面超过这一时间，和一个子集废除透镜免疫豁免的能力， 渗入透镜，表明它们的长期存在可能导致病理结果。在目标3中，我们 确定LC-AIC穿过透镜囊以渗透透镜的机制及其结局， 包括它们是否可以通过成为产生胶原I的肌成纤维细胞而成为白内障发生的试剂。在 此外，我们还将研究LC-AIC在基底上保持的纤维状网络的性质。 透镜的表面变得封闭，并且虹膜在葡萄膜炎的晚期阶段变得附着于其上， 可能与葡萄膜炎的病理结果有关了解这些联系可能会导致新的治疗方法 与慢性炎症相关的眼部病变患者的选择。