Paradigms of Wound Healing and Fibrosis in the Eye

眼睛伤口愈合和纤维化的范例

• 批准号: 10174935
• 负责人: A. Sue Menko
• 金额: $ 50.94万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174935
• 关键词: Adult; Antigens; Aqueous Humor; Area; Autoimmune Diseases; Birth; Cataract; Cataract Extraction; Cells; Ciliary Body; Complex; Cornea; Corneal Injury; Debridement; Development; Dry Eye Syndromes; Elements; Embryo; Environment; Eye; Fibrosis; Grant; Homeostasis; Immune; Immune response; Immune system; Immunologic Surveillance; Injury; Integrins; Lead; Lens Opacities; Light; Link; Mesenchymal; Morphology; Mus; Myofibroblast; Neuraxis; Nutrient; Organ; PTPRC gene; Pathogenesis; Pathology; Peripheral; Phenotype; Play; Population; Process; Regulation; Rest; Retina; Role; Signal Transduction; Sjogren' s Syndrome; Source; Stress; Time; Tissues; Travel; Tunica Vasculosa; Ultraviolet Rays; Vimentin; Visual; Visual Pathways; Visual impairment; adaptive immunity; anterior chamber; capsule; cell type; corneal scar; epithelial repair; injury and repair; insight; lens; lens capsule; novel; recruit; regenerative; regenerative repair; repaired; response; response to injury; stem; trafficking; wound; wound healing

Abstract/Project Summary Immune privilege of the eye results from the need to keep vasculature from the central light path where it would impair vision. Therefore, organs and tissues of the eye like the cornea, have developed alternative mechanisms of immune surveillance to protect them and in response to injury or tissue pathogenesis. In the CNS, novel immune surveillance adaptations have been discovered for protection and repair that demonstrate a state of immune quiescence. In the cornea, which can tolerate foreign antigens, there are immune cells that surveille it in the peripheral regions of the cornea, the aqueous humor, and the tears. The lens has remained an enigma in terms of immune surveillance and protection. We now show that, like other tissues, the lens has developed mechanisms of immune surveillance to protect it throughout a lifetime and to respond to stresses and injury while maintaining its transparency. Since dysregulation of immune surveillance is tightly linked to development of fibrosis, it is possible that the immune cells that associate with the lens may be an unexplored cause of cataract and posterior capsule opacification (PCO). We have discovered resident immune cells (β2 integrin/CD45+) in the lens, that are activated upon mock cataract surgery and have essential functions in regenerative repair of the wound area. These cells are susceptible to being diverted from this role, and induced to acquire a myofibroblast phenotype, the cell type that underlies fibrotic PCO. The resident immune cells first appear in the lens during development, delivered by the tunica vasculosa, a vasculature that surrounds the developing lens; however, this vasculature degenerates after birth. It was assumed that there are no active sources of immune cells that could surveille and protect the adult lens during homeostasis and in response to stress, injury, or pathogenesis. However, we discovered that in response to lens dysgenesis (N-cad∆lens mice) or corneal debridement wounding, an extrinsic immune surveillance mechanism is activated resulting in the recruitment of immune cells to the lens. These immune cells move between the ciliary body and the lens across the ciliary zonules that connect them, in the absence of a vasculature. Over time, these immune cells can acquire a myofibroblast phenotype and lead to lens opacity. Studies of eyes from these N-cad∆lens mice also revealed that there is an immune response to lens dysgenesis in the central cornea, vitreous, and retina. We will build on these findings in three specific aims expected to elucidate how extrinsic immune cells are able to travel to the lens, how the immune system is activated to protect the lens in response to corneal injury and to protect the cornea in response to lens dysgenesis, and how immune cells that surveille the lens in response to its damage/pathogenesis, or that of another tissue, may lead to cataract and PCO.

摘要/项目摘要 眼睛的免疫特权是由于需要保持脉管系统远离中央光路而产生的。 会损害视力。因此，眼睛的器官和组织（如角膜）已经开发出替代品 免疫监视机制来保护它们并对损伤或组织发病机制做出反应。在 中枢神经系统（CNS）发现了新的免疫监视适应性，可用于保护和修复 表现出免疫静止状态。在可以耐受外来抗原的角膜中，有 免疫细胞在角膜、房水和眼泪的周边区域对其进行监视。这 晶状体在免疫监视和保护方面仍然是一个谜。我们现在表明，像其他 组织，晶状体已经发展出免疫监视机制，可以在一生中保护它并 应对压力和伤害，同时保持透明度。由于免疫调节失调 监测与纤维化的发展密切相关，有可能与纤维化相关的免疫细胞 晶状体可能是导致白内障和后囊混浊 (PCO) 的一个尚未探索的原因。 我们在晶状体中发现了常驻免疫细胞（β2 整合素/CD45+），这些细胞在 模拟白内障手术，在伤口区域的再生修复中具有重要功能。这些细胞是 容易从这个角色转移，并被诱导获得肌成纤维细胞表型，细胞类型 这是纤维化 PCO 的基础。常驻免疫细胞在发育过程中首先出现在晶状体中， 血管膜，一种围绕正在发育的晶状体的脉管系统；然而，这种脉管系统 出生后就会退化。假设没有可以监视的免疫细胞的活跃来源 并在稳态期间以及应对压力、损伤或发病机制时保护成人晶状体。然而， 我们发现 针对晶状体发育不全（N-cadΔlens 小鼠）或角膜清创损伤，外源性免疫 监视机制被激活，导致免疫细胞募集到晶状体。这些免疫 细胞在睫状体和晶状体之间穿过连接它们的睫状小带移动，在没有 脉管系统的。随着时间的推移，这些免疫细胞可以获得肌成纤维细胞表型并导致晶状体 不透明度。对这些 N-cadΔlens 小鼠眼睛的研究还表明，对晶状体有免疫反应 中央角膜、玻璃体和视网膜发育不全。 我们将在这些发现的基础上实现三个具体目标，期望阐明外源性免疫细胞如何 能够到达晶状体，免疫系统如何响应角膜反应而被激活以保护晶状体 损伤和保护角膜以应对晶状体发育不全，以及免疫细胞如何监视晶状体 对其损伤/发病机制或其他组织的损伤/发病机制的反应可能会导致白内障和 PCO。