Complement Mediated Neovascularization in Retinopathy

视网膜病变中补体介导的新生血管形成

• 批准号: 8656119
• 负责人: Kip M Connor
• 金额: $ 39.69万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656119
• 关键词: Address; Affect; Alternative Complement Pathway; Animals; Apoptotic; Binding; Biology; Blindness; Blood Vessels; Cell Death; Cells; Clinical; Complement; Complement 1q; Complement 3; Complement Factor B; Complement Inactivators; Data; Deposition; Development; Diabetic Retinopathy; Disease; Disease Marker; Disease Progression; Dissection; Dropout; Equilibrium; Excision; Goals; Growth; Homeostasis; Hypoxia; Immune; Immune system; Immunohistochemistry; Immunologic Surveillance; Injury; Knockout Mice; Knowledge; Laboratories; Lasers; Lead; Lectin; Left; Location; Mediating; Mediator of activation protein; Membrane; Membrane Proteins; Messenger RNA; Modeling; Mus; Natural Immunity; Oxygen; Pathologic; Pathologic Neovascularization; Pathology; Pathway interactions; Pennsylvania; Pharmacologic Substance; Phase; Pilot Projects; Play; Process; Proteins; Regulation; Resolution; Retina; Retinal; Retinal Diseases; Retinopathy of Prematurity; Role; Serum; Severities; Severity of illness; Source; System; Therapeutic; Tissues; Universities; cell type; complement pathway; complement system; genetic regulatory protein; interest; medical schools; mouse model; neovascular; neovascularization; novel; ocular neovascularization; postnatal; receptor binding; repaired; response; skills; tissue repair; vascular bed; vessel regression

Pathological neovascularization is a hallmark of retinopathy of prematurity (ROP) and diabetic retinopathy (DR), where the balance between neovessel formation and regression determines disease severity. This proposal investigates a novel mechanism whereby pathological neovessels are targeted for regression while preserving the required normal vascular bed. Retinopathy is a two-phased disease initiated by vessel loss. The resulting hypoxia drives a pathologic response, neovascularization, which when unchecked can progress to blindness. Optimal therapy would eliminate neovascular growth while sparing normal vessels that are essential to tissue homeostasis. An attractive approach in this context considers innate immunity, mediated in part by the complement system. To date, the contribution of complement in proliferative retinopathy is poorly understood. Here we will characterize the role of the complement system in the formation and clearance of pathological neovessels in a mouse model of oxygen-induced retinopathy (OIR). We will determine the contribution of the classical, alternative and lectin complement pathways and endogenous membrane- bound complement inhibitors in vascular dropout, vessel regrowth after injury, neovessel development and neovessel regression during OIR progression. We will utilize knockout mice lacking each complement pathway and in mice containing only one functional complement pathway. Preliminary data demonstrates that the complement system plays an important role in eliminating neovessels while sparing normal vasculature. Complement factor-B, an activator of the alternative complement cascade, is significantly increased in retinas with neovascularization and is localized to neovessels. Mice lacking complement factor- B show increased severity and duration of neovascularization. Cd55, a complement inhibitor that protects healthy host cells from complement-associated destruction, is associated only with the normal vasculature and not neovessels. These data indicate that the alternative complement cascade is important in mediating the clearance of pathological neovessels in the retina. However the contributions of the other complement pathways in this process remain unknown. Understanding the mechanism by which the complement system mediates neovessel clearance may open new avenues of therapy for ROP and other blinding neovascular ophthalmic diseases.

病理新血管形成是预性预性（ROP）的标志 和糖尿病性视网膜病（DR），其中Neovessel形成与 回归决定疾病的严重程度。该提案调查了一种新型机制 因此，将病理新闻针对回归，同时保留 需要正常的血管床。视网膜病是由血管引发的两阶段疾病 损失。由此产生的缺氧驱动了病理反应，新血管形成，这 当不受限制的时候可以发展为失明。最佳疗法将消除 新生血管生长，同时保留对组织必不可少的正常血管 稳态。在这种情况下，有吸引力的方法考虑了先天免疫，调解 部分由补充系统。迄今为止，补充的贡献 增殖性视网膜病知之甚少。在这里，我们将表征 在形成和清除病理中新系列中的补体系统 氧诱导的视网膜病（OIR）的小鼠模型。我们将确定 经典，替代和凝集素补体途径以及内源性膜 绑定的补体抑制剂在血管辍学中，受伤后血管再生，新塞尔 OIR进展过程中的发育和新闻回归。我们将利用淘汰赛 缺乏每个补体途径的小鼠，在只有一个功能的小鼠中 补体途径。 初步数据表明，补体系统扮演重要 在避免正常脉管系统的同时消除新系列的作用。补体因子-B， 视网膜中替代补体级联反应的激活剂显着增加 具有新生血管形成，并局限于新精灵。缺乏补体因子的小鼠 - B显示了新血管形成的严重程度和持续时间。 CD55，补充 保护健康宿主细胞免受补体相关破坏的抑制剂，IS 仅与正常的脉管系统相关，而不与新系列相关。这些数据表明 替代补充级联对于调解清除率很重要 视网膜中的病理性新闻。但是对方的贡献 在此过程中的补体途径仍然未知。了解机制 补体系统介导Neovesl的间隙可能会开放新的 ROP和其他盲目的神经眼科疾病的治疗途径。