Complement Mediated Neovascularization in Retinopathy

病理性新生血管是早产儿视网膜病变的标志 以及糖尿病视网膜病变(DR)，其中新生血管形成和视网膜病变之间的平衡 回归决定疾病的严重程度。这项提议调查了一种新的机制 因此，病理性新生血管以消退为目标，同时保留 所需的正常血管床。视网膜病变是一种由血管引起的两期疾病。 损失。由此产生的缺氧引发了一种病理反应，即新生血管，这 如果不加以检查，可能会发展为失明。最佳的治疗方法将消除 新生血管生长，同时保留对组织必不可少的正常血管 动态平衡。在这种情况下，一种有吸引力的方法认为，通过 在一定程度上是由补充制决定的。到目前为止，补充剂在 增殖性视网膜病变目前知之甚少。在这里，我们将描述 补体系统在青光眼病理性新生血管形成和清除中的作用 氧诱导视网膜病变(OIR)的小鼠模型。我们将确定以下方面的贡献 经典的、替代的和凝集素补充途径和内源膜- 结合补体抑制剂在血管脱落、损伤后血管再生、新生血管中的作用 OIR进展过程中的发育和新陈代谢回归。我们将利用淘汰赛 缺乏每个补体途径的小鼠和只包含一个功能途径的小鼠 补体途径。 初步数据表明，补语系统发挥着重要的作用 在保留正常血管系统的同时消除新生血管的作用。补体B因子， 一种替代补体级联的激活剂在视网膜中显著增加 有新生血管，并局限于新生血管。缺乏补体因子的小鼠- B显示新生血管的严重程度和持续时间增加。CD55，一个补充 保护健康宿主细胞免受补体相关破坏的抑制物，是 仅与正常血管系统有关，与新生血管无关。这些数据表明 另一种补体级联在调节补体清除过程中起重要作用 视网膜中的病理性新生血管。然而，另一个人的贡献 这一过程中的补体途径尚不清楚。对机制的理解 补体系统通过它来调节新的清除可能会打开新的 ROP和其他致盲新生血管眼病的治疗途径。

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.