Complement Mediated Neovascularization in Retinopathy

描述（由申请人提供）：病理性新生血管是早产儿视网膜病变（ROP）和糖尿病视网膜病变（DR）的标志，其中新生血管形成和消退之间的平衡决定了疾病的严重程度。这一建议探讨了一种新的机制，即病理新生血管在保留所需的正常血管床的同时靶向回归。视网膜病变是一种由血管丧失引起的两期疾病。由此产生的缺氧会引发一种病理反应，即新生血管形成，如果不加以控制，就会发展为失明。最佳的治疗方法是消除新生血管的生长，同时保留对组织稳态至关重要的正常血管。在这种情况下，一个有吸引力的方法是考虑先天免疫，部分由补体系统介导。迄今为止，补体在增殖性视网膜病变中的作用尚不清楚。在这里，我们将描述补体系统在氧诱导视网膜病变（OIR）小鼠模型中病理新生血管的形成和清除中的作用。我们将确定经典、替代和凝集素补体途径以及内源性膜结合补体抑制剂在血管脱落、损伤后血管再生、新血管发育和OIR进展过程中新血管退化中的作用。我们将利用缺乏每种补体途径的敲除小鼠和只含有一种功能性补体途径的小鼠。初步数据表明，补体系统在清除新生血管而保留正常血管方面起着重要作用。补体因子- b是替代补体级联的激活剂，在新生血管形成的视网膜中显著增加，并局限于新生血管。缺乏补体因子- B的小鼠新生血管的严重程度和持续时间增加。Cd55是一种保护健康宿主细胞免受补体相关破坏的补体抑制剂，仅与正常脉管系统相关，而与新生血管无关。这些数据表明，替代补体级联在介导视网膜病理新生血管的清除中是重要的。然而，其他补体途径在这一过程中的作用尚不清楚。了解补体系统介导新血管清除的机制可能为ROP和其他致盲性新血管性眼病的治疗开辟新的途径。

DESCRIPTION (provided by applicant): 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.