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: 8220020
• 负责人: Kip M Connor
• 金额: $ 40.25万
• 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/8220020
• 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

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. PUBLIC HEALTH RELEVANCE: In proliferative retinopathies, neovessels may regress, leaving only normal vessels; persistent neovessels can cause retinal cell death and progression to blindness. Emerging data implicate the complement system in host tissue repair and homeostasis during disease resolution. Elucidating the mechanism of endogenous neovessel regression while leaving the normal healthy vasculature untouched would be of great clinical interest.

描述（由申请人提供）：病理性新生血管形成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。该提案研究了一种新的机制，即病理性新生血管被靶向用于消退，同时保留所需的正常血管床。视网膜病变是一种由血管损失引发的两阶段疾病。由此产生的缺氧会导致病理反应，即新血管形成，如果不加以控制，可能会导致失明。最佳治疗将消除新血管生长，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认为先天免疫，部分介导的补体系统。到目前为止，补体在增殖性视网膜病变中的作用还知之甚少。在此，我们将描述补体系统在氧诱导视网膜病变（OIR）小鼠模型中病理性新血管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OIR进展期间血管脱落、损伤后血管再生长、新血管发育和新血管消退中的作用。我们将利用缺乏每种补体途径的敲除小鼠和仅含有一种功能性补体途径的小鼠。 初步数据表明，补体系统在消除新生血管同时保留正常血管系统中起重要作用。补体因子-B是一种补体级联反应的激活剂，在视网膜新生血管形成中显著增加，并定位于新生血管。缺乏补体因子- B的小鼠显示新血管形成的严重性和持续时间增加。Cd 55是一种补体抑制剂，保护健康宿主细胞免受补体相关破坏，仅与正常血管系统相关，而不与新生血管相关。这些数据表明，替代补体级联在介导视网膜中病理性新生血管的清除中是重要的。然而，在这一过程中的其他补体途径的贡献仍然是未知的。了解补体系统介导新生血管清除的机制可能为ROP和其他致盲性新生血管性眼科疾病的治疗开辟新的途径。 公共卫生相关性：在增生性视网膜病变中，新生血管可能消退，仅留下正常血管;持续的新生血管可导致视网膜细胞死亡并进展至失明。新出现的数据表明，疾病消退期间，补体系统参与宿主组织修复和体内平衡。阐明内源性新生血管消退的机制，同时保持正常的健康血管系统不变，将是巨大的临床利益。