Membrane complement regulators in RPE degeneration and retinal injury

RPE 变性和视网膜损伤中的膜补体调节因子

• 批准号: 8561611
• 负责人: Wenchao Song
• 金额: $ 50.36万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8561611
• 关键词: Address; Age; Age related macular degeneration; Alleles; Anaphylatoxins; Animal Model; Blindness; Blood Vessels; Breeding; CD46 Antigen; CD55 Antigens; Cell model; Cells; Cessation of life; Choroidal Neovascularization; Clinical Trials; Complement; Complement 3a; Complement 5a; Complement Activation; Complement Factor B; Complement Factor H; Complement Inactivators; Deposition; Development; Disease; Drusen; Elderly; Electroretinography; Eye; Eye diseases; Functional disorder; Fundus photography; Future; Gene Targeting; Genes; Genetic; Growth; High Prevalence; Homologous Gene; Host Defense; Human; Impairment; Individual; Injury; Knockout Mice; Link; Liquid substance; Mediating; Mediator of activation protein; Membrane; Modeling; Monoclonal Antibodies; Mus; Mutant Strains Mice; Natural Immunity; Nonexudative age-related macular degeneration; Optical Coherence Tomography; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Penetrance; Phase; Phenotype; Photoreceptors; Play; Properdin; Proteins; Resistance; Retina; Retinal; Retinal Degeneration; Risk; Role; Route; Serum; Single Nucleotide Polymorphism; Staging; Structure of retinal pigment epithelium; Testing; Tissues; Transgenic Mice; animal model development; complement pathway; disease characteristic; drug candidate; geographic atrophy; human disease; inhibitor/antagonist; intravitreal injection; macula; mouse model; neutralizing monoclonal antibodies; novel; photoreceptor degeneration; pre-clinical; prevent; public health relevance; research study

DESCRIPTION (provided by applicant): Complement is an important form of innate immunity that plays a key role in host defense. However, recent studies have revealed that it is also implicated in many human diseases, both rare and common. One of the high-prevalence diseases that have been linked to abnormal complement activation is age-related macular degeneration (AMD), a progressive blinding condition in the elderly. Genetic studies have provided evidence that individuals carrying single nucleotide polymorphism (SNP) in complement genes such as complement factor H (fH), factor B (fB), component 2 (C2) and component 3 (C3) are at increased risk of developing AMD. Although mouse models have been developed to study the role of complement in wet AMD with choroidal neovascularization (CNV) as an endpoint, and several anti-complement agents are being evaluated in clinical trials for wet AMD, better understanding of the role of complement in the development of dry AMD is required, and will be aided by development of animal models. RPE dysfunction is an overlapping pathological cause for both dry and wet AMD. In this project, we will study the pathogenesis of RPE dysfunction and retinal injury in the context of abnormal complement activation in the eye. We have created a mouse model by selectively deleting a key membrane complement regulator Crry in RPE cells. Crry is a murine C3 convertase inhibitor that is considered a functional homolog of human membrane cofactor protein (MCP, CD46). CD46 is down- regulated in the RPE in regions of expanding geographic atrophy (GA), making it a disease-relevant target. By using the cre-lox conditional gene targeting strategy, we selectively inactivated the Crry gene in RPE cells, modeling loss of CD46 in GA. Preliminary characterization of the RPE-specific Crry knockout (KO) mice revealed local complement activation together with features of RPE degeneration akin to human dry AMD. Furthermore, the mutant mice developed sub-RPE deposits and neurosensory retinal dysfunction. The RPE- specific Crry KO mouse thus represents a novel animal model that develops complement-mediated RPE degeneration/deposits with features of dry AMD. The overall objective of this proposal is to use the RPE- specific Crry KO mouse and investigate the mechanism of action of dysregulated complement in the pathogenesis of retinal degeneration, to define the complement mediators responsible and to explore anti- complement therapies for this disorder. These studies will help guide future anti-complement clinical trials with respect to effective complement cascade targets and routes of administration.

描述（由申请人提供）：补充是一种重要的先天免疫力，在宿主防御中起着关键作用。但是，最近的研究表明，这也与许多人类疾病有关，无论是罕见和常见的。与异常补体激活相关的高尚疾病之一是与年龄相关的黄斑变性（AMD），这是老年人的进行性盲目疾病。遗传研究提供了证据，表明在补体基因（例如补体因子H（FH），因子B（FB），成分2（C2）和组件3（C3）等补体基因中携带单核苷酸多态性（SNP）的个体有增加患AMD的风险。尽管已经开发了小鼠模型来研究补体在脉络性新生血管形成（CNV）作为终点的湿AMD中的作用，并且在临床试验中评估了几种抗补充剂的湿AMD，对湿AMD的临床试验进行了更好的了解，但对补体在干燥AMD发展中的作用的理解是必需的，并且将由动物模型的开发提供帮助。 RPE功能障碍是干和湿AMD的重叠病理原因。在这个项目中，我们将研究眼睛异常补体激活的背景下RPE功能障碍和视网膜损伤的发病机理。我们通过选择性地删除RPE单元格中的密钥膜补体调节器crry来创建鼠标模型。 Crry是一种鼠C3转化酶抑制剂，被认为是人膜辅因子蛋白的功能同源物（MCP，CD46）。在扩展地理萎缩（GA）地区的RPE中，CD46受到了调节，使其成为与疾病相关的靶标。通过使用CRE-LOX条件基因靶向策略，我们有选择地将RPE细胞中的Crry基因灭活，对GA中CD46的损失进行了建模。 RPE特异性crry敲除（KO）小鼠的初步表征揭示了局部补体激活以及类似于人类干AMD的RPE变性的特征。此外，突变小鼠产生了亚rpe沉积物和神经感觉视网膜功能障碍。因此，rpe-特异性的crry ko小鼠代表了一种新型的动物模型，该模型具有带有干amd特征的补体介导的RPE变性/沉积物。该提案的总体目的是使用特定于特异性的Crry KO小鼠，并研究视网膜变性发病机理失调补体的作用机理，以定义负责的补体介体并探索该疾病的抗补体疗法。这些研究将有助于指导有关有效补体的未来反混合临床试验 级联目标和行政途径。