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: 8879152
• 负责人: Wenchao Song
• 金额: $ 49.36万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8879152
• 关键词: Address; Age; Age related macular degeneration; Anaphylatoxins; Animal Model; Blindness; Blood Vessels; Breeding; CD46 Antigen; CD55 Antigens; Cell model; Cells; Cessation of life; Characteristics; 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 study; Growth; Health; 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; drug candidate; geographic atrophy; human disease; inhibitor/antagonist; intravitreal injection; macula; mouse model; neutralizing monoclonal antibodies; novel; photoreceptor degeneration; pre-clinical; prevent; research study; risk variant

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）：补体是先天免疫的一种重要形式，在宿主防御中发挥关键作用。然而，最近的研究表明，它也与许多罕见和常见的人类疾病有关。与补体激活异常相关的高患病率疾病之一是年龄相关性黄斑变性（AMD），这是一种老年人进行性致盲疾病。遗传学研究提供的证据表明，补体基因（例如补体因子 H (fH)、因子 B (fB)、成分 2 (C2) 和成分 3 (C3)）中携带单核苷酸多态性 (SNP) 的个体患 AMD 的风险增加。尽管已经开发了小鼠模型来研究补体在湿性 AMD 中的作用，并以脉络膜新生血管 (CNV) 作为终点，并且正在湿性 AMD 的临床试验中评估几种抗补体药物，但更好地了解补体在湿性 AMD 中的作用干性 AMD 的开发是必要的，并且将通过动物模型的开发得到帮助。 RPE 功能障碍是干性和湿性 AMD 的重叠病理原因。在这个项目中，我们将研究眼睛补体激活异常的情况下 RPE 功能障碍和视网膜损伤的发病机制。我们通过选择性删除 RPE 细胞中关键的膜补体调节因子 Crry 来创建小鼠模型。 Crry 是一种鼠 C3 转化酶抑制剂，被认为是人膜辅因子蛋白（MCP、CD46）的功能同源物。 CD46 在地理萎缩 (GA) 扩大区域的 RPE 中下调，使其成为疾病相关靶点。通过使用 cre-lox 条件基因靶向策略，我们选择性地灭活 RPE 细胞中的 Crry 基因，模拟 GA 中 CD46 的丢失。 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性 AMD 的 RPE 变性特征。此外，突变小鼠出现亚 RPE 沉积和神经感觉视网膜功能障碍。因此，RPE 特异性 Crry KO 小鼠代表了一种新的动物模型，该模型开发了具有干性 AMD 特征的补体介导的 RPE 变性/沉积。本提案的总体目标是使用 RPE 特异性 Crry KO 小鼠，研究补体失调在视网膜变性发病机制中的作用机制，以确定负责的补体介质并探索针对该疾病的抗补体疗法。这些研究将有助于指导未来关于有效补体的抗补体临床试验 级联目标和给药途径。