Elucidating the developmental and molecular mechanism of chorioretinal anastomoses in a model of type 3 neovascular age-related macular degeneration

阐明3型新生血管性年龄相关性黄斑变性模型中脉络膜视网膜吻合的发育和分子机制

• 批准号: 10672984
• 负责人: Tyson Nam Kim
• 金额: $ 22.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672984
• 关键词: Adult; Age related macular degeneration; Anastomosis - action; Animal Model; Arteries; Atrophic; Attention; Automobile Driving; Blindness; Blood Vessels; Blood capillaries; Blood flow; Cells; Choroid; Chronic; Classification; Collagen Type IV; Communities; Data Set; Development; Disease; Elderly; Endothelial Cells; Endothelium; Exudate; Exudative age-related macular degeneration; Eye; Fibrosis; Gene Expression; Genes; Goals; Hemorrhage; High Prevalence; Histologic; Hot Spot; Image; Interdisciplinary Study; Lesion; Mentorship; Modeling; Modernization; Molecular; Mus; Mutant Strains Mice; Mutation; Newly Diagnosed; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Physiologic arteriovenous anastomosis; Population; Prognosis; Protocols documentation; RNA; Recurrence; Refractory; Research; Research Personnel; Research Project Grants; Research Proposals; Resistance; Resolution; Retina; Retinal Detachment; Role; Sclera; Serous; Shunt Device; Specific qualifier value; Specificity; Specimen; Structure of retinal pigment epithelium; Testing; Therapeutic; Tissues; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular Proliferation; Veins; Venous; Visual; Work; angiogenesis; candidate identification; career development; choroidal circulation; disorder subtype; human disease; innovation; insight; intravital imaging; mouse model; multiphoton imaging; multiphoton microscopy; neovascularization; novel; novel strategies; novel therapeutics; resilience; retina circulation; serial imaging; single-cell RNA sequencing; skills; spatiotemporal; three photon microscopy; transcriptomics; vision science

PROJECT SUMMARY Neovascular age-related macular degeneration (AMD) is a leading cause of vision loss and blindness in the elderly. Among the subtype of neovascular AMD, type 3 neovascularization (type 3 NV) is associated with a guarded visual prognosis and is uniquely characterized by vascular proliferation in both the retina and choroid. A defining feature of advanced type 3 NV is the development of chorioretinal anastomoses (CRA), abnormal direct connections between the retinal and choroidal circulations. Unfortunately, CRA can act as ‘hot spots’ for recurrent exudation which are resilient to available therapies. The developmental mechanism of CRA remains unclear. We established a murine model for type 3 NV, wherein mice harboring a mutation of type IV collagen (Col4a1) develop features of human disease including serous retinal detachment, hemorrhage, atrophy, and pronounced CRA. As in patients, CRA in Col4a1 mutant mice form in adulthood and mature into large de novo fusions between retinal and choroidal circulations, reminiscent of high-flow arteriovenous (AV) shunts. Recently, AV specification has emerged as a potent regulator of vascular patterning, and dysregulation of key genes governing AV identity induces formation of AV shunts. Notably, normalizing AV specification has been shown to reverse AV shunts despite their high-flow state in certain animal models. Elucidating a role for AV specification in CRA may offer novel insights into both disease pathogenesis and therapeutic strategies. Our central hypothesis is that CRA in Col4a1 mutant mice are AV shunts with a conserved developmental origin from either the retina or choroid. We have recently enabled multiphoton imaging of the choroid directly through the sclera of pigmented eyes using optimized multiphoton microscopy. The objectives of this inter-disciplinary research proposal are therefore to: 1) optimize intravital imaging of chorioretinal vascular dynamics with transscleral multiphoton microscopy; 2) determine the origin, blood flow, and arteriovenous identity of CRA in Col4a1 mutant mice; and 3) identify candidate pathways driving CRA in the endothelium using single cell RNA sequencing. The long-term goal of this career development research project is to provide the investigator with a cross- disciplinary skillset in advanced intravital imaging and single-cell transcriptomics that will allow him to investigate fundamental mechanisms of oculovascular dysgenesis toward the discovery of new therapies in vascular disease.

项目摘要 新生血管相关的MACUALAR变性（AMD）是视力丧失和失明的主要原因 老年人。 守卫的视觉预后，我以视网膜和脉络膜中的血管增生为特征。 高级3型NV的定义特征是脉络膜视网膜吻合（CRA）的发展，异常 视网膜和脉络膜圆形之间的直接连接。 复发性渗出剂对可用疗法有弹性。 CRA的发展机制尚不清楚。 其中携带IV型胶原蛋白突变（COL4A1）的小鼠发展了人类疾病的特征 浆液性视网膜脱离，出血，萎缩和明显的CRA。 成年后形成的小鼠并成熟地进入视网膜和脉络膜之间的大型从头融合， 让人联想到高流动的动脉（AV）分流器。 血管图案的调节剂和关键产生AV身份的失调导致AV AV AV AV的形成 分流器。 在某些动物模型中，阐明CRA中AV规范的角色 疾病发病机理和治疗策略。 是我们最近拥有的视网膜或脉络膜具有保守的发育起源的AV分流 使用优化的脉络膜启用了脉络膜的多光子成像。 多光子显微镜。 1）优化带有跨尺度多光显微镜的脉络膜静脉内成像； 确定COR4A1突变小鼠中CRA的起源，血流和动静脉身份； 使用celle细胞RNA测序在内皮中驱动CRA的候选途径。 Theer Development Research项目的长期目标是为研究人员提供交叉 高级静脉成像和单细胞转录组学中的纪律技能，这将使他能够 调查眼血管发病障碍对发现新疗法的基本机制 血管疾病。