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 新生血管相关的黄斑变性（AMD）是视力丧失和失明的主要原因 老年。在新血管AMD的亚型中，3型新血管化（3型NV）与A相关 守卫的视觉预后，其特征是视网膜和脉络膜中的血管增殖。 高级3型NV的定义特征是开发常见吻合术（CRA），异常 视网膜和脉络膜圆之间的直接连接。不幸的是，CRA可以充当“热点” 反复经验，对可用疗法有弹性。 CRA的发展机制尚不清楚。我们建立了一个用于3型NV的鼠模型， 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。与患者一样，COL4A1突变体中的CRA 成年后形成的小鼠，成熟成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底（AV）分流。最近，AV规格已成为有效的 血管图案的调节剂和控制AV身份的关键基因的失调诱导AV的形成 值得注意的是，尽管具有高流量 在某些动物模型中陈述。阐明在CRA中的AV规范角色可能会为这两者提供新颖的见解 疾病发病机理和治疗策略。我们的中心假设是COL4A1突变小鼠中的CRA 是来自视网膜或脉络膜具有保守发育起源的AV分流。我们最近有 使用优化的眼睛的巩膜启用脉络膜的多光子成像 多光子显微镜。因此，该跨学科研究建议的目标是： 1）使用经肿瘤多光子显微镜优化常见血管动力学的浸润成像； 2） 确定CL4A1突变小鼠中CRA的起源，血流和动静脉认同； 3）识别 使用单细胞RNA测序在内皮中驱动CRA的候选途径。 该职业发展研究项目的长期目标是为研究人员提供跨 高级插入式成像和单细胞转录组学中的纪律技能，这将使他能够 调查眼血管发育不全的基本机制，以发现新疗法 血管疾病。