The role of Angiopoietin-TEK signaling in polypoidal choroidal vasculopathy

血管生成素-TEK 信号在息肉状脉络膜血管病变中的作用

• 批准号: 10412011
• 负责人: Benjamin R. Thomson
• 金额: $ 38.99万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412011
• 关键词: ANGPT1 gene; ANGPT2 gene; Address; Adult; Affect; African ancestry; Age related macular degeneration; Angiopoietins; Animal Model; Asian ancestry; Atrophic; Automobile Driving; Biology; Blindness; Blood Vessels; Caliber; Cells; Characteristics; Chimeric Proteins; Choroid; Choroidal Neovascularization; Clinic; Clinical; Cre driver; Data; Defect; Development; Differentiation Antigens; Disease; Disease Progression; Drug Targeting; Drusen; Endothelial Cells; Endothelial Growth Factors Receptor; Endothelium; European; Exhibits; Eye; Eye diseases; Functional disorder; Future; Genes; Genetic; Genetic Models; Genetic study; Growth Factor; Growth Factor Inhibition; Human; Injectable; KDR gene; Knockout Mice; Lead; Lesion; Link; Macular degeneration; Maintenance; Modeling; Morphology; Mus; NOS3 gene; Neural Crest; PDGFRB gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Photoreceptors; Polyps; Prevalence; Production; Protein Tyrosine Kinase; Proto-Oncogene Proteins c-akt; Recombinants; Rodent; Rodent Model; Role; Secondary to; Serous; Signal Pathway; Signal Transduction; Structure of retinal pigment epithelium; System; Testing; Therapeutic; Therapeutic Uses; Tissues; Translating; Translations; Variant; Vascular Diseases; Vascular Endothelial Growth Factors; age related; attenuation; cell type; disease prognosis; drug candidate; endothelial dysfunction; experimental study; eye blood vessel; inhibitor; insight; member; mimetics; mouse model; neovascular; new therapeutic target; novel; novel therapeutics; optimal treatments; prevent; recruit; response; single-cell RNA sequencing; targeted treatment; therapeutic target; tool; transcriptomics; vascular bed; vascular endothelial protein tyrosine phosphatase

PROJECT SUMMARY Age-dependent macular degeneration (AMD) is a leading cause of vision loss. Late stage AMD is divided into two types, neovascular or exudative (wet) and atrophic (dry). Wet AMD is increasingly recognized as a group of diseases with differential presentations in patients of different ethnic backgrounds. In patients of European ancestry, it is typically characterized by large drusen and progression to choroidal neovascularization caused by excessive production of vascular endothelial growth factor (VEGF), which is central to disease progression. Wet AMD is therefore treated with intravitreal VEGF inhibitors which have transformed disease prognosis. However, in patients of Asian or African ancestry exudative AMD is most associated with a paucity of drusen and polypoidal choroidal vasculopathy (PCV), a member of the pachychoroid disease spectrum. Despite the prevalence of PCV, this disease remains poorly understood and anti-VEGF therapy is often less effective for these eyes than for those with typical neovascular AMD, leaving a critical need for new therapeutic targets and treatments specifically targeted at this disease. Pachychoroid diseases are characterized by the formation of dilated “pachyvessels” which originate from the choroid and are accompanied by aneurysmal polyps in PCV. Recent genetic studies have linked members of the angiopoietin (Angpt)-TEK endothelial signaling system with PCV and central serous chorioretinopathy, another member of the pachychoroid spectrum. Directly testing this association, we discovered that neural crest specific Angpt1 knockout mice exhibit choriocapillaris attenuation and encroachment of dilated pachyvessels characteristic of pachychoroid and PCV, representing a new genetic model of these poorly understood diseases and a key tool for understanding the role of angiopoietin signaling in disease progression and as a therapeutic target. To further characterize ANGPT1 signaling in the choroidal vasculature, we performed preliminary single cell transcriptomics analysis which revealed that ANGPT1 is essential for maintenance of the differentiated choriocapillaris phenotype. Angpt1 knockout mice exhibited markedly reduced expression of key choriocapillaris functional genes, including the VEGF receptor encoded by Kdr. In contrast, Kdr expression was elevated in other vascular beds, providing a potential mechanism by which ANGPT1 deficiency leads to choriocapillaris dysfunction and pachyvessel formation through dilation of choroidal vessels. In this proposal, we will leverage these findings and our new mouse model to (1) fully characterize the role of angiopoietin signaling in the choriocapillaris and identify unique markers differentiating pachyvessels from the healthy choroid, (2) Understand the respective role(s) of choriocapillaris dysfunction and direct ANGPT1 signaling in pachyvessel formation and (3) investigate the potential of a new ANGPT1 mimetic drug as a targeted therapeutic in pachychoroid diseases including PCV. The results of these studies will provide new therapeutic targets and characterize a potential lead compound for treatment of this understudied group of diseases.

项目摘要 依赖年龄的黄斑变性（AMD）是视力丧失的主要原因。后期AMD分为 两种类型的新血管或正宗（湿）和萎缩（干）。湿AMD越来越被认为是一组 不同种族背景患者的疾病表现不同。在欧洲患者中 祖先，通常以大drusen和由脉络膜新生血管形成为特征 血管内皮生长因子（VEGF）过多产生，这对于疾病进展至关重要。湿的 因此，AMD用玻璃体内VEGF抑制剂治疗，这些抑制剂已改变了疾病促病。然而， 在亚洲或非洲血统专家AMD的患者中，AMD与drusen和Polypoidal的稀少有关 脉络膜血管病（PCV），pachychoroid疾病谱的成员。尽管PCV的流行率 这种疾病的理解仍然不足，抗VEGF疗法对这些眼睛的有效效果通常不如 那些具有典型的新生血管AMD的人，对新的治疗靶标和治疗造成了迫切需求 pachychoroid疾病的特征是扩张的形成 “ Pachyvessels”起源于脉络膜，并伴有PCV中的动脉瘤息肉。最近的 遗传研究已将血管生成素（Angpt） - TEK内皮信号系统的成员与PCV联系起来 和中央浆液性脉络膜结构病，这是pachychoroid谱的另一个成员。直接测试此 协会，我们发现神经特定的angpt1敲除小鼠暴露了绒毛膜毛细血管衰减 并编码pachychoroid和pcv的扩张的Pachyvessels，代表新的通用 这些不良理解的疾病的模型和了解血管生成素信号传导作用的关键工具 疾病进展和治疗靶标。进一步表征脉络膜中的angpt1信号传导 脉管系统，我们进行了初步的单细胞转录组学分析，该分析表明Angpt1是 维持分化的绒毛膜表型至关重要。 Angpt1淘汰小鼠暴露 明显降低了关键脉络膜毛细血管功能基因的表达，包括编码的VEGF受体 KDR。相反，其他血管床中KDR表达升高，提供了潜在的机制 Angpt1缺乏会导致脉络膜毛细血管功能障碍和Pachyvessel通过脉络膜词典形成 船只。在此提案中，我们将利用这些发现和新的鼠标模型来完全表征 血管生成素信号传导在绒毛膜上的作用 健康的脉络膜，（2）了解脉络膜毛细血管功能障碍的相对作用和直接Angpt1 Pachyvessel形成中的信号传导，（3）研究新Angpt1模拟药物作为目标的潜力 包括PCV在内的Pachychoroid疾病中的治疗性。这些研究的结果将提供新的治疗性 靶标并表征潜在的铅化合物，以治疗这种已知的疾病。