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: 10183715
• 负责人: Benjamin R. Thomson
• 金额: $ 41.28万
• 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/10183715
• 关键词: ANGPT1 gene; ANGPT2 gene; Address; Adult; Affect; African; Age related macular degeneration; Angiopoietins; Animal Model; Asians; 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; Prognosis; 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; drug candidate; endothelial dysfunction; experimental study; eye blood vessel; inhibitor/antagonist; 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.

项目总结 老年性黄斑变性(AMD)是导致视力丧失的主要原因。晚期AMD分为 两种类型，新生血管或渗出型(湿性)和萎缩性(干性)。湿性AMD越来越被认为是一组 不同种族背景的患者表现不同的疾病。在欧洲的患者中 家系，其典型的特征是巨大的玻璃体和进展到脉络膜新生血管所致的 过度产生血管内皮生长因子(VEGF)，这是疾病进展的核心。湿的 因此，AMD可以用玻璃体内注射的血管内皮生长因子抑制剂来治疗，这改变了疾病的预后。然而， 在具有亚洲或非洲血统的患者中，渗出性AMD最常与少见的黄褐斑和息肉有关。 脉络膜血管病(PCV)是厚脉络膜病的一种。尽管PCV很流行， 这种疾病仍然知之甚少，抗血管内皮生长因子治疗对这些眼睛的疗效往往不如对 患有典型的新生血管性AMD的患者，迫切需要新的治疗靶点和治疗方法 专门针对这种疾病。厚脉络膜疾病的特征是形成扩张的脉络膜 起源于脉络膜的“厚血管”，在PCV中伴有动脉瘤性息肉。近期 遗传学研究已将血管生成素(Angpt)-TEK内皮信号系统成员与PCV联系起来 和中心性浆液性脉络膜视网膜病变，这是厚脉络膜光谱的另一种成员。直接测试这个 协会，我们发现神经峰特异性Angpt1基因敲除小鼠表现出脉络膜毛细血管的衰减 以厚脉络膜和PCV为特征的扩张的厚血管侵犯，代表了一种新的遗传方式 这些鲜为人知的疾病的模型，以及理解血管生成素信号在 疾病的进展和作为治疗的目标。为了进一步研究脉络膜中的ANGPT1信号 血管系统，我们进行了初步的单细胞转录分析，发现ANGPT1是 对于维持分化的脉络膜毛细血管表型是必不可少的。Angpt1基因敲除小鼠展示 显著降低关键的脉络膜毛细血管功能基因的表达，包括由 KDR。相反，KDR在其他血管床中的表达升高，提供了一种潜在的机制，通过 血管紧张素转换酶1缺乏导致脉络膜毛细血管功能障碍和脉络膜扩张形成厚血管 船只。在这项提案中，我们将利用这些发现和我们的新老鼠模型来(1)充分描述 血管生成素信号在绒毛膜毛细血管中的作用及鉴别厚壁血管和绒毛毛细血管的独特标志物 健康的脉络膜，(2)了解脉络膜毛细血管功能障碍和直接血管生成素1的各自作用(S) 厚血管形成中的信号转导和(3)研究一种新的ANGPT1模拟药物作为靶向药物的潜力 治疗包括PCV在内的厚脉络膜疾病。这些研究的结果将提供新的治疗方法 针对并描述一种潜在的先导化合物，用于治疗这组未被研究的疾病。