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.

项目摘要 视网膜依赖性黄斑变性（AMD）是视力丧失的主要原因。晚期AMD分为 两种类型，新生血管性或渗出性（湿性）和萎缩性（干性）。湿性AMD越来越被认为是一组 不同种族背景患者的疾病表现不同。欧洲患者 其典型特征在于大玻璃疣和进展为脉络膜新血管形成， 血管内皮生长因子（VEGF）的过度产生，这是疾病进展的核心。湿 因此，AMD用玻璃体内VEGF抑制剂治疗，其改变了疾病预后。然而，在这方面， 在亚洲或非洲血统的患者中，渗出性AMD最与玻璃疣和息肉样小疣的缺乏相关， 脉络膜血管病变（PCV）是厚脉络膜疾病谱的一员。尽管PCV流行， 这种疾病仍然知之甚少，抗VEGF治疗对这些眼睛的效果通常不如对 典型的新生血管性AMD患者，因此迫切需要新的治疗靶点和治疗方法 专门针对这种疾病。厚脉络膜疾病的特点是形成扩张的 PCV中起源于脉络膜并伴有囊样息肉的“厚血管”。最近 遗传学研究已经将血管生成素（Angpt）-TEK内皮信号系统的成员与PCV联系起来 和中心性浆液性脉络膜视网膜病变，厚脉络膜谱系的另一个成员。直接测试这个 关联，我们发现神经嵴特异性Angpt 1敲除小鼠表现出脉络膜毛细血管衰减， 以及脉络膜增厚和PCV特征的扩张增厚血管的侵犯，代表了一种新的遗传学 这些知之甚少的疾病的模型和一个关键的工具，了解血管生成素信号的作用， 疾病进展和作为治疗靶点。为了进一步表征脉络膜中的ANGPT 1信号传导， 在血管系统中，我们进行了初步的单细胞转录组学分析，结果显示ANGPT 1是 对于维持分化的脉络膜毛细血管表型至关重要。Angpt 1敲除小鼠表现出 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表达在其他血管床中升高，提供了一种潜在的机制， ANGPT 1缺乏通过脉络膜扩张导致脉络膜毛细血管功能障碍和厚血管形成 船舶.在本提案中，我们将利用这些发现和我们的新小鼠模型（1）充分表征 血管生成素信号在脉络膜毛细血管中的作用，并确定区分厚血管和 （2）了解脉络膜毛细血管功能障碍和直接ANGPT 1 （3）研究一种新的ANGPT 1模拟药物作为靶向药物的潜力。 治疗厚脉络膜疾病，包括PCV。这些研究的结果将提供新的治疗方法。 靶向并表征用于治疗这组未充分研究的疾病的潜在先导化合物。