Molecular Engineering of Novel Therapies to Treat Corneal Neovascularization

治疗角膜新生血管的新疗法的分子工程

基本信息

批准号：
10592879
负责人：
Akrit Singh Sodhi
金额：
$ 24.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592879
关键词：
ANGPTL4 gene Affect Affinity Angiogenesis Inhibitors Angiogenic Factor Anterior Binding Blindness Blood Vessels Cell membrane Cicatrix Combined Modality Therapy Conjunctival Pterygium Cornea Corneal Neovascularization Corneal Opacity Corneal Stroma Data Deposition Development Diabetic Retinopathy Disease Edema Engineering Etiology Eye Family Goals Growth In Vitro Inflammation Investigation KDR gene Limbus Corneae Lipids Lymphangiogenesis Lymphatic Endothelial Cells Mediator Medical Modality Molecular NRP1 gene Neuropilin-1 Neuropilin-2 Neuropilins Optics Pathogenesis Pathologic Pathologic Neovascularization Pathway interactions Patients Persons Play Prevention Process Protein Isoforms Proteins Regimen Reporting Retina Retinal Diseases Role Signal Transduction Structure Technology Therapeutic Tissues Uveal Melanoma VEGFA gene VEGFC gene Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factors Vision Visual impairment alternative treatment angiogenesis antagonist bevacizumab cell motility combinatorial design effective therapy in vivo insight lymphatic development lymphatic vessel member migration mutant neovascular novel novel therapeutics receptor sickling synergism targeted treatment

项目摘要

PROJECT SUMMARY: The cornea is a unique structure that remarkably maintains its optic clarity by remaining completely avascular. Diseases in which the optical clarity of the cornea is lost are the third most common cause of blindness worldwide. Although the etiology of these diseases may be distinct, most converge on a common pathway leading to the growth of pathological vessels in this tissue, a process known as corneal neovascularization (CoNV). CoNV is ultimately a consequence of an imbalance between proangiogenic factors and antiangiogenic factors in the corneal limbus. As vascular and lymphatic vessels grow into the corneal stroma, edema, inflammation, protein and lipid deposition, and scarring can occur, leading to corneal opacities, visual impairment or blindness. It is estimated that 1.4 million people develop CoNV per year, 12% of whom suffer the subsequent significant loss of vision. We have recently described the role of Angiopoeitin-like 4 (ANGPTL4), as a potent pro-angiogenic and vessel hyperpermeability factor in posterior segment diseases, including diabetic retinopathy, proliferative sickle retinopathy, and uveal melanoma. Interestingly, we recently found an additive effect in the induction of vessel hyperpermeability by ANGPTL4 and VEGFA. Furthermore, we found that ANGPTL4 binds Neuropilin (NRP)1 and 2, two plasma membrane isoforms that act as co-receptors for several members of the VEGF family. More recently, we have observed a role for ANGPTL4 in promoting angiogenesis in the anterior segment, leading to the development of CoNV and corneal pterygia. Growing appreciation of the role of lymphangiogenesis in the development of anterior segment pathological angiogenesis prompted us to explore a role for ANGPTL4 in this process. Recently, we have observed that ANGPTL4 potently induces the migration and sprouting of lymphatic endothelial cells (lECs), and this appears to be dependent on ANGPTL4 binding to NRP2. Collectively, these observations suggest that ANGPTL4 could play a central role in the development of CoNV. We propose that a combinatorial therapy targeting VEGFs and ANGPTL4 may be a more effective treatment for CoNV patients. The objective of this proposal is to investigate the role of ANGPTL4/NRPs alone or in combination with VEGFs as regulators of hemangiogenesis and lymphangionesis and thus as important pathways influencing the avascularity of the cornea. The successful completion of these investigations will move us towards a combinational therapy targeting ANGPTL4 and VEGF signaling as a novel alternative for the treatment of CoNV.

项目概要：角膜是一种独特的结构，可以完全保持角膜的光学清晰度。无血管。角膜光学透明度丧失的疾病是第三大常见原因全世界失明。尽管这些疾病的病因可能不同，但大多数都集中在一个共同点上导致该组织中病理血管生长的途径，这一过程称为角膜新生血管形成（CoNV）。冠状病毒最终是促血管生成因子之间不平衡的结果和角膜缘的抗血管生成因子。随着血管和淋巴管长入角膜可能会发生基质、水肿、炎症、蛋白质和脂质沉积以及疤痕，导致角膜混浊，视力障碍或失明。据估计，每年有 140 万人感染冠状病毒，其中 12% 遭受随后的视力严重丧失。我们最近描述了血管生成素样 4 (ANGPTL4) 的作用，作为一种有效的促血管生成和后段疾病中的血管通透性过高因素，包括糖尿病性视网膜病变、增殖性视网膜病变镰状视网膜病和葡萄膜黑色素瘤。有趣的是，我们最近发现在诱导中存在附加效应 ANGPTL4 和 VEGFA 导致血管通透性过高。此外，我们发现 ANGPTL4 结合 Neuropilin (NRP)1 和 2，两种质膜亚型，充当 VEGF 多个成员的共同受体家庭。最近，我们观察到 ANGPTL4 在促进前部血管生成中的作用段，导致 CV 和角膜翼状胬肉的发展。人们日益认识到其作用淋巴管生成在眼前段病理性血管生成的发展中促使我们探索 ANGPTL4 在此过程中扮演的角色。最近，我们观察到 ANGPTL4 有效诱导迁移以及淋巴管内皮细胞 (IEC) 的萌芽，这似乎依赖于 ANGPTL4 与 NRP2。总的来说，这些观察结果表明 ANGPTL4 可能在病毒。我们建议针对 VEGF 和 ANGPTL4 的联合疗法可能是更有效的冠状病毒患者的治疗。本提案的目的是研究 ANGPTL4/NRP 单独或与 VEGF 作为血管生成和淋巴管生成的调节因子，因此是影响血管生成和淋巴管生成的重要途径角膜的无血管性。这些调查的成功完成将推动我们走向靶向 ANGPTL4 和 VEGF 信号传导的联合疗法作为治疗以下疾病的新替代方案病毒。