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

• 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
• 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

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.

项目摘要： 角膜是一种独特的结构，可以完全保持光学的清晰度。 尸体。丢失角膜的光学清晰度是第三大最常见原因的疾病 全球盲目。尽管这些疾病的病因可能是明显的，但大多数融合了共同 导致该组织中病理血管生长的途径，这一过程称为角膜 新血管化（Cons）。最终是促血管生成因素之间不平衡的结果 和角膜缘中的抗血管生成因子。随着血管和淋巴管生长到角膜 可能发生基质，水肿，炎症，蛋白质和脂质沉积以及疤痕，导致角膜泥泞， 视觉障碍或失明。据估计，每年有140万人发展，其中12％ 遭受随后的明显视力丧失。 我们最近将类似血管毒素的4（Angptl4）的作用描述为有效的促血管生成和 血管后部疾病中的血管高度过敏因子，包括糖尿病性视网膜病，增生性 镰状视网膜病和紫veal黑色素瘤。有趣的是，我们最近发现 Angptl4和Vegfa的血管过敏性。此外，我们发现ANGPTL4结合神经蛋白酶 （NRP）1和2，两个质膜同工型，可作为VEGF几个成员的共受体 家庭。最近，我们观察到angptl4在促进前血管生成中的作用 细分市场，导致Conv和Corneal Pterygia的发展。越来越感谢 淋巴管生成在前部段病理血管生成的发展促使我们探索 在此过程中，angptl4的角色。最近，我们观察到Angptl4有效地诱导了迁移 和淋巴内皮细胞（LEC）的发芽，这似乎取决于Angptl4的结合 NRP2。总的来说，这些观察结果表明，angptl4可以在发展中发挥核心作用 cons。我们建议针对VEGFS和ANGPTL4的组合治疗可能更有效 Cons患者的治疗。 该提案的目的是单独研究Angptl4/NRP的作用或与 VEGFS作为血管生成和淋巴管的调节剂，因此作为影响的重要途径 角膜的血管性。这些调查的成功完成将使我们走向 靶向ANGPTL4和VEGF信号传导的组合疗法作为治疗的新替代方法 cons。