Cellular Mechanisms of Pathological Retinal Neovascularization

视网膜新生血管是糖尿病、早产儿和年龄相关的视网膜病变的眼部表现 黄斑变性，导致视力丧失。尽管使用了抗血管内皮生长因子和激光治疗， 视网膜新生血管的进展继续导致失明。新疗法的发展 由于缺乏对视网膜新生血管的了解，抗视网膜新生血管的方法有限 病理生理学。视网膜新生血管的特征是产生几种血管生成因子， 视网膜表面异常新生血管的生长干扰了光的传输 并导致视力丧失。观察到炎症和炎症介质水平的升高 病理性视网膜新生血管患者的视网膜或玻璃体。因此，有能力 调节炎症和炎症介质，从而选择性地调节视网膜异常 新生血管是治疗病理性视网膜新生血管的重要手段。至 了解炎症和炎症介质在视网膜中的功能意义 在新生血管方面，我们使用氧气诱导的视网膜病变的小鼠模型进行了初步研究。我们的 初步研究表明，caspase-3和炎性caspase(caspase-1)在视网膜中起主导作用 新生血管。我们要检验的主要假设是新颖的，填补了我们理解中的一些空白 关于病理性新生血管的问题。我们建议的研究的具体目的是检验以下假设 (1)IL-33和caspase介导低氧诱导的病理性视网膜新生血管；(2)IL-33/ST2L 介导的ADAMTS10或VE-钙粘蛋白激活调节萌芽血管生成和血管分支，以及 (3)IL-33/ST2L信号转导调控炎性细胞向M2样巨噬细胞的功能极化 缺氧性视网膜。实现这些特定的目标将阐明各种不同的 炎症分子影响视网膜新生血管开辟了一条新的认识思路 各种增殖性视网膜病变的病理生理学。此外，拟议的研究肯定会 有助于开发针对增殖性糖尿病视网膜病变的新治疗策略和 早产儿视网膜病变。

Retinal neovascularization is an ocular manifestation of diabetes, retinopathy of prematurity and age-related macular degeneration, which leads to vision loss. Despite the use of anti-VEGF and laser treatments, progression of retinal neovascularization continues to cause blindness. The development of new therapeutic approaches against retinal neovascularization is limited, because of lack of knowledge about its pathophysiology. Retinal neovascularization is characterized by production of several angiogenic factors, with consequential growth of aberrant new blood vessels on retinal surface that interferes with light transmission and results in vision loss. An elevated levels of inflammation and inflammatory mediators have been observed in retinas or vitreous isolated from patients with pathological retinal neovascularization. Therefore, the ability to modulate inflammation and inflammatory mediators and thereby selectively modulating aberrant retinal neovascularization, would be a great strategy in the treatment of pathological retinal neovascularization. To understand the functional significance of inflammation and inflammatory mediators in retinal neovascularization, we performed preliminary studies using mouse model of oxygen-induced retinopathy. Our preliminary studies suggest a predominant role caspase-3 and inflammatory caspase (caspase-1) in retinal neovascularization. Our primary hypothesis to be tested is novel and fills some voids in our understanding about pathological neoangiogenesis. The specific aims of our proposed studies are to test the hypotheses that (1) IL-33 and caspases mediates hypoxia-induced pathological retinal neovascularization, (2) IL-33/ST2L mediated ADAMTS10 or VE-cadherin activation regulates sprouting angiogenesis and vessel branching, and (3) IL-33/ST2L signaling regulates the functional polarization of inflammatory cells to M2-like macrophages in hypoxic retina. Achieving these specific aims will elucidate the mechanisms through which various inflammatory molecules affect retinal neovascularization and open up a new line of understanding about the pathophysiology of various proliferative retinopathies. In addition, the proposed research will certainly contribute to the development of new therapeutic strategies against proliferative diabetic retinopathy and retinopathy of prematurity.