Cellular Mechanisms of Pathological Retinal Neovascularization

视网膜新生血管是糖尿病、早产儿视网膜病变和年龄相关性视网膜病变的眼部表现。 黄斑变性会导致视力丧失尽管使用了抗VEGF和激光治疗， 视网膜新生血管形成的进展继续导致失明。开发新的治疗 由于缺乏对视网膜新生血管形成的认识， 病理生理学视网膜新生血管形成的特征在于产生几种血管生成因子， 视网膜表面异常新生血管的生长，干扰光的传输 并导致视力丧失。已经观察到炎症和炎症介质水平升高， 从患有病理性视网膜新生血管形成的患者分离的视网膜或玻璃体。因此， 调节炎症和炎性介质，从而选择性地调节异常视网膜 新血管形成，将是治疗病理性视网膜新血管形成的重要策略。到 了解炎症和炎症介质在视网膜病变中的功能意义， 为了观察新生血管的形成，我们使用氧诱导的视网膜病变的小鼠模型进行了初步研究。我们 初步研究表明，caspase-3和炎性caspase-1在视网膜病变中起主要作用， 新生血管形成我们要测试的主要假设是新颖的，并填补了我们理解中的一些空白 关于病理性新生血管的。我们提出的研究的具体目的是检验以下假设， (1)IL-33和caspase介导缺氧诱导的病理性视网膜新生血管;（2）IL-33/ST 2L 介导的ADAMTS 10或VE-钙粘蛋白激活调节出芽血管生成和血管分支，和 (3)IL-33/ST 2L信号转导调节炎症细胞向M2样巨噬细胞的功能极化 视网膜缺氧实现这些具体目标将阐明各种机制， 炎性分子影响视网膜新生血管形成，并开辟了一条新的认识路线， 各种增生性视网膜病的病理生理学。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， 早产儿视网膜病

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.