Immune Mechanisms in Choroidal Neovascularization

描述（由申请人提供）：候选人的长期目标是研究效应免疫系统在调节视网膜下空间中的眼部血管生成中的作用。年龄相关性黄斑变性（AMD）中的眼部受累通常由于视网膜下空间中的新血管形成而导致显著的视力损害，随后损害下面的脉络膜毛细血管和上面的视网膜光感受器。AMD是北美、欧洲和澳大利亚65岁以上人群致盲的主要原因。随着人口老龄化，预计AMD的发病率将呈指数级上升。目前的治疗在本质上充其量是姑息性的。包括视网膜色素上皮（RPE）和布鲁赫膜在内的眼组织中的视网膜病变相关变化扰乱了眼微环境中微妙的氧平衡，并可能影响视网膜和脉络膜内的免疫效应机制。正常的RPE在维持一个有活力和健康的外视网膜中起着至关重要的作用。它还抑制促血管生成刺激，并且在维持正常的视网膜脉络膜界面中至关重要。RPE功能障碍和失调的免疫效应系统的组合在视网膜下空间中产生潜在的促血管生成环境。免疫系统可能在改变RPE和脉络膜内皮细胞的天然特性中起关键作用。视网膜下腔成为脉络膜新生血管（CNV）形成的有利环境。在动物模型中确实显示，免疫效应细胞对于CNV的起始和维持是关键的。对促进眼部血管生成的病理生理学和信号级联以及免疫系统对这些过程的影响的理解对于理解影响不同年龄组的眼科疾病如AMD、糖尿病性视网膜病、早产儿视网膜病和眼部黑素瘤具有广泛的意义，并且其中血管生成对疾病过程至关重要。候选人建议在申办者的实验室研究眼部血管生成的免疫学和分子机制。在研究期间，他将a）研究免疫系统和相关细胞因子极化在眼部血管生成中的作用，B）在CNV的小鼠激光诱导模型中寻求识别和表征受效应细胞因子调节的宿主眼部组织因子，以及c）定义在CNV发展期间促进视网膜下腔血管内皮细胞增殖的信号传导途径。

DESCRIPTION (provided by applicant): The candidate's long term goals are to study the role of the effector immune system in regulating ocular angiogenesis in the sub-retinal space. Ocular involvement in age-related macular degeneration (AMD) often leads to significant visual impairment as a result of neovascularization in the sub-retinal space with subsequent damage to the underlying choriocapillaris and overlying retinal photoreceptors. AMD is the leading cause of blindness among the population over 65 years of age in North America, Europe and Australia. The morbidity from AMD is expected to rise exponentially as the population ages. Current treatments are at best palliative in nature. Age-related changes in the ocular tissues including the retinal pigment epithelium (RPE) and Bruch's membrane perturb the delicate oxygen balance within the ocular micromilieu and might affect immune effector mechanisms within the retina and choroid. Normal RPE plays a crucial role in maintaining a viable and healthy outer retina. It also inhibits pro-angiogenic stimuli and is critical in maintaining a normal retinochoroidal interface. A combination of RPE dysfunction and a dysregulated immune effector system create a potentially pro-angiogenic environment in the sub-retinal space. The immune system might play a critical role in altering the native characteristics of the RPE and choroidal endothelial cells. The sub-retinal space then becomes a favorable environment for the development of choroidal neovascularization (CNV). It has indeed been shown in animal models that immune effector cells are critical for the initiation and sustenance of CNV. An understanding of the pathophysiology and signaling cascades that promote ocular angiogenesis and the influence of the immune system on these processes has broad implications for the understanding of ophthalmic diseases such as AMD, diabetic retinopathy, retinopathy of prematurity and ocular melanomas which affect diverse age groups and wherein angiogenesis is critical to the disease processes. The candidate proposes to study the immunology and molecular mechanisms of ocular angiogenesis in the sponsor's laboratory. During the duration of the proposal, he will a) study the role of the immune system and associated cytokine polarization in ocular angiogenesis, b) seek to identify and characterize host ocular tissue factors modulated by effector cytokines in a murine laser-induced model of CNV, and c) define the signaling pathways that promote vascular endothelial cell proliferation in the sub-retinal space during the development of CNV.