Immune Mechanisms in Choroidal Neovascularization

描述(由申请人提供)：应聘者的长期目标是研究效应器免疫系统在调节视网膜下空间眼血管生成中的作用。眼部参与老年性黄斑变性(AMD)往往会导致严重的视力损害，这是由于视网膜下空间新生血管的结果，继而导致潜在的脉络膜毛细血管和上层视网膜光感受器的损害。AMD是北美、欧洲和澳大利亚65岁以上人群失明的主要原因。随着人口老龄化，AMD的发病率预计将呈指数级上升。目前的治疗方法在本质上充其量是姑息治疗。与年龄相关的眼组织包括视网膜色素上皮(RPE)和Bruchs膜的变化扰乱了眼微环境内微妙的氧平衡，并可能影响视网膜和脉络膜内的免疫效应机制。正常的RPE对于维持一个有活力和健康的外层视网膜起着至关重要的作用。它还抑制促血管生成的刺激，对维持正常的视网膜脉络膜界面至关重要。RPE功能障碍和免疫效应系统失调的组合在视网膜下空间创造了一个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固有特性方面发挥关键作用。视网膜下间隙成为脉络膜新生血管(CNV)形成的良好环境。事实上，动物模型已经表明，免疫效应细胞对CNV的启动和维持至关重要。了解促进眼血管生成的病理生理学和信号级联反应，以及免疫系统对这些过程的影响，对于了解AMD、糖尿病视网膜病变、早产儿视网膜病变和眼部黑色素瘤等眼科疾病具有广泛的意义，这些疾病影响不同年龄组，其中血管生成在疾病过程中起关键作用。候选人建议在赞助商的实验室研究眼部血管生成的免疫学和分子机制。在提案期间，他将a)研究免疫系统和相关的细胞因子极化在眼血管生成中的作用，b)在小鼠激光诱导的CNV模型中寻求识别和表征由效应性细胞因子调控的宿主眼组织因子，以及c)确定在CNV发展过程中促进视网膜下间隙血管内皮细胞增殖的信号通路。

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.