Role of Retinal Microvasculature in Posterior Uveitis

描述(申请人提供)：后葡萄膜炎是一组潜在的致盲性炎症性疾病，主要累及视网膜和/或脉络膜。虽然已知后葡萄膜炎的不同亚型是自身免疫性、感染性和肿瘤性的，但导致这些疾病的基本致病机制仍不清楚。与最近认识到全身不同的血管床具有特定的细胞黏附分子和趋化物质组的特征一致，我们假设理解后葡萄膜炎的发病机制和开发有效的治疗干预措施的关键是定义由视网膜微血管内皮细胞表达的独特的一组分子信号。使用独特的、供体匹配的眼血管内皮细胞培养和基因芯片技术，研究人员将研究视网膜内皮细胞在不同刺激条件下超过8000个基因的表达，并与虹膜和脉络膜内皮细胞的基因表达进行比较。此外，调查人员还将利用两种视网膜内皮细胞“探针”，即弓形虫速殖子，一种优先感染视网膜的原虫寄生虫的感染形式，以及来自原发性中枢神经系统淋巴瘤患者的恶性B细胞，这是一种也优先累及视网膜的肿瘤。新的分析方法将被用来研究与这些微生物和视网膜血管内皮细胞上的淋巴细胞结合并分离其潜在受体的特异性。预计这些研究将提供关于后葡萄膜炎中白细胞和微生物归巢到眼睛的机制的新信息。这一认识可能会指导后葡萄膜炎新疗法的开发，这些疗法针对的是视网膜微血管内皮细胞与浸润性细胞或入侵微生物之间的特定相互作用。这项研究还应该对影响视网膜循环的无关疾病以及身体其他部位的组织特异性炎症和感染产生影响。

DESCRIPTION (provided by applicant): Posterior uveitis is a heterogeneous group of potentially blinding inflammatory disorders that primarily involve the retina and/or choroid. While different subtypes of posterior uveitis are known to be autoimmune, infectious and neoplastic, the basic pathogenic mechanisms responsible for these diseases remain unclear. Consistent with recent recognition that different vascular beds throughout the body are characterized by specific sets of cell adhesion molecules and chemoattractants, we hypothesize that the key to understanding the pathogenesis of posterior uveitis, and to developing effective therapeutic interventions, is defining the unique set of molecular signals expressed by retinal microvascular endothelium. Using unique, donor-matched, ocular vascular endothelial cell cultures and cDNA microarray technology, the investigators will study expression of over 8,000 genes by retinal endothelium, under different conditions of stimulation, and in comparison to gene expression by iris and choroidal endothelium. In addition, the investigators will make use of two retinal endothelial cell "probes", namely, Toxoplasma gondii tachyzoites, infectious forms of a protozoan parasite that preferentially infect the retina, and malignant B cells from patients with primary central nervous system lymphoma, a tumor that also preferentially involves retina. Novel assays will be employed to investigate specificity of binding to, and isolate potential receptors for, these microbes and lymphocytes on retinal vascular endothelium. It is anticipated that these studies will provide new information about the mechanisms that are responsible for homing of leukocytes and microrganisms to the eye in posterior uveitis. This understanding may direct the development of new treatments for posterior uveitis that target specific interactions between the retinal microvascular endothelium and the infiltrating cell or invading microbe. The studies should also have implications for unrelated diseases affecting the retinal circulation, as well as tissue-specific inflammations and infections at other body sites.